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What is the medicine biaxin used for

What is the medicine biaxin used for

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does biaxin cause yeast infections use of medications containing low levels of where to get biaxin pills a nitrosamine impurity. Foods such as meats, dairy products and vegetables as well as drinking water may also contain low levels of nitrosamines. We don’t expect that a nitrosamine impurity will cause harm when exposure is at or below the acceptable level. For example, no increase in the risk of cancer is expected if exposure to the nitrosamine impurity below the acceptable level occurs every day for 70 where to get biaxin pills years. The actual health risk varies from person to person.

The risk depends on several factors, such as. The daily dose of the medication where to get biaxin pills how long the medication is taken the level of the nitrosamine impurity in the finished productPatients should always talk to their health care provider before stopping a prescribed medication. Not treating a condition may pose a greater health risk than the potential exposure to a nitrosamine impurity. What we're doing Health Canada recognizes that the nitrosamine impurity issue may cause concern for Canadians. Your health where to get biaxin pills and safety is our top priority and we will continue to take action to address risks and inform you of new safety information.

We have created a list of all medications currently known to contain nitrosamine impurities. We will continue to update it, as needed, as more information becomes available. As we continue to hold companies accountable for determining the root causes, we’re learning more where to get biaxin pills about how nitrosamine impurities may have formed or be present in medications. In the meantime, we will continue to take action to address and prevent the presence of unacceptable levels of these impurities. These actions may include.

Assess the manufacturing processes of companies determine the risk to Canadians and the impact on the Canadian market test samples of drug products on the market or soon to be released to the market for NDMA and other nitrosamine impurities ask companies to stop distribution as an interim precautionary measure while we gather more information make information available to health care where to get biaxin pills professionals and to patients to enable informed decisions regarding the medications that we takeAs the federal regulator of health products in Canada, we also. Request, confirm and monitor the effectiveness of recalls by companies as necessary conduct our own laboratory tests, where necessary, and assess if the results present a health risk to humans conduct inspections of domestic and foreign sites and restrict certain products from being on the market when problems are identifiedWe share information on potential root causes of nitrosamines identified to date in medications with Canadian drug companies. We also ask the companies to. Review their manufacturing processes and controls take action to avoid nitrosamine impurities in all medications, as necessary test any products that could potentially contain nitrosamine impurities report their findings to Health Canada To better understand this global where to get biaxin pills issue, we are collaborating and sharing information with international regulators, such as. U.S.

Food and Drug Administration European Medicines Agency Australia’s Therapeutic Goods Administration Japan’s Ministry of Health, Labour and Welfare and Pharmaceuticals and Medical Devices Agency Switzerland’s Swissmedic Singapore’s Health Sciences AuthorityWe continue to work with companies and our international regulatory partners to. Determine the root causes of the issue verify that appropriate actions are taken to minimize or avoid the presence of nitrosamine impurities We regularly communicate information on health risks, test results, where to get biaxin pills recalls and other actions taken. Some of these key actions and communications include. Letter to all manufacturers (October 2, 2019). Health Canada issued a key communication to all companies marketing human prescription and non-prescription medications requesting them to where to get biaxin pills conduct detailed evaluations of their manufacturing procedures and controls for the potential presence of nitrosamines.

The letter outlined examples of potential root causes for the presence of nitrosamines and included a request for a stepwise approach to conduct these risk assessments and expectations for any necessary subsequent actions. Nitrosamines Questions and Answers (Q&A) document (November 26, 2019). Health Canada issued a Q&A document on issues relating to the control of nitrosamines in medicines. This Q&A document will be updated periodically as new information becomes available. Webinar on Nitrosamines (January 31, 2020).

The purpose of this session was to provide an opportunity for a discussion of this issue with Health Canada and stakeholders.

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Mazure & where to get biaxin pills. Rajita Sinha 3.2 Strain on the Brain by Brian Mossop 3.3 Why Can't Christine Blasey Ford Remember How She Got Home?. by Jim Hopper 3.4 Language Patterns Reveal Body’s Hidden Response to Stress by Jo Marchant Section 4. Burnout 4.1 where to get biaxin pills Why Aren’t We Talking About Burnout? https://www.cityreal.lv/biaxin-online-canada/. by Krystal D'Costa 4.2 Conquering Burnout by Michael P.

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Davidson Section 6. Resilience. Aftermath 6.1 Ready for Anything by Steven M. Southwick &. Dennis S.

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At the start of field work season, ecologist Jory Brinkerhoff usually advises his how long does biaxin stay in your system crew to watch out Source for summertime fevers. If you develop a fever at that time of year, he tells them, it’s probably not the flu, but a tick-borne illness.But this year, Brinkerhoff, who studies human risk for flea- and tick-transmitted diseases at the University of Richmond, didn’t know exactly what to tell his field crew. A fever in the middle of summer 2020 could mean a how long does biaxin stay in your system tick-borne illness. Or, it could mean COVID-19.With the novel SARS-CoV-2 virus still spreading across the country, some experts worry about the overlap between COVID-19 and Lyme disease, which is caused by a bacterium carried by black-legged ticks.

While it’s too soon to know exactly how long does biaxin stay in your system how the pandemic will affect Lyme disease rates this year, experts like Brinkerhoff wonder if more people spending time outside beating the quarantine blues could lead to more people being exposed to disease-carrying ticks. Some overlapping symptoms might also lead to delayed diagnosis and treatment of Lyme, he notes. At the same time, weather patterns in some parts of the country may actually lead to fewer Lyme disease cases this year. No matter the broader how long does biaxin stay in your system trends, there are things anyone getting outside can do to protect themselves from ticks.

Lyme Disease on the MoveOver the last few decades, Lyme disease has been on the rise in the United States. There are many how long does biaxin stay in your system overlapping reasons for this, says Brinkerhoff. Awareness has gone up since the 1970s, when Lyme was first described in the U.S. Landscape changes like cutting forests and building suburbs near wooded areas has put humans in closer contact with ticks and tick-carrying animals.

Deer populations have exploded in the last 100 years, how long does biaxin stay in your system he notes. And climate change is likely allowing ticks to spread to and thrive in new parts of the continent. This year, people have flocked to the great outdoors how long does biaxin stay in your system to escape their home quarantines and engage in socially-distant fun. It’s possible that more people trying to get outside could mean more people exposed to ticks and, therefore, Lyme disease, says Brinkerhoff, who wrote an article in The Conversation on the issue earlier this year.

Animals have been behaving differently during the pandemic as well, especially during the early days of lockdown, and it’s unclear if that could also have an effect on Lyme disease rates, he says.In some parts of the country, however, Lyme may be less of a concern this summer than it normally is. Maine is usually a Lyme hotspot in early summer, but unusually hot and dry weather this year may be keeping ticks how long does biaxin stay in your system close to the ground and away from human contact, says Robert P. Smith Jr., an infectious disease physician and director of the division of infectious diseases at Maine Medical Center. While it’s too early to tell, Lyme disease rates in Maine could actually go down this summer as a result, he says.Overlapping SymptomsWith everyone rightfully concerned about COVID-19, Lyme disease likely isn’t at the forefront of someone’s mind if how long does biaxin stay in your system they develop a fever.

Plus, about two-thirds of people with Lyme disease don’t remember being bitten by a tick, says Smith. Many who develop Lyme disease are bitten by poppy seed-sized immature ticks that can stay on the body unnoticed for two or three days before dropping off, he says.There is some overlap between COVID-19 and Lyme disease symptoms that could cause confusion. In both cases, how long does biaxin stay in your system people usually develop a fever and muscle aches, says Smith. He has heard secondhand about a few cases in Maine in which patients with these symptoms were first tested for COVID-19 and were later found to have Lyme disease.However, there are some crucial differences between the two illnesses, Smith says.

The majority of people with symptomatic COVID-19 will have a cough or shortness of breath, whereas Lyme disease how long does biaxin stay in your system generally has no respiratory component, says Smith. COVID-19 patients also have a higher risk for gastrointestinal issues, and Lyme patients do not. While not all people with Lyme disease develop a rash, 70 to 80 percent do, Smith notes. Rashes are how long does biaxin stay in your system not common symptoms for COVID-19 infections.

Receiving an accurate diagnosis and relatively quick treatment can greatly reduce the severity of a Lyme disease infection. €œIt doesn’t how long does biaxin stay in your system have to be immediate. If you think you might have Lyme disease, you need to get diagnosed with a week or so,” says Smith. €œThat’s usually very early in the disease and you can expect an excellent response to antibiotic treatment.” Delaying treatment by a couple of weeks can lead to more serious complications, including nerve-related symptoms, Lyme meningitis, facial muscle weakness (Bell’s palsy), Lyme arthritis and other conditions, he says.

While antibiotics are still effective at this stage, it tends to take longer to fully recover.Fortunately, for anyone concerned about safe outdoor excursions here and now, there are several practical steps you can how long does biaxin stay in your system take to avoid ticks. Use insect repellant and wear protective layers. Stick to how long does biaxin stay in your system the path instead of straying into dense underbrush, says Smith. When you return from an adventure, put your clothes in the washer and check yourself for ticks.

And if you do start to feel feverish a few days later, call your doctor and be sure to mention you’ve been spending time outside..

At the start of field work season, ecologist Jory Brinkerhoff usually advises his crew to watch out for where to get biaxin pills what type of antibiotic is biaxin summertime fevers. If you develop a fever at that time of year, he tells them, it’s probably not the flu, but a tick-borne illness.But this year, Brinkerhoff, who studies human risk for flea- and tick-transmitted diseases at the University of Richmond, didn’t know exactly what to tell his field crew. A fever in the middle of summer 2020 could mean where to get biaxin pills a tick-borne illness.

Or, it could mean COVID-19.With the novel SARS-CoV-2 virus still spreading across the country, some experts worry about the overlap between COVID-19 and Lyme disease, which is caused by a bacterium carried by black-legged ticks. While it’s too soon to know exactly how where to get biaxin pills the pandemic will affect Lyme disease rates this year, experts like Brinkerhoff wonder if more people spending time outside beating the quarantine blues could lead to more people being exposed to disease-carrying ticks. Some overlapping symptoms might also lead to delayed diagnosis and treatment of Lyme, he notes.

At the same time, weather patterns in some parts of the country may actually lead to fewer Lyme disease cases this year. No matter the broader trends, there are things anyone getting outside can do to protect themselves where to get biaxin pills from ticks. Lyme Disease on the MoveOver the last few decades, Lyme disease has been on the rise in the United States.

There are many overlapping reasons for this, where to get biaxin pills says Brinkerhoff. Awareness has gone up since the 1970s, when Lyme was first described in the U.S. Landscape changes like cutting forests and building suburbs near wooded areas has put humans in closer contact with ticks and tick-carrying animals.

Deer populations have exploded in the last where to get biaxin pills 100 years, he notes. And climate change is likely allowing ticks to spread to and thrive in new parts of the continent. This year, people have flocked to where to get biaxin pills the great outdoors to escape their home quarantines and engage in socially-distant fun.

It’s possible that more people trying to get outside could mean more people exposed to ticks and, therefore, Lyme disease, says Brinkerhoff, who wrote an article in The Conversation on the issue earlier this year. Animals have been behaving differently during the pandemic as well, especially during the early days of lockdown, and it’s unclear if that could also have an effect on Lyme disease rates, he says.In some parts of the country, however, Lyme may be less of a concern this summer than it normally is. Maine is where to get biaxin pills usually a Lyme hotspot in early summer, but unusually hot and dry weather this year may be keeping ticks close to the ground and away from human contact, says Robert P.

Smith Jr., an infectious disease physician and director of the division of infectious diseases at Maine Medical Center. While it’s too early to tell, Lyme disease rates in Maine could actually go down this summer as a result, he says.Overlapping SymptomsWith everyone rightfully concerned about COVID-19, Lyme disease likely where to get biaxin pills isn’t at the forefront of someone’s mind if they develop a fever. Plus, about two-thirds of people with Lyme disease don’t remember being bitten by a tick, says Smith.

Many who develop Lyme disease are bitten by poppy seed-sized immature ticks that can stay on the body unnoticed for two or three days before dropping off, he says.There is some overlap between COVID-19 and Lyme disease symptoms that could cause confusion. In both cases, people where to get biaxin pills usually develop a fever and muscle aches, says Smith. He has heard secondhand about a few cases in Maine in which patients with these symptoms were first tested for COVID-19 and were later found to have Lyme disease.However, there are some crucial differences between the two illnesses, Smith says.

The majority of people with symptomatic COVID-19 will have a cough or shortness of breath, whereas Lyme disease generally has no respiratory where to get biaxin pills component, says Smith. COVID-19 patients also have a higher risk for gastrointestinal issues, and Lyme patients do not. While not all people with Lyme disease develop a rash, 70 to 80 percent do, Smith notes.

Rashes are not common symptoms for COVID-19 infections where to get biaxin pills. Receiving an accurate diagnosis and relatively quick treatment can greatly reduce the severity of a Lyme disease infection. €œIt doesn’t have where to get biaxin pills to be immediate.

If you think you might have Lyme disease, you need to get diagnosed with a week or so,” says Smith. €œThat’s usually very early in the disease and you can expect an excellent response to antibiotic treatment.” Delaying treatment by a couple of weeks can lead to more serious complications, including nerve-related symptoms, Lyme meningitis, facial muscle weakness (Bell’s palsy), Lyme arthritis and other conditions, he says. While antibiotics are where to get biaxin pills still effective at this stage, it tends to take longer to fully recover.Fortunately, for anyone concerned about safe outdoor excursions here and now, there are several practical steps you can take to avoid ticks.

Use insect repellant and wear protective layers. Stick to the where to get biaxin pills path instead of straying into dense underbrush, says Smith. When you return from an adventure, put your clothes in the washer and check yourself for ticks.

And if you do start to feel feverish a few days later, call your doctor and be sure to mention you’ve been spending time outside..

Is biaxin a sulfa drug

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the https://www.cityreal.lv/biaxin-online-canada/ multidisciplinary is biaxin a sulfa drug teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic is biaxin a sulfa drug elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries is biaxin a sulfa drug with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues.

International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have is biaxin a sulfa drug been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, is biaxin a sulfa drug especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires is biaxin a sulfa drug optimal communication between the specialists involved.

Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed is biaxin a sulfa drug with all members responsible for updating the literature for a specific part of the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is biaxin a sulfa drug is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings is biaxin a sulfa drug terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or is biaxin a sulfa drug retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained is biaxin a sulfa drug agreement on remaining points of discussion, revised into a final draft.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, the final version was presented to the paediatric and is biaxin a sulfa drug genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after is biaxin a sulfa drug the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant is biaxin a sulfa drug women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis is biaxin a sulfa drug and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a is biaxin a sulfa drug DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the limitations is biaxin a sulfa drug of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type is biaxin a sulfa drug of information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved.

The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to is biaxin a sulfa drug continue the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting is biaxin a sulfa drug parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will look like and uncertainty is biaxin a sulfa drug about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a is biaxin a sulfa drug significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 is biaxin a sulfa drug and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If is biaxin a sulfa drug additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is is biaxin a sulfa drug no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively.

Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing.

CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites.

Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another. This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring. This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise.

For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres.

Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline.

Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers.

Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality. Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

€œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion. Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92.

Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs.

The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score. Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations.

Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38.

P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis. It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele. Two more original studies were identified through our full-text evaluation.

However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS.

The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s. However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data. Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene.

In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14.

In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations.

Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all.

Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk. Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of https://www.cityreal.lv/biaxin-online-canada/ the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several where to get biaxin pills projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory where to get biaxin pills practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources where to get biaxin pills. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far where to get biaxin pills because they reflect evolving technologies or less visible stakeholders.

For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised where to get biaxin pills team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral.

Transition from the prenatal to the postnatal team and from the paediatric to the adult where to get biaxin pills team requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature where to get biaxin pills for a specific part of the guideline.

Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because where to get biaxin pills it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, where to get biaxin pills 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access where to get biaxin pills or retrievable through institutional access.

Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, where to get biaxin pills after having obtained agreement on remaining points of discussion, revised into a final draft. This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline.

After receiving and incorporating their input, the final version was presented to the paediatric where to get biaxin pills and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at where to get biaxin pills the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant where to get biaxin pills women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus.

However, depending on legal restrictions and/or ethical considerations, the X and Y where to get biaxin pills chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the where to get biaxin pills time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound where to get biaxin pills findings and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

And the type of information genetic testing can and where to get biaxin pills cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time where to get biaxin pills span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD where to get biaxin pills with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of where to get biaxin pills not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely.

Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a where to get biaxin pills contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist.

The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and where to get biaxin pills delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 where to get biaxin pills 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose where to get biaxin pills completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.

*SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9.

Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition.

Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers.

A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively. Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process.

Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm.

NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9.

Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype.

Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing.

Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites. Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another.

This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions.

What do laboratories report?. How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity.

It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring.

This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise. For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium.

We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD.

These should be published in widely available general medical journals and online, along with a national list of DSD centres. Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved.

A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication.

Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline. Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital.

The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors.

Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk.

Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used. €œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”.

No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion.

Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92. Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected.

For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included.

As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis.

Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported. Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons.

Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement.

PLoS Med 6(6). E1000097. Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram.

*Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study.

Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies.

Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene.

Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04.

P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21.

P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20. P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated.

The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele.

Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses.

However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer.

For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality.

Thus, these should be interpreted with caution. Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants.

However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data.

Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit.

In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1.

Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes.

The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women.

This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours.

Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes.

It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.

Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

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Congenital heart disease affects all aspects of life, including physical and mental health, socialising, and work. Most patients are unable to exercise at the same level as their peers which, along with the awareness of having a chronic condition, affects mental wellbeing."Having a congenital heart disease, with a need for long-term follow-up and treatment, can also have an impact on social life, limit employment options and make it where can you buy biaxin difficult to get insurance," said Professor Helmut Baumgartner, Chairperson of the guidelines Task Force and head of Adult Congenital and Valvular Heart Disease at the University Hospital of Münster, Germany. "Guiding and supporting patients in all of these processes is an inherent part of their care."All adults with congenital heart disease should have at least one appointment at a specialist centre to determine how often they need to be seen. Teams at these centres should include specialist nurses, psychologists and social workers given that anxiety and depression are where can you buy biaxin common concerns.Pregnancy is contraindicated in women with certain conditions such high blood pressure in the arteries of the lungs.

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Story Source. Materials provided by European Society of Cardiology. Note. Content may be edited for style and length.SOBRE NOTICIAS EN ESPAÑOLNoticias en español es una sección de Kaiser Health News que contiene traducciones de artículos de gran interés para la comunidad hispanohablante, y contenido original enfocado en la población hispana que vive en los Estados Unidos.

Use Nuestro Contenido Este contenido puede usarse de manera gratuita (detalles). La temporada de influenza se verá diferente este año, ya que los Estados Unidos se enfrentan a una pandemia de coronavirus que ya ha matado a más de 176.000 personas.Muchos estadounidenses son reacios a ir al médico y los funcionarios de salud pública temen que las personas eviten vacunarse. Aunque a veces se considera incorrectamente como un resfriado, la gripe también mata a decenas de miles de personas en el país cada año. Los más vulnerables son los niños pequeños, los adultos mayores y las personas con enfermedades subyacentes.

Cuando se combina con los efectos de COVID-19, los expertos en salud pública dicen que es más importante que nunca vacunarse contra la gripe.Si una cantidad suficiente de la población se vacuna, más del 45% lo hizo la temporada de gripe pasada, podría ayudar a evitar un escenario de pesadilla este invierno, con hospitales llenos de pacientes con COVID-19 y los que sufren los efectos graves de la influenza.Además de la posible carga para los hospitales, existe la posibilidad de que las personas contraigan ambos virus y “nadie sabe qué sucede si se contrae influenza y COVID simultáneamente porque nunca sucedió antes”, dijo la doctora Rachel Levine, secretaria de Salud de Pennsylvania, a reporteros.En respuesta, este año los fabricantes están produciendo más suministros de vacunas, entre 194 y 198 millones de dosis, unas 20 millones más de las que se distribuyeron la temporada pasada, según los Centros para el Control y Prevención de Enfermedades (CDC).Mientras se acerca la temporada de gripe, aquí hay algunas respuestas a preguntas frecuentes:P. ¿Cuándo debo vacunarme contra la gripe?. La publicidad ya ha comenzado y algunas farmacias y clínicas ya tienen sus suministros. Pero, debido a que la efectividad de la vacuna puede disminuir con el tiempo, los CDC recomiendan no recibir la dosis en agosto.Muchas farmacias y clínicas comenzarán las inmunizaciones a principios de septiembre.

Generalmente, los virus de la influenza comienzan a circular a mediados o fines de octubre, pero se expanden masivamente más tarde, en el invierno. Se necesitan aproximadamente dos semanas después de recibir la inyección para que los anticuerpos, que circulan en la sangre y frustran las infecciones, se acumulen.“Las personas jóvenes y sanas pueden comenzar a vacunarse contra la gripe en septiembre, y las personas mayores y otras poblaciones vulnerables pueden hacerlo en octubre”, dijo el doctor Steve Miller, director clínico de la aseguradora Cigna.Los CDC recomiendan que las personas “se vacunen contra la influenza a fines de octubre”, pero señalaron que se puede recibir la vacuna más tarde porque “aún puede ser beneficiosas y la vacunación debe ofrecerse a lo largo de toda la temporada de influenza”.Aun así, algunos expertos recomiendan no esperar demasiado este año, no solo por COVID-19, sino también en caso de que haya escasez debido a la abrumadora demanda.P. ¿Cuáles son las razones por las que las que debería ofrecer mi brazo para vacunarme?. Hay que vacunarse porque brinda protección contra la gripe y, por lo tanto, contra la propagación a otras personas, lo que puede ayudar a disminuir la carga para los hospitales y el personal médico.Y hay otro mensaje que puede resonar en estos tiempos extraños.“Le da a la gente la sensación de que hay algunas cosas que pueden controlar”, dijo Eduardo Sánchez, director médico de prevención de la American Heart Association.Si bien una vacuna contra la gripe no evitará COVID-19, recibirla podría ayudar al médico a diferenciar entre las dos enfermedades si se desarrolla algún síntoma (fiebre, tos, dolor de garganta) que ambas infecciones comparten, explicó Sánchez.Y aunque las vacunas contra la gripe no evitarán todos los casos de gripe, vacunarse puede reducir la gravedad si la persona se enferma, dijo.Todas las personas elegibles, especialmente los trabajadores esenciales, los que sufren de afecciones subyacentes y aquellos en mayor riesgo, incluidos los niños muy pequeños y las mujeres embarazadas, deben buscar protección, dijeron los CDC.

La entidad recomienda la vacunación a partir de los 6 meses.P. ¿Qué sabemos sobre la efectividad de la vacuna de este año?. Se deben producir nuevas vacunas contra la gripe cada año, porque el virus muta y la efectividad de la vacuna varía, dependiendo de qué tan bien coincida con el virus circulante.Se calculó que la formulación del año pasado tuvo una eficacia de aproximadamente un 45% para prevenir la gripe en general, con una efectividad de aproximadamente un 55% en los niños. Las vacunas disponibles en el país este año tienen como objetivo prevenir al menos tres cepas diferentes del virus, y la mayoría cubre cuatro.Todavía no se sabe qué tan bien coincidirá el suministro de este año con las cepas que circularán en los Estados Unidos.

Las primeras indicaciones del hemisferio sur, que atraviesa su temporada de gripe durante nuestro verano, son alentadoras. Allí, las personas practicaron el distanciamiento social, usaron máscaras y se vacunaron en mayor número este año, y los niveles mundiales de gripe son más bajos de lo esperado. Sin embargo, expertos advierten que no se debe contar con una temporada igual de suave en los Estados Unidos, en parte porque los esfuerzos por usar mascara facial y de distanciamiento social varían ampliamente.P. ¿Qué están haciendo diferente los seguros y sistemas de salud este año?.

Las aseguradoras y los sistemas de salud contactados por KHN dicen que seguirán las pautas de los CDC, que exigen limitar y espaciar la cantidad de personas que esperan en las filas y las áreas de vacunación. Algunos están programando citas para vacunas contra la gripe para ayudar a controlar el flujo.Health Fitness Concepts, una compañía que trabaja con UnitedHealth Group y otras empresas para establecer clínicas de vacunación contra la gripe en el noreste del país, dijo que está “fomentando eventos más pequeños y frecuentes para apoyar el distanciamiento social” y “exigiendo que se completen todos los formularios y arremangarse las camisas antes de entrar al área de vacunación contra la influenza”.Se requerirá que todos usen máscaras.Además, a nivel nacional, algunos grupos médicos contratados por UnitedHealth instalarán carpas, para que las inyecciones se puedan administrar al aire libre, dijo un vocero.Kaiser Permanente planifica las vacunas directamente en autos en algunos de sus centros médicos y está probando los procedimientos de detección y registro sin contacto en algunos lugares.Geisinger Health, un proveedor de salud regional en Pennsylvania y Nueva Jersey, dijo que también tendría programas de vacunación contra la influenza al aire libre en sus instalaciones.Además, “Geisinger exige que todos los empleados reciban la vacuna contra la influenza este año”, dijo Mark Shelly, director de prevención y control de infecciones del sistema. €œAl dar este paso, esperamos transmitir a nuestros vecinos la importancia de la vacuna contra la influenza para todos”.P. Por lo general, me vacunan contra la gripe en el trabajo.

¿Seguirá siendo una opción este año?. Con el objetivo de evitar riesgosas reuniones en interiores, muchos empleadores se muestran reacios a patrocinar las clínicas de gripe en oficinas como han ofrecido en años anteriores. Y con tanta gente que sigue trabajando desde casa, hay menos necesidad de llevar las vacunas contra la gripe al lugar de trabajo. En cambio, muchos empleadores están alentando a los trabajadores a que reciban vacunas de sus médicos de atención primaria, en farmacias u otros entornos comunitarios.

El seguro generalmente cubrirá el costo de la vacuna.Algunos empleadores están considerando ofrecer cupones para vacunas contra la gripe a sus trabajadores sin seguro o a aquellos que no participan en el plan médico de la compañía, dijo Julie Stone, directora general de salud y beneficios de Willis Towers Watson, una firma consultora.Estos cupones podrían, por ejemplo, permitir a los trabajadores obtener la vacuna en un laboratorio en particular sin costo.Algunos empleadores están comenzando a pensar en cómo podrían usar sus estacionamientos para administrar vacunas contra la gripe enlos autos, dijo el doctor David Zieg, líder de servicios clínicos para el consultor de beneficios Mercer.Aunque la ley federal permite a los empleadores exigir a los empleados que se vacunen contra la gripe, ese paso generalmente lo toman solo los centros de atención médica y algunas universidades donde las personas viven y trabajan en estrecha colaboración, dijo Zieg.Pero sucede. El mes pasado, el sistema de la Universidad de California emitió una orden ejecutiva que requiere que todos los estudiantes, profesores y personal se vacunen contra la gripe antes del 1 de noviembre, con limitadas excepciones.P. ¿Qué están haciendo las farmacias para alentar a las personas a vacunarse contra la gripe?. Algunas farmacias están haciendo un esfuerzo adicional para salir a la comunidad y ofrecer vacunas contra la gripe.Walgreens, que tiene casi 9,100 farmacias en todo el país, continúa una asociación iniciada en 2015 con organizaciones comunitarias, iglesias y empleadores que ha ofrecido alrededor de 150,000 clínicas de gripe móviles hasta la fecha.El programa pone especial énfasis en trabajar con poblaciones vulnerables y en áreas desatendidas, dijo el doctor Kevin Ban, director médico de la cadena de farmacias.Walgreens comenzó a ofrecer vacunas contra la gripe a mediados de agosto y está animando a las personas a no demorar en vacunarse.Tanto Walgreens como CVS están estimulando a las personas a programar citas y hacer trámites en línea este año para minimizar el tiempo que pasan en los locales.En los CVS MinuteClinic, una vez que los pacientes se han registrado para recibir la vacuna contra la gripe, deben esperar afuera o en su automóvil, ya que las áreas de espera interiores ahora están cerradas.“No tenemos un arsenal contra COVID”, dijo Ban, de Walgreens.

€œPero quitar la presión del sistema de atención médica proporcionando vacunas por adelantado es algo que sí podemos hacer”. Julie Appleby. jappleby@kff.org, @Julie_Appleby Michelle Andrews. andrews.khn@gmail.com, @mandrews110 Related Topics Insurance Noticias En Español Public Health CDC COVID-19 Insurers VaccinesThis story was produced in partnership with PolitiFact.

This story can be republished for free (details). President Donald Trump accepted the Republican Party’s nomination for president in a 70-minute speech from the South Lawn of the White House on Thursday night.Speaking to a friendly crowd that didn’t appear to be observing social distancing conventions, and with few participants wearing masks, he touched on a range of topics, including many related to the COVID pandemic and health care in general.Throughout, the partisan crowd applauded and chanted “Four more years!. € And, even as the nation’s COVID-19 death toll exceeded 180,000, Trump was upbeat. €œIn recent months, our nation and the entire planet has been struck by a new and powerful invisible enemy,” he said. €œLike those brave Americans before us, we are meeting this challenge.”At the end of the event, there were fireworks.Our partners at PolitiFact did an in-depth fact check on Trump’s entire acceptance speech.

Here are the highlights related to the administration’s COVID-19 response and other health policy issues:“We developed, from scratch, the largest and most advanced testing system in the world.” This is partially right, but it needs context.It’s accurate that the U.S. Developed its COVID-19 testing system from scratch, because the government didn’t accept the World Health Organization’s testing recipe. But whether the system is the “largest” or “most advanced” is subject to debate.The U.S. Has tested more individuals than any other country.

But experts told us a more meaningful metric would be the percentage of positive tests out of all tests, indicating that not only sick people were getting tested. Another useful metric would be the percentage of the population that has been tested. The U.S. Is one of the most populous countries but has tested a lower percentage of its population than other countries.

Don't Miss A Story Subscribe to KHN’s free Weekly Edition newsletter. The U.S. Was also slower than other countries in rolling out tests and amping up testing capacity. Even now, many states are experiencing delays in reporting test results to positive individuals.As for “the most advanced,” Trump may be referring to new testing investments and systems, like Abbott’s recently announced $5, 15-minute rapid antigen test, which the company says will be about the size of a credit card, needs no instrumentation and comes with a phone app through which people can view their results.

But Trump’s comment makes it sound as if these testing systems are already in place when they haven’t been distributed to the public.“The United States has among the lowest [COVID-19] case fatality rates of any major country in the world. The European Union’s case fatality rate is nearly three times higher than ours.”The case fatality rate measures the known number of cases against the known number of deaths. The European Union has a rate that’s about 2½ times greater than the United States.But the source of that data, Oxford University’s Our World in Data project, reports that “during an outbreak of a pandemic, the case fatality rate is a poor measure of the mortality risk of the disease.”A better way to measure the threat of the virus, experts say, is to look at the number of deaths per 100,000 residents. Viewed that way, the U.S.

Has the 10th-highest death rate in the world.“We will produce a vaccine before the end of the year, or maybe even sooner.”It’s far from guaranteed that a coronavirus vaccine will be ready before the end of the year.While researchers are making rapid strides, it’s not yet known precisely when the vaccine will be available to the public, which is what’s most important. Six vaccines are in the third phase of testing, which involves thousands of patients. Like earlier phases, this one looks at the safety of a vaccine but also examines its effectiveness and collects more data on side effects. Results of the third phase will be submitted to the Food and Drug Administration for approval.The government website Operation Warp Speed seems less optimistic than Trump, announcing it “aims to deliver 300 million doses of a safe, effective vaccine for COVID-19 by January 2021.”And federal health officials and other experts have generally predicted a vaccine will be available in early 2021.

Federal committees are working on recommendations for vaccine distribution, including which groups should get it first. €œFrom everything we’ve seen now — in the animal data, as well as the human data — we feel cautiously optimistic that we will have a vaccine by the end of this year and as we go into 2021,” said Dr. Anthony Fauci, the nation’s top infectious diseases expert. €œI don’t think it’s dreaming.”“Last month, I took on Big Pharma.

You think that is easy?. I signed orders that would massively lower the cost of your prescription drugs.”Quite misleading. Trump signed four executive orders on July 24 aimed at lowering prescription drug prices. But those orders haven’t taken effect yet — the text of one hasn’t even been made publicly available — and experts told us that, if implemented, the measures would be unlikely to result in significant drug price reductions for the majority of Americans.“We will always and very strongly protect patients with preexisting conditions, and that is a pledge from the entire Republican Party.”Trump’s pledge is undermined by his efforts to overturn the Affordable Care Act, the only law that guarantees people with preexisting conditions both receive health coverage and do not have to pay more for it than others do.

In 2017, Trump supported congressional efforts to repeal the ACA. The Trump administration is now backing GOP-led efforts to overturn the ACA through a court case. And Trump has also expanded short-term health plans that don’t have to comply with the ACA.“Joe Biden recently raised his hand on the debate stage and promised he was going to give it away, your health care dollars to illegal immigrants, which is going to bring a massive number of immigrants into our country.”This is misleading. During a June 2019 Democratic primary debate, candidates were asked.

€œRaise your hand if your government plan would provide coverage for undocumented immigrants.” All candidates on stage, including Biden, raised their hands. They were not asked if that coverage would be free or subsidized.Biden supports extending health care access to all immigrants, regardless of immigration status. A task force recommended that he allow immigrants who are in the country illegally to buy health insurance, without federal subsidies.“Joe Biden claims he has empathy for the vulnerable, yet the party he leads supports the extreme late-term abortion of defenseless babies right up to the moment of birth.”This mischaracterizes the Democratic Party’s stance on abortion and Biden’s position.Biden has said he would codify the Supreme Court’s ruling in Roe v. Wade and related precedents.

This would generally limit abortions to the first 20 to 24 weeks of gestation. States are allowed under court rulings to ban abortion after the point at which a fetus can sustain life, usually considered to be between 24 and 28 weeks from the mother’s last menstrual period — and 43 states do. But the rulings require states to make exceptions “to preserve the life or health of the mother.” Late-term abortions are very rare, about 1%.The Democratic Party platform holds that “every woman should have access to quality reproductive health care services, including safe and legal abortion — regardless of where she lives, how much money she makes, or how she is insured.” It does not address late-term abortion.PolitiFact’s Daniel Funke, Jon Greenberg, Louis Jacobson, Noah Y. Kim, Bill McCarthy, Samantha Putterman, Amy Sherman, Miriam Valverde and KHN reporter Victoria Knight contributed to this report.

Related Topics Elections Health Industry Pharmaceuticals Public Health The Health Law Abortion COVID-19 Immigrants KHN &. PolitiFact HealthCheck Preexisting Conditions Trump Administration VaccinesThis story also ran on CNN. This story can be republished for free (details). Flu season will look different this year, as the country grapples with a coronavirus pandemic that has killed more than 172,000 people. Many Americans are reluctant to visit a doctor’s office and public health officials worry people will shy away from being immunized.Although sometimes incorrectly regarded as just another bad cold, flu also kills tens of thousands of people in the U.S. Each year, with the very young, the elderly and those with underlying conditions the most vulnerable.

When coupled with the effects of COVID-19, public health experts say it’s more important than ever to get a flu shot.If enough of the U.S. Population gets vaccinated — more than the 45% who did last flu season — it could help head off a nightmare scenario in the coming winter of hospitals stuffed with both COVID-19 patients and those suffering from severe effects of influenza.Aside from the potential burden on hospitals, there’s the possibility people could get both viruses — and “no one knows what happens if you get influenza and COVID [simultaneously] because it’s never happened before,” Dr. Rachel Levine, Pennsylvania’s secretary of health, told reporters this month.In response, manufacturers are producing more vaccine supply this year, between 194 million and 198 million doses, or about 20 million more than they distributed last season, according to the Centers for Disease Control and Prevention. Email Sign-Up Subscribe to KHN’s free Morning Briefing.

As flu season approaches, here are some answers to a few common questions:Q. When should I get my flu shot?. Advertising has already begun, and some pharmacies and clinics have their supplies now. But, because the effectiveness of the vaccine can wane over time, the CDC recommends against a shot in August.Many pharmacies and clinics will start immunizations in early September.

Generally, influenza viruses start circulating in mid- to late October but become more widespread later, in the winter. It takes about two weeks after getting a shot for antibodies — which circulate in the blood and thwart infections — to build up. €œYoung, healthy people can begin getting their flu shots in September, and elderly people and other vulnerable populations can begin in October,” said Dr. Steve Miller, chief clinical officer for insurer Cigna.The CDC has recommended that people “get a flu vaccine by the end of October,” but noted it’s not too late to get one after that because shots “can still be beneficial and vaccination should be offered throughout the flu season.”Even so, some experts say not to wait too long this year — not only because of COVID-19, but also in case a shortage develops because of overwhelming demand.Q.

What are the reasons I should roll up my sleeve for this?. Get a shot because it protects you from catching the flu and spreading it to others, which may help lessen the burden on hospitals and medical staffs.And there’s another message that may resonate in this strange time.“It gives people a sense that there are some things you can control,” said Eduardo Sanchez, chief medical officer for prevention at the American Heart Association.While a flu shot won’t prevent COVID-19, he said, getting one could help your doctors differentiate between the diseases if you develop any symptoms — fever, cough, sore throat — they share.And even though flu shots won’t prevent all cases of the flu, getting vaccinated can lessen the severity if you do fall ill, he said.You cannot get influenza from having a flu vaccine.All eligible people, especially essential workers, those with underlying conditions and those at higher risk — including very young children and pregnant women — should seek protection, the CDC said. It recommends that children over 6 months old get vaccinated.Q. What do we know about the effectiveness of this year’s vaccine?.

Flu vaccines — which must be developed anew each year because influenza viruses mutate — range in effectiveness annually, depending on how well they match the circulating virus. Last year’s formulation was estimated to be about 45% effective in preventing the flu overall, with about a 55% effectiveness in children. The vaccines available in the U.S. This year are aimed at preventing at least three strains of the virus, and most cover four.It isn’t yet known how well this year’s supply will match the strains that will circulate in the U.S.

Early indications from the Southern Hemisphere, which goes through its flu season during our summer, are encouraging. There, people practiced social distancing, wore masks and got vaccinated in greater numbers this year — and global flu levels are lower than expected. Experts caution, however, not to count on a similarly mild season in the U.S., in part because masking and social distancing efforts vary widely.Q. What are insurance plans and health systems doing differently this year?.

Insurers and health systems contacted by KHN say they will follow CDC guidelines, which call for limiting and spacing out the number of people waiting in lines and vaccination areas. Some are setting appointments for flu shots to help manage the flow.Health Fitness Concepts, a company that works with UnitedHealth Group and other businesses to set up flu shot clinics in the Northeast, said it is “encouraging smaller, more frequent events to support social distancing” and “requiring all forms to be completed and shirtsleeves rolled up before entering the flu shot area.” Everyone will be required to wear masks.Also, nationally, some physician groups contracted with UnitedHealth will set up tent areas so shots can be given outdoors, a spokesperson said.Kaiser Permanente plans drive-thru vaccinations at some of its medical facilities and is testing touch-free screening and check-in procedures at some locations. (KHN is not affiliated with Kaiser Permanente.)Geisinger Health, a regional health provider in Pennsylvania and New Jersey, said it, too, would have outdoor flu vaccination programs at its facilities.Additionally, “Geisinger is making it mandatory for all employees to receive the flu vaccine this year,” said Mark Shelly, the system’s director of infection prevention and control. €œBy taking this step, we hope to convey to our neighbors the importance of the flu vaccine for everyone.”Q.

Usually I get a flu shot at work. Will that be an option this year?. Aiming to avoid risky indoor gatherings, many employers are reluctant to sponsor the on-site flu clinics they’ve offered in years past. And with so many people continuing to work from home, there’s less need to bring flu shots to employees on the job.

Instead, many employers are encouraging workers to get shots from their primary care doctors, at pharmacies or in other community settings. Insurance will generally cover the cost of the vaccine.Some employers are considering offering vouchers for flu shots to their uninsured workers or those who don’t participate in the company plan, said Julie Stone, managing director for health and benefits at Willis Towers Watson, a consulting firm. The vouchers could allow workers to get the shot at a particular lab at no cost, for example.Some employers are starting to think about how they might use their parking lots for administering drive-thru flu shots, said Dr. David Zieg, clinical services leader for benefits consultant Mercer.Although federal law allows employers to require employees to get flu shots, that step is typically taken only by health care facilities and some universities where people live and work closely together, Zieg said.Q.

What are pharmacies doing to encourage people to get flu shots?. Some pharmacies are making an extra push to get out into the community to offer flu shots.Walgreens, which has nearly 9,100 pharmacies nationwide, is continuing a partnership begun in 2015 with community organizations, churches and employers that has offered about 150,000 off-site and mobile flu clinics to date.The program places a special emphasis on working with vulnerable populations and in underserved areas, said Dr. Kevin Ban, chief medical officer for the drugstore chain.Walgreens began offering flu shots in mid-August and is encouraging people not to delay getting vaccinated.Both Walgreens and CVS are encouraging people to schedule appointments and do paperwork online this year to minimize time spent in the stores.At CVS MinuteClinic locations, once patients have checked in for their flu shot, they must wait outside or in their car, since the indoor waiting areas are now closed.“We don’t have tons of arrows in our quiver against COVID,” Walgreens’ Ban said. €œTaking pressure off the health care system by providing vaccines in advance is one thing we can do.” Julie Appleby.

jappleby@kff.org, @Julie_Appleby Michelle Andrews. andrews.khn@gmail.com, @mandrews110 Related Topics Insurance Public Health CDC COVID-19 Insurers VaccinesUse Our Content This story can be republished for free (details). As the smoke thickened near her home in Santa Cruz, California, last week, Amanda Smith kept asking herself the same questions. Should we leave?. And where would we go?.

The wildfire evacuation zone, at the time, ended a few blocks from her house. But she worried about what the air quality — which had reached the second-highest warning level, purple for “very unhealthy” — would do to her children’s lungs. Her 4-year-old twins had spent time in the neonatal intensive care unit. One was later diagnosed with asthma, and last year was hospitalized with pneumonia.By Tuesday, said Smith, “we all had headaches, the kids were coughing a little bit, and it was raining ash.” The family had been conscientiously isolating at home because of the COVID pandemic, and leaving meant potential exposures.

But on Wednesday, Smith said, “I looked at my partner and said, maybe we should leave.”She called a friend in Orange County, about 380 miles south, who offered her parents’ empty condo. But the next day, the friend’s child spiked a fever — a possible case of COVID-19 — and the plan fell through amid the distraction.Amanda Smith takes a selfie of herself and her twin children in Santa Cruz, California, in April. (Amanda Smith)So Smith looked on Airbnb, careful to seek out hosts who detailed their COVID precautions, and found an apartment in San Bruno, about an hour’s drive north. She stuffed photos and documents into a suitcase, grabbed the go-bags, and her family headed out.“It’s coming out of our savings to stay here,” Smith said from the safety of her apartment rental, which runs about $1,150 a week.

€œIt was a really fraught decision to leave, but as soon as we got over the hill and the sky was blue, I took a big sigh of relief and knew that it had been a good decision.”As the twin disasters of COVID-19 and fire season sweep through California, thousands of residents like Smith are weighing difficult options, pitting risk against risk as they decide where to evacuate, whether from imminent flames or the toxic air. Amid a virulent pandemic, which is safest?. Doubling up at a friend’s home?. A hotel?.

An evacuation center?. And when do the risks of smoke inhalation outweigh the risk of a deadly infection?. €œObviously the most important thing is for people to do what they can to protect their lives, not only from the fire, but also from COVID,” said Detective Rosemerry Blankswade, public information officer for the San Mateo County Sheriff’s Office, which is helping coordinate response to the massive CZU Lightning Complex fires.“You have to evaluate the big picture here. If fire is your most imminent danger, maybe take the COVID risk.

But if you can avoid both of them, that’s obviously going to be the best option. It’s kind of a little bit of triage that we’re asking for people to do in their own lives right now.” Email Sign-Up Subscribe to KHN’s free Morning Briefing. In San Mateo, one of two counties where the CZU Lightning Complex fires are blazing, officials are advising people to head to an evacuation center, where county workers will assist them in finding a hotel room. Meanwhile, in neighboring Santa Cruz, where tens of thousands of residents have evacuated and shelters have limited space, officials are asking those under orders to leave to stay with family and friends whenever possible.What’s the right choice when all options pose additional risks?.

We spoke with several experts to help guide your thought process.You have to evacuate. Where should you go?. If your region is under an evacuation order, do not hesitate. Leave immediately.

If you can afford it, booking a room at a hotel or motel outside the evacuation zones may be the best option, said Dr. Michael Wilkes, a professor at the University of California-Davis School of Medicine. They almost always have air-conditioning units, which help filter the air from both smoke and virus. Many hotels are implementing new cleaning processes.

Ask staffers to detail what they’re doing to sanitize rooms, and consider skipping the daily cleaning service during your stay. You might also check review sites such as TripAdvisor to see what other guests report. When possible, avoid the lobby and other shared spaces, and opt for contactless check-in.Amanda Smith at home in Santa Cruz, California, with her twin children. Smith and her family decided to voluntarily evacuate their home on Aug.

20, due to heavy smoke in the area from the CZU Lightning Complex fires in the nearby Santa Cruz Mountains. (Anna Maria Barry-Jester/KHN)With so many people in Northern California fleeing the fires, many hotels are already full, especially in more remote areas. So what about staying with family or friends?. After months of being shut in and avoiding close contact beyond immediate family, moving into someone else’s home means a host of potential exposures.

Consider whether you or anyone else in the home is at high risk from COVID-19 because of age or a preexisting condition.“If so, that’s a reason to think twice before going to someone’s home,” said Dr. Gina Solomon, a program director at the Oakland-based Public Health Institute.Consider, too, what precautions your friends or family have been taking. Sheltering with someone whose job brings them into frequent contact with other people may not be as safe as sheltering with people who largely have been staying home. Another question is how crowded the home is.

If you have your own room and, preferably, your own bathroom, that makes staying with friends a better option. If a separate bedroom is not available and smoky skies are not a problem, you might consider pitching a tent in their backyard.For those with an RV or tent, camping can present another good option — although, with hundreds of wildfires burning across California, it may be challenging to drive far enough away to avoid fire and smoke. If you do camp, try to find a site away from wooded areas. And think twice before using group bathrooms.Is an evacuation center safe?.

Many counties have implemented new precautions at emergency shelters to prevent the spread of the coronavirus. In Santa Cruz, for example, officials are scaling back the capacity in each shelter to allow for social distancing, providing tents for people to use as shielding inside and allowing camping in the parking lots.Still, staying in a shelter should probably not be your first choice. In terms of COVID risk, deciding between a hotel and a friend’s house is “nipping at the edges,” said Dr. John Swartzberg, a clinical professor emeritus at the UC-Berkeley School of Public Health, while “being in a congregate setting is only better than being completely exposed to the elements.”If an evacuation shelter is your best immediate option, again, do not hesitate.

€œYou have these standards you want to practice for yourselves,” Swartzberg said, “but when something worse comes along, it trumps how careful we can be with COVID because the need for shelter is greater.” You can lower your risk of infection by wearing a mask, washing hands frequently and sanitizing surfaces.Smith’s partner, Grant Whipple, walks with their children in Big Sur on March 7. That was their last camping trip before the COVID-19 pandemic hit, Smith says. That area is now under threat from wildfire. (Amanda Smith)If you aren’t in a fire zone, should you invite friends and family to stay with you?.

Deciding whether to open your home to friends who are evacuating is an intensely personal decision and may depend on whether anyone in your family has a preexisting condition.“I guess it depends on how good a friend they are and how desperate they are,” said Swartzberg. It may also depend on how much space you have. If your guests can have their own bedroom and bathroom, it might be safer.If you do offer your home, experts advise against simply considering yourself a new pod with your guests. Instead, take steps to lower your chances of infection.“It might not be pleasant, but wearing a mask anytime you’re not in your own bedroom is the safest way to go,” said Solomon.

Stay outside as much as possible, she added, and consider eating meals outdoors or eating in shifts to avoid being maskless with those outside your family unit. Sanitize surfaces and wash hands frequently. If air quality permits, keep the windows open to improve airflow.If you’re in a region with hazardous smoke conditions, should you leave?. If your area has dense smoke but no imminent fire risk, the thought of heading somewhere else may be appealing, especially if you have respiratory issues.

But in most cases, Wilkes said, it would be safer not to leave your COVID bubble. And given the expanse of California’s fires, anywhere you flee could end up having lousy air quality by the time you arrive.“The better part of rationality,” Wilkes said, “would be to stay at home, not exercise [outdoors], stay inside as much as you can, turn on the air conditioning.”California Healthline senior correspondent Anna Maria Barry-Jester contributed to this report. Jenny Gold. jgold@kff.org, @JennyAGold Related Topics California Public Health States COVID-19 Environmental Health Natural DisastersIn the 2014 elections, Republicans rode a wave of anti-Affordable Care Act sentiment to pick up nine Senate seats, the largest gain for either party since 1980.

Newly elected Republicans such as Cory Gardner in Colorado and Steve Daines in Montana had hammered their Democratic opponents over the health care law during the campaign and promised to repeal it.Six years later, those senators are up for reelection. Not only is the law still around, but it’s gaining in popularity. What was once a winning strategy has become a political liability.Public sentiment about the ACA, also known as Obamacare, has shifted considerably during the Trump administration after Republicans tried but failed to repeal it. Now, in the midst of the COVID-19 pandemic and the ensuing economic crisis, which has led to the loss of jobs and health insurance for millions of people, health care again looks poised to be a key issue for voters this election.

Don't Miss A Story Subscribe to KHN’s free Weekly Edition newsletter. With competitive races in Colorado, Montana, Arizona, North Carolina and Iowa pitting Republican incumbents who voted to repeal the ACA against Democratic challengers promising to protect it, attitudes surrounding the health law could help determine control of the Senate. Republicans hold a slim three-vote majority in the Senate but are defending 23 seats in the Nov. 3 election.

Only one Democratic Senate seat — in Alabama, where incumbent Doug Jones is up against former Auburn University football coach Tommy Tuberville — is considered in play for Republicans.“The fall election will significantly revolve around people’s belief about what [candidates] will do for their health coverage,” said Dr. Daniel Derksen, a professor of public health at the University of Arizona.The Affordable Care Act has been a wedge issue since it was signed into law in 2010. Because it then took four years to enact, its opponents talked for years about how bad the not-yet-created marketplace for insurance would be, said Joe Hanel, spokesperson for the Colorado Health Institute, a nonpartisan nonprofit focused on health policy analysis. And they continued to attack the law as it took full effect in 2014.Gardner, for example, ran numerous campaign ads that year criticizing the ACA and, in particular, President Barack Obama’s assertion that “if you like your health care plan, you’ll be able to keep your health care plan.”But now, Hanel said, the ACA’s policies have become much more popular in Colorado as the costs of health exchange plans have dropped.

Thus, political messaging has changed, too.“This time it’s the opposite,” Hanel said. €œThe people bringing up the Affordable Care Act are the Democrats.”Despite Gardner’s multiple votes to repeal the ACA, he has largely avoided talking about the measure during the 2020 campaign. He even removed his pro-repeal position from his campaign website.Democratic attack ads in July blasted Gardner for repeatedly dodging questions in an interview with Colorado Public Radio about his stance on a lawsuit challenging the ACA.His opponent, Democrat John Hickenlooper, fully embraced the law when he was Colorado governor, using the measure to expand Medicaid eligibility to more low-income people and to create a state health insurance exchange. Now, he’s campaigning on that record, with promises to expand health care access even further.Polling DataPolling conducted by KFF for the past 10 years shows a shift in public opinion has occurred nationwide.

(KHN is an editorially independent program of KFF, the Kaiser Family Foundation.)“Since Trump won the election in 2016, we now have consistently found that a larger share of the public holds favorable views” of the health law, said Ashley Kirzinger, associate director of public opinion and survey research for the foundation. €œThis really solidified in 2017 after the failed repeal in the Senate.”The foundation’s polling found that, in July 2014, 55% of voters opposed the law, while 36% favored it. By July 2020, that had flipped, with 51% favoring the law and 38% opposing it. A shift was seen across all political groups, though 74% of Republicans still viewed it unfavorably in the latest poll.Public support for individual provisions of the ACA — such as protections for people with preexisting conditions or allowing young adults to stay on their parents’ health plans until age 26 — have proved even more popular than the law as a whole.

And the provision that consistently polled unfavorably — the mandate that those without insurance must pay a fine — was eliminated in 2017.“We’re 10 years along and the sky hasn’t caved in,” said Sabrina Corlette, a health policy professor at Georgetown University.Political MessagingFollowing the passage of the ACA, Democrats didn’t reference the law in their campaigns, said Erika Franklin Fowler, a government professor at Wesleyan University and the director of the Wesleyan Media Project, which tracks political advertising.“They ran on any other issue they could find,” Fowler said.Republicans, she said, kept promising to “repeal and replace” but weren’t able to do so.Then, in the 2018 election, Democrats seized on the shift in public opinion, touting the effects of the law and criticizing Republicans for their attempts to overturn it.“In the decade I have been tracking political advertising, there wasn’t a single-issue topic that was as prominent as health care was in 2018,” she said.As the global health crisis rages, health care concerns again dominate political ads in the 2020 races, Fowler said, although most ads haven’t explicitly focused on the ACA. Many highlight Republicans’ support for the lawsuit challenging preexisting condition protections or specific provisions of the ACA that their votes would have overturned. Republicans say they, too, will protect people with preexisting conditions but otherwise have largely avoided talking about the ACA.“Cory Gardner has been running a lot on his environmental bills and conservation funding,” Fowler said. €œIt’s not difficult to figure out why he’s doing that.

It’s easier for him to tout that in a state like Colorado than it is to talk about health care.”Similar dynamics are playing out in other key Senate races. In Arizona, Republican Sen. Martha McSally was one of the more vocal advocates of repealing the ACA while she served in the House of Representatives. She publicly acknowledged those votes may have hurt her 2018 Senate bid.“I did vote to repeal and replace Obamacare,” McSally said on conservative pundit Sean Hannity’s radio show during the 2018 campaign.

€œI’m getting my ass kicked for it right now.”She indeed lost but was appointed to fill the seat of Sen. Jon Kyl after he resigned at the end of 2018. Now McSally is in a tight race with Democratic challenger Mark Kelly, an astronaut and the husband of former Rep. Gabby Giffords.“Kelly doesn’t have a track record of voting one way or another, but certainly in his campaign this is one of his top speaking points.

What he would do to expand coverage and reassure people that coverage won’t be taken away,” said Derksen, the University of Arizona professor.The ACA has proved a stumbling block for Republican Sens. Thom Tillis of North Carolina and Joni Ernst of Iowa. In Maine, GOP Sen. Susan Collins cast a key vote that prevented the repeal of the law but cast other votes that weakened it.

She now also appears vulnerable — but more for her vote to confirm Brett Kavanaugh’s nomination to the Supreme Court and for not doing more to oppose President Donald Trump.In Montana, Daines, who voted to repeal the ACA, is trying to hold on to his seat against Democratic Gov. Steve Bullock, who used the law to expand the state’s Medicaid enrollment in 2015. At its peak, nearly 1 in 10 Montanans were covered through the expansion.As more Montanans now face the high cost of paying for health care on their own amid pandemic-related job losses, Montana State University political science professor David Parker said he expects Democrats to talk about Daines’ votes to repeal cost-saving provisions of the ACA.“People are losing jobs, and their jobs bring health care with them,” Parker said. €œI don’t think it’s a good space for Daines to be right now.” Markian Hawryluk.

MarkianH@kff.org, @MarkianHawryluk Related Topics Elections Health Care Costs Health Care Reform Insurance States Arizona Colorado Montana North Carolina Obamacare Plans.

More than 90% of babies born with heart defects where to get biaxin pills survive into adulthood. As a result, there are now more adults living with congenital where to get biaxin pills heart disease than children. These adults have a chronic, lifelong condition and the European Society of Cardiology (ESC) has produced advice to give the best chance of a normal life.

The guidelines are published where to get biaxin pills online today in European Heart Journal,1 and on the ESC website.2Congenital heart disease refers to any structural defect of the heart and/or great vessels (those directly connected to the heart) present at birth. Congenital heart disease affects all aspects of life, including physical and mental health, socialising, and work. Most patients are unable to exercise at the same level as their peers which, along with the awareness of having where to get biaxin pills a chronic condition, affects mental wellbeing."Having a congenital heart disease, with a need for long-term follow-up and treatment, can also have an impact on social life, limit employment options and make it difficult to get insurance," said Professor Helmut Baumgartner, Chairperson of the guidelines Task Force and head of Adult Congenital and Valvular Heart Disease at the University Hospital of Münster, Germany.

"Guiding and supporting patients in all of these processes is an inherent part of their care."All adults with congenital heart disease should have at least one appointment at a specialist centre to determine how often they need to be seen. Teams at these centres should include specialist nurses, psychologists and social workers given that anxiety and depression are common concerns.Pregnancy is contraindicated in women with where to get biaxin pills certain conditions such high blood pressure in the arteries of the lungs. "Pre-conception counselling is recommended for women and men to discuss the risk of the defect in offspring and the option of foetal screening," said Professor Julie De Backer, Chairperson of the guidelines Task Force and cardiologist and clinical geneticist at Ghent University Hospital, Belgium.Concerning sports, recommendations are provided for each condition.

Professor De Backer where to get biaxin pills said. "All adults with congenital heart disease should be encouraged to exercise, taking into account the nature of the underlying defect and their own abilities."The guidelines state when and how to diagnose complications. This includes proactively monitoring for arrhythmias, cardiac imaging and blood tests to detect problems with heart function.Detailed recommendations are provided on how and when to where to get biaxin pills treat complications.

Arrhythmias are an important cause of sickness and death and the guidelines stress the importance of correct and timely referral to a specialised treatment centre. They also list when particular treatments should be considered such as ablation (a procedure to destroy heart tissue and stop faulty electrical where to get biaxin pills signals) and device implantation.For several defects, there are new recommendations for catheter-based treatment. "Catheter-based treatment should be performed by specialists in adult congenital heart disease working within a multidisciplinary team," said Professor Baumgartner.

Story Source where to get biaxin pills. Materials provided by European Society of Cardiology. Note.

Content may be edited for style and length.One in five patients die within a year after the most common type of heart attack. European Society of Cardiology (ESC) treatment guidelines for non-ST-segment elevation acute coronary syndrome are published online today in European Heart Journal, and on the ESC website.Chest pain is the most common symptom, along with pain radiating to one or both arms, the neck, or jaw. Anyone experiencing these symptoms should call an ambulance immediately.

Complications include potentially deadly heart rhythm disorders (arrhythmias), which are another reason to seek urgent medical help.Treatment is aimed at the underlying cause. The main reason is fatty deposits (atherosclerosis) that become surrounded by a blood clot, narrowing the arteries supplying blood to the heart. In these cases, patients should receive blood thinners and stents to restore blood flow.

For the first time, the guidelines recommend imaging to identify other causes such as a tear in a blood vessel leading to the heart.Regarding diagnosis, there is no distinguishing change on the electrocardiogram (ECG), which may be normal. The key step is measuring a chemical in the blood called troponin. When blood flow to the heart is decreased or blocked, heart cells die, and troponin levels rise.

If levels are normal, the measurement should be repeated one hour later to rule out the diagnosis. If elevated, hospital admission is recommended to further evaluate the severity of the disease and decide the treatment strategy.Given that the main cause is related to atherosclerosis, there is a high risk of recurrence, which can also be deadly. Patients should be prescribed blood thinners and lipid lowering therapies.

"Equally important is a healthy lifestyle including smoking cessation, exercise, and a diet emphasising vegetables, fruits and whole grains while limiting saturated fat and alcohol," said Professor Jean-Philippe Collet, Chairperson of the guidelines Task Force and professor of cardiology, Sorbonne University, Paris, France.Behavioural change and adherence to medication are best achieved when patients are supported by a multidisciplinary team including cardiologists, general practitioners, nurses, dietitians, physiotherapists, psychologists, and pharmacists.The likelihood of triggering another heart attack during sexual activity is low for most patients, and regular exercise decreases this risk. Healthcare providers should ask patients about sexual activity and offer advice and counselling.Annual influenza vaccination is recommended -- especially for patients aged 65 and over -- to prevent further heart attacks and increase longevity."Women should receive equal access to care, a prompt diagnosis, and treatments at the same rate and intensity as men," said Professor Holger Thiele, Chairperson of the guidelines Task Force and medical director, Department of Internal Medicine/Cardiology, Heart Centre Leipzig, Germany. Story Source.

Materials provided by European Society of Cardiology. Note. Content may be edited for style and length.SOBRE NOTICIAS EN ESPAÑOLNoticias en español es una sección de Kaiser Health News que contiene traducciones de artículos de gran interés para la comunidad hispanohablante, y contenido original enfocado en la población hispana que vive en los Estados Unidos.

Use Nuestro Contenido Este contenido puede usarse de manera gratuita (detalles). La temporada de influenza se verá diferente este año, ya que los Estados Unidos se enfrentan a una pandemia de coronavirus que ya ha matado a más de 176.000 personas.Muchos estadounidenses son reacios a ir al médico y los funcionarios de salud pública temen que las personas eviten vacunarse. Aunque a veces se considera incorrectamente como un resfriado, la gripe también mata a decenas de miles de personas en el país cada año.

Los más vulnerables son los niños pequeños, los adultos mayores y las personas con enfermedades subyacentes. Cuando se combina con los efectos de COVID-19, los expertos en salud pública dicen que es más importante que nunca vacunarse contra la gripe.Si una cantidad suficiente de la población se vacuna, más del 45% lo hizo la temporada de gripe pasada, podría ayudar a evitar un escenario de pesadilla este invierno, con hospitales llenos de pacientes con COVID-19 y los que sufren los efectos graves de la influenza.Además de la posible carga para los hospitales, existe la posibilidad de que las personas contraigan ambos virus y “nadie sabe qué sucede si se contrae influenza y COVID simultáneamente porque nunca sucedió antes”, dijo la doctora Rachel Levine, secretaria de Salud de Pennsylvania, a reporteros.En respuesta, este año los fabricantes están produciendo más suministros de vacunas, entre 194 y 198 millones de dosis, unas 20 millones más de las que se distribuyeron la temporada pasada, según los Centros para el Control y Prevención de Enfermedades (CDC).Mientras se acerca la temporada de gripe, aquí hay algunas respuestas a preguntas frecuentes:P. ¿Cuándo debo vacunarme contra la gripe?.

La publicidad ya ha comenzado y algunas farmacias y clínicas ya tienen sus suministros. Pero, debido a que la efectividad de la vacuna puede disminuir con el tiempo, los CDC recomiendan no recibir la dosis en agosto.Muchas farmacias y clínicas comenzarán las inmunizaciones a principios de septiembre. Generalmente, los virus de la influenza comienzan a circular a mediados o fines de octubre, pero se expanden masivamente más tarde, en el invierno.

Se necesitan aproximadamente dos semanas después de recibir la inyección para que los anticuerpos, que circulan en la sangre y frustran las infecciones, se acumulen.“Las personas jóvenes y sanas pueden comenzar a vacunarse contra la gripe en septiembre, y las personas mayores y otras poblaciones vulnerables pueden hacerlo en octubre”, dijo el doctor Steve Miller, director clínico de la aseguradora Cigna.Los CDC recomiendan que las personas “se vacunen contra la influenza a fines de octubre”, pero señalaron que se puede recibir la vacuna más tarde porque “aún puede ser beneficiosas y la vacunación debe ofrecerse a lo largo de toda la temporada de influenza”.Aun así, algunos expertos recomiendan no esperar demasiado este año, no solo por COVID-19, sino también en caso de que haya escasez debido a la abrumadora demanda.P. ¿Cuáles son las razones por las que las que debería ofrecer mi brazo para vacunarme?. Hay que vacunarse porque brinda protección contra la gripe y, por lo tanto, contra la propagación a otras personas, lo que puede ayudar a disminuir la carga para los hospitales y el personal médico.Y hay otro mensaje que puede resonar en estos tiempos extraños.“Le da a la gente la sensación de que hay algunas cosas que pueden controlar”, dijo Eduardo Sánchez, director médico de prevención de la American Heart Association.Si bien una vacuna contra la gripe no evitará COVID-19, recibirla podría ayudar al médico a diferenciar entre las dos enfermedades si se desarrolla algún síntoma (fiebre, tos, dolor de garganta) que ambas infecciones comparten, explicó Sánchez.Y aunque las vacunas contra la gripe no evitarán todos los casos de gripe, vacunarse puede reducir la gravedad si la persona se enferma, dijo.Todas las personas elegibles, especialmente los trabajadores esenciales, los que sufren de afecciones subyacentes y aquellos en mayor riesgo, incluidos los niños muy pequeños y las mujeres embarazadas, deben buscar protección, dijeron los CDC.

La entidad recomienda la vacunación a partir de los 6 meses.P. ¿Qué sabemos sobre la efectividad de la vacuna de este año?. Se deben producir nuevas vacunas contra la gripe cada año, porque el virus muta y la efectividad de la vacuna varía, dependiendo de qué tan bien coincida con el virus circulante.Se calculó que la formulación del año pasado tuvo una eficacia de aproximadamente un 45% para prevenir la gripe en general, con una efectividad de aproximadamente un 55% en los niños.

Las vacunas disponibles en el país este año tienen como objetivo prevenir al menos tres cepas diferentes del virus, y la mayoría cubre cuatro.Todavía no se sabe qué tan bien coincidirá el suministro de este año con las cepas que circularán en los Estados Unidos. Las primeras indicaciones del hemisferio sur, que atraviesa su temporada de gripe durante nuestro verano, son alentadoras. Allí, las personas practicaron el distanciamiento social, usaron máscaras y se vacunaron en mayor número este año, y los niveles mundiales de gripe son más bajos de lo esperado.

Sin embargo, expertos advierten que no se debe contar con una temporada igual de suave en los Estados Unidos, en parte porque los esfuerzos por usar mascara facial y de distanciamiento social varían ampliamente.P. ¿Qué están haciendo diferente los seguros y sistemas de salud este año?. Las aseguradoras y los sistemas de salud contactados por KHN dicen que seguirán las pautas de los CDC, que exigen limitar y espaciar la cantidad de personas que esperan en las filas y las áreas de vacunación.

Algunos están programando citas para vacunas contra la gripe para ayudar a controlar el flujo.Health Fitness Concepts, una compañía que trabaja con UnitedHealth Group y otras empresas para establecer clínicas de vacunación contra la gripe en el noreste del país, dijo que está “fomentando eventos más pequeños y frecuentes para apoyar el distanciamiento social” y “exigiendo que se completen todos los formularios y arremangarse las camisas antes de entrar al área de vacunación contra la influenza”.Se requerirá que todos usen máscaras.Además, a nivel nacional, algunos grupos médicos contratados por UnitedHealth instalarán carpas, para que las inyecciones se puedan administrar al aire libre, dijo un vocero.Kaiser Permanente planifica las vacunas directamente en autos en algunos de sus centros médicos y está probando los procedimientos de detección y registro sin contacto en algunos lugares.Geisinger Health, un proveedor de salud regional en Pennsylvania y Nueva Jersey, dijo que también tendría programas de vacunación contra la influenza al aire libre en sus instalaciones.Además, “Geisinger exige que todos los empleados reciban la vacuna contra la influenza este año”, dijo Mark Shelly, director de prevención y control de infecciones del sistema. €œAl dar este paso, esperamos transmitir a nuestros vecinos la importancia de la vacuna contra la influenza para todos”.P. Por lo general, me vacunan contra la gripe en el trabajo.

¿Seguirá siendo una opción este año?. Con el objetivo de evitar riesgosas reuniones en interiores, muchos empleadores se muestran reacios a patrocinar las clínicas de gripe en oficinas como han ofrecido en años anteriores. Y con tanta gente que sigue trabajando desde casa, hay menos necesidad de llevar las vacunas contra la gripe al lugar de trabajo.

En cambio, muchos empleadores están alentando a los trabajadores a que reciban vacunas de sus médicos de atención primaria, en farmacias u otros entornos comunitarios. El seguro generalmente cubrirá el costo de la vacuna.Algunos empleadores están considerando ofrecer cupones para vacunas contra la gripe a sus trabajadores sin seguro o a aquellos que no participan en el plan médico de la compañía, dijo Julie Stone, directora general de salud y beneficios de Willis Towers Watson, una firma consultora.Estos cupones podrían, por ejemplo, permitir a los trabajadores obtener la vacuna en un laboratorio en particular sin costo.Algunos empleadores están comenzando a pensar en cómo podrían usar sus estacionamientos para administrar vacunas contra la gripe enlos autos, dijo el doctor David Zieg, líder de servicios clínicos para el consultor de beneficios Mercer.Aunque la ley federal permite a los empleadores exigir a los empleados que se vacunen contra la gripe, ese paso generalmente lo toman solo los centros de atención médica y algunas universidades donde las personas viven y trabajan en estrecha colaboración, dijo Zieg.Pero sucede. El mes pasado, el sistema de la Universidad de California emitió una orden ejecutiva que requiere que todos los estudiantes, profesores y personal se vacunen contra la gripe antes del 1 de noviembre, con limitadas excepciones.P.

¿Qué están haciendo las farmacias para alentar a las personas a vacunarse contra la gripe?. Algunas farmacias están haciendo un esfuerzo adicional para salir a la comunidad y ofrecer vacunas contra la gripe.Walgreens, que tiene casi 9,100 farmacias en todo el país, continúa una asociación iniciada en 2015 con organizaciones comunitarias, iglesias y empleadores que ha ofrecido alrededor de 150,000 clínicas de gripe móviles hasta la fecha.El programa pone especial énfasis en trabajar con poblaciones vulnerables y en áreas desatendidas, dijo el doctor Kevin Ban, director médico de la cadena de farmacias.Walgreens comenzó a ofrecer vacunas contra la gripe a mediados de agosto y está animando a las personas a no demorar en vacunarse.Tanto Walgreens como CVS están estimulando a las personas a programar citas y hacer trámites en línea este año para minimizar el tiempo que pasan en los locales.En los CVS MinuteClinic, una vez que los pacientes se han registrado para recibir la vacuna contra la gripe, deben esperar afuera o en su automóvil, ya que las áreas de espera interiores ahora están cerradas.“No tenemos un arsenal contra COVID”, dijo Ban, de Walgreens. €œPero quitar la presión del sistema de atención médica proporcionando vacunas por adelantado es algo que sí podemos hacer”.

Julie Appleby. jappleby@kff.org, @Julie_Appleby Michelle Andrews. andrews.khn@gmail.com, @mandrews110 Related Topics Insurance Noticias En Español Public Health CDC COVID-19 Insurers VaccinesThis story was produced in partnership with PolitiFact.

This story can be republished for free (details). President Donald Trump accepted the Republican Party’s nomination for president in a 70-minute speech from the South Lawn of the White House on Thursday night.Speaking to a friendly crowd that didn’t appear to be observing social distancing conventions, and with few participants wearing masks, he touched on a range of topics, including many related to the COVID pandemic and health care in general.Throughout, the partisan crowd applauded and chanted “Four more years!. € And, even as the nation’s COVID-19 death toll exceeded 180,000, Trump was upbeat. €œIn recent months, our nation and the entire planet has been struck by a new and powerful invisible enemy,” he said.

€œLike those brave Americans before us, we are meeting this challenge.”At the end of the event, there were fireworks.Our partners at PolitiFact did an in-depth fact check on Trump’s entire acceptance speech. Here are the highlights related to the administration’s COVID-19 response and other health policy issues:“We developed, from scratch, the largest and most advanced testing system in the world.” This is partially right, but it needs context.It’s accurate that the U.S. Developed its COVID-19 testing system from scratch, because the government didn’t accept the World Health Organization’s testing recipe.

But whether the system is the “largest” or “most advanced” is subject to debate.The U.S. Has tested more individuals than any other country. But experts told us a more meaningful metric would be the percentage of positive tests out of all tests, indicating that not only sick people were getting tested.

Another useful metric would be the percentage of the population that has been tested. The U.S. Is one of the most populous countries but has tested a lower percentage of its population than other countries.

Don't Miss A Story Subscribe to KHN’s free Weekly Edition newsletter. The U.S. Was also slower than other countries in rolling out tests and amping up testing capacity.

Even now, many states are experiencing delays in reporting test results to positive individuals.As for “the most advanced,” Trump may be referring to new testing investments and systems, like Abbott’s recently announced $5, 15-minute rapid antigen test, which the company says will be about the size of a credit card, needs no instrumentation and comes with a phone app through which people can view their results. But Trump’s comment makes it sound as if these testing systems are already in place when they haven’t been distributed to the public.“The United States has among the lowest [COVID-19] case fatality rates of any major country in the world. The European Union’s case fatality rate is nearly three times higher than ours.”The case fatality rate measures the known number of cases against the known number of deaths.

The European Union has a rate that’s about 2½ times greater than the United States.But the source of that data, Oxford University’s Our World in Data project, reports that “during an outbreak of a pandemic, the case fatality rate is a poor measure of the mortality risk of the disease.”A better way to measure the threat of the virus, experts say, is to look at the number of deaths per 100,000 residents. Viewed that way, the U.S. Has the 10th-highest death rate in the world.“We will produce a vaccine before the end of the year, or maybe even sooner.”It’s far from guaranteed that a coronavirus vaccine will be ready before the end of the year.While researchers are making rapid strides, it’s not yet known precisely when the vaccine will be available to the public, which is what’s most important.

Six vaccines are in the third phase of testing, which involves thousands of patients. Like earlier phases, this one looks at the safety of a vaccine but also examines its effectiveness and collects more data on side effects. Results of the third phase will be submitted to the Food and Drug Administration for approval.The government website Operation Warp Speed seems less optimistic than Trump, announcing it “aims to deliver 300 million doses of a safe, effective vaccine for COVID-19 by January 2021.”And federal health officials and other experts have generally predicted a vaccine will be available in early 2021.

Federal committees are working on recommendations for vaccine distribution, including which groups should get it first. €œFrom everything we’ve seen now — in the animal data, as well as the human data — we feel cautiously optimistic that we will have a vaccine by the end of this year and as we go into 2021,” said Dr. Anthony Fauci, the nation’s top infectious diseases expert.

€œI don’t think it’s dreaming.”“Last month, I took on Big Pharma. You think that is easy?. I signed orders that would massively lower the cost of your prescription drugs.”Quite misleading.

Trump signed four executive orders on July 24 aimed at lowering prescription drug prices. But those orders haven’t taken effect yet — the text of one hasn’t even been made publicly available — and experts told us that, if implemented, the measures would be unlikely to result in significant drug price reductions for the majority of Americans.“We will always and very strongly protect patients with preexisting conditions, and that is a pledge from the entire Republican Party.”Trump’s pledge is undermined by his efforts to overturn the Affordable Care Act, the only law that guarantees people with preexisting conditions both receive health coverage and do not have to pay more for it than others do. In 2017, Trump supported congressional efforts to repeal the ACA.

The Trump administration is now backing GOP-led efforts to overturn the ACA through a court case. And Trump has also expanded short-term health plans that don’t have to comply with the ACA.“Joe Biden recently raised his hand on the debate stage and promised he was going to give it away, your health care dollars to illegal immigrants, which is going to bring a massive number of immigrants into our country.”This is misleading. During a June 2019 Democratic primary debate, candidates were asked.

€œRaise your hand if your government plan would provide coverage for undocumented immigrants.” All candidates on stage, including Biden, raised their hands. They were not asked if that coverage would be free or subsidized.Biden supports extending health care access to all immigrants, regardless of immigration status. A task force recommended that he allow immigrants who are in the country illegally to buy health insurance, without federal subsidies.“Joe Biden claims he has empathy for the vulnerable, yet the party he leads supports the extreme late-term abortion of defenseless babies right up to the moment of birth.”This mischaracterizes the Democratic Party’s stance on abortion and Biden’s position.Biden has said he would codify the Supreme Court’s ruling in Roe v.

Wade and related precedents. This would generally limit abortions to the first 20 to 24 weeks of gestation. States are allowed under court rulings to ban abortion after the point at which a fetus can sustain life, usually considered to be between 24 and 28 weeks from the mother’s last menstrual period — and 43 states do.

But the rulings require states to make exceptions “to preserve the life or health of the mother.” Late-term abortions are very rare, about 1%.The Democratic Party platform holds that “every woman should have access to quality reproductive health care services, including safe and legal abortion — regardless of where she lives, how much money she makes, or how she is insured.” It does not address late-term abortion.PolitiFact’s Daniel Funke, Jon Greenberg, Louis Jacobson, Noah Y. Kim, Bill McCarthy, Samantha Putterman, Amy Sherman, Miriam Valverde and KHN reporter Victoria Knight contributed to this report. Related Topics Elections Health Industry Pharmaceuticals Public Health The Health Law Abortion COVID-19 Immigrants KHN &.

PolitiFact HealthCheck Preexisting Conditions Trump Administration VaccinesThis story also ran on CNN. This story can be republished for free (details). Flu season will look different this year, as the country grapples with a coronavirus pandemic that has killed more than 172,000 people. Many Americans are reluctant to visit a doctor’s office and public health officials worry people will shy away from being immunized.Although sometimes incorrectly regarded as just another bad cold, flu also kills tens of thousands of people in the U.S. Each year, with the very young, the elderly and those with underlying conditions the most vulnerable.

When coupled with the effects of COVID-19, public health experts say it’s more important than ever to get a flu shot.If enough of the U.S. Population gets vaccinated — more than the 45% who did last flu season — it could help head off a nightmare scenario in the coming winter of hospitals stuffed with both COVID-19 patients and those suffering from severe effects of influenza.Aside from the potential burden on hospitals, there’s the possibility people could get both viruses — and “no one knows what happens if you get influenza and COVID [simultaneously] because it’s never happened before,” Dr. Rachel Levine, Pennsylvania’s secretary of health, told reporters this month.In response, manufacturers are producing more vaccine supply this year, between 194 million and 198 million doses, or about 20 million more than they distributed last season, according to the Centers for Disease Control and Prevention.

Email Sign-Up Subscribe to KHN’s free Morning Briefing. As flu season approaches, here are some answers to a few common questions:Q. When should I get my flu shot?.

Advertising has already begun, and some pharmacies and clinics have their supplies now. But, because the effectiveness of the vaccine can wane over time, the CDC recommends against a shot in August.Many pharmacies and clinics will start immunizations in early September. Generally, influenza viruses start circulating in mid- to late October but become more widespread later, in the winter.

It takes about two weeks after getting a shot for antibodies — which circulate in the blood and thwart infections — to build up. €œYoung, healthy people can begin getting their flu shots in September, and elderly people and other vulnerable populations can begin in October,” said Dr. Steve Miller, chief clinical officer for insurer Cigna.The CDC has recommended that people “get a flu vaccine by the end of October,” but noted it’s not too late to get one after that because shots “can still be beneficial and vaccination should be offered throughout the flu season.”Even so, some experts say not to wait too long this year — not only because of COVID-19, but also in case a shortage develops because of overwhelming demand.Q.

What are the reasons I should roll up my sleeve for this?. Get a shot because it protects you from catching the flu and spreading it to others, which may help lessen the burden on hospitals and medical staffs.And there’s another message that may resonate in this strange time.“It gives people a sense that there are some things you can control,” said Eduardo Sanchez, chief medical officer for prevention at the American Heart Association.While a flu shot won’t prevent COVID-19, he said, getting one could help your doctors differentiate between the diseases if you develop any symptoms — fever, cough, sore throat — they share.And even though flu shots won’t prevent all cases of the flu, getting vaccinated can lessen the severity if you do fall ill, he said.You cannot get influenza from having a flu vaccine.All eligible people, especially essential workers, those with underlying conditions and those at higher risk — including very young children and pregnant women — should seek protection, the CDC said. It recommends that children over 6 months old get vaccinated.Q.

What do we know about the effectiveness of this year’s vaccine?. Flu vaccines — which must be developed anew each year because influenza viruses mutate — range in effectiveness annually, depending on how well they match the circulating virus. Last year’s formulation was estimated to be about 45% effective in preventing the flu overall, with about a 55% effectiveness in children.

The vaccines available in the U.S. This year are aimed at preventing at least three strains of the virus, and most cover four.It isn’t yet known how well this year’s supply will match the strains that will circulate in the U.S. Early indications from the Southern Hemisphere, which goes through its flu season during our summer, are encouraging.

There, people practiced social distancing, wore masks and got vaccinated in greater numbers this year — and global flu levels are lower than expected. Experts caution, however, not to count on a similarly mild season in the U.S., in part because masking and social distancing efforts vary widely.Q. What are insurance plans and health systems doing differently this year?.

Insurers and health systems contacted by KHN say they will follow CDC guidelines, which call for limiting and spacing out the number of people waiting in lines and vaccination areas. Some are setting appointments for flu shots to help manage the flow.Health Fitness Concepts, a company that works with UnitedHealth Group and other businesses to set up flu shot clinics in the Northeast, said it is “encouraging smaller, more frequent events to support social distancing” and “requiring all forms to be completed and shirtsleeves rolled up before entering the flu shot area.” Everyone will be required to wear masks.Also, nationally, some physician groups contracted with UnitedHealth will set up tent areas so shots can be given outdoors, a spokesperson said.Kaiser Permanente plans drive-thru vaccinations at some of its medical facilities and is testing touch-free screening and check-in procedures at some locations. (KHN is not affiliated with Kaiser Permanente.)Geisinger Health, a regional health provider in Pennsylvania and New Jersey, said it, too, would have outdoor flu vaccination programs at its facilities.Additionally, “Geisinger is making it mandatory for all employees to receive the flu vaccine this year,” said Mark Shelly, the system’s director of infection prevention and control.

€œBy taking this step, we hope to convey to our neighbors the importance of the flu vaccine for everyone.”Q. Usually I get a flu shot at work. Will that be an option this year?.

Aiming to avoid risky indoor gatherings, many employers are reluctant to sponsor the on-site flu clinics they’ve offered in years past. And with so many people continuing to work from home, there’s less need to bring flu shots to employees on the job. Instead, many employers are encouraging workers to get shots from their primary care doctors, at pharmacies or in other community settings.

Insurance will generally cover the cost of the vaccine.Some employers are considering offering vouchers for flu shots to their uninsured workers or those who don’t participate in the company plan, said Julie Stone, managing director for health and benefits at Willis Towers Watson, a consulting firm. The vouchers could allow workers to get the shot at a particular lab at no cost, for example.Some employers are starting to think about how they might use their parking lots for administering drive-thru flu shots, said Dr. David Zieg, clinical services leader for benefits consultant Mercer.Although federal law allows employers to require employees to get flu shots, that step is typically taken only by health care facilities and some universities where people live and work closely together, Zieg said.Q.

What are pharmacies doing to encourage people to get flu shots?. Some pharmacies are making an extra push to get out into the community to offer flu shots.Walgreens, which has nearly 9,100 pharmacies nationwide, is continuing a partnership begun in 2015 with community organizations, churches and employers that has offered about 150,000 off-site and mobile flu clinics to date.The program places a special emphasis on working with vulnerable populations and in underserved areas, said Dr. Kevin Ban, chief medical officer for the drugstore chain.Walgreens began offering flu shots in mid-August and is encouraging people not to delay getting vaccinated.Both Walgreens and CVS are encouraging people to schedule appointments and do paperwork online this year to minimize time spent in the stores.At CVS MinuteClinic locations, once patients have checked in for their flu shot, they must wait outside or in their car, since the indoor waiting areas are now closed.“We don’t have tons of arrows in our quiver against COVID,” Walgreens’ Ban said.

€œTaking pressure off the health care system by providing vaccines in advance is one thing we can do.” Julie Appleby. jappleby@kff.org, @Julie_Appleby Michelle Andrews. andrews.khn@gmail.com, @mandrews110 Related Topics Insurance Public Health CDC COVID-19 Insurers VaccinesUse Our Content This story can be republished for free (details). As the smoke thickened near her home in Santa Cruz, California, last week, Amanda Smith kept asking herself the same questions.

Should we leave?. And where would we go?. The wildfire evacuation zone, at the time, ended a few blocks from her house.

But she worried about what the air quality — which had reached the second-highest warning level, purple for “very unhealthy” — would do to her children’s lungs. Her 4-year-old twins had spent time in the neonatal intensive care unit. One was later diagnosed with asthma, and last year was hospitalized with pneumonia.By Tuesday, said Smith, “we all had headaches, the kids were coughing a little bit, and it was raining ash.” The family had been conscientiously isolating at home because of the COVID pandemic, and leaving meant potential exposures.

But on Wednesday, Smith said, “I looked at my partner and said, maybe we should leave.”She called a friend in Orange County, about 380 miles south, who offered her parents’ empty condo. But the next day, the friend’s child spiked a fever — a possible case of COVID-19 — and the plan fell through amid the distraction.Amanda Smith takes a selfie of herself and her twin children in Santa Cruz, California, in April. (Amanda Smith)So Smith looked on Airbnb, careful to seek out hosts who detailed their COVID precautions, and found an apartment in San Bruno, about an hour’s drive north.

She stuffed photos and documents into a suitcase, grabbed the go-bags, and her family headed out.“It’s coming out of our savings to stay here,” Smith said from the safety of her apartment rental, which runs about $1,150 a week. €œIt was a really fraught decision to leave, but as soon as we got over the hill and the sky was blue, I took a big sigh of relief and knew that it had been a good decision.”As the twin disasters of COVID-19 and fire season sweep through California, thousands of residents like Smith are weighing difficult options, pitting risk against risk as they decide where to evacuate, whether from imminent flames or the toxic air. Amid a virulent pandemic, which is safest?.

Doubling up at a friend’s home?. A hotel?. An evacuation center?.

And when do the risks of smoke inhalation outweigh the risk of a deadly infection?. €œObviously the most important thing is for people to do what they can to protect their lives, not only from the fire, but also from COVID,” said Detective Rosemerry Blankswade, public information officer for the San Mateo County Sheriff’s Office, which is helping coordinate response to the massive CZU Lightning Complex fires.“You have to evaluate the big picture here. If fire is your most imminent danger, maybe take the COVID risk.

But if you can avoid both of them, that’s obviously going to be the best option. It’s kind of a little bit of triage that we’re asking for people to do in their own lives right now.” Email Sign-Up Subscribe to KHN’s free Morning Briefing. In San Mateo, one of two counties where the CZU Lightning Complex fires are blazing, officials are advising people to head to an evacuation center, where county workers will assist them in finding a hotel room.

Meanwhile, in neighboring Santa Cruz, where tens of thousands of residents have evacuated and shelters have limited space, officials are asking those under orders to leave to stay with family and friends whenever possible.What’s the right choice when all options pose additional risks?. We spoke with several experts to help guide your thought process.You have to evacuate. Where should you go?.

If your region is under an evacuation order, do not hesitate. Leave immediately. If you can afford it, booking a room at a hotel or motel outside the evacuation zones may be the best option, said Dr.

Michael Wilkes, a professor at the University of California-Davis School of Medicine. They almost always have air-conditioning units, which help filter the air from both smoke and virus. Many hotels are implementing new cleaning processes.

Ask staffers to detail what they’re doing to sanitize rooms, and consider skipping the daily cleaning service during your stay. You might also check review sites such as TripAdvisor to see what other guests report. When possible, avoid the lobby and other shared spaces, and opt for contactless check-in.Amanda Smith at home in Santa Cruz, California, with her twin children.

Smith and her family decided to voluntarily evacuate their home on Aug. 20, due to heavy smoke in the area from the CZU Lightning Complex fires in the nearby Santa Cruz Mountains. (Anna Maria Barry-Jester/KHN)With so many people in Northern California fleeing the fires, many hotels are already full, especially in more remote areas.

So what about staying with family or friends?. After months of being shut in and avoiding close contact beyond immediate family, moving into someone else’s home means a host of potential exposures. Consider whether you or anyone else in the home is at high risk from COVID-19 because of age or a preexisting condition.“If so, that’s a reason to think twice before going to someone’s home,” said Dr.

Gina Solomon, a program director at the Oakland-based Public Health Institute.Consider, too, what precautions your friends or family have been taking. Sheltering with someone whose job brings them into frequent contact with other people may not be as safe as sheltering with people who largely have been staying home. Another question is how crowded the home is.

If you have your own room and, preferably, your own bathroom, that makes staying with friends a better option. If a separate bedroom is not available and smoky skies are not a problem, you might consider pitching a tent in their backyard.For those with an RV or tent, camping can present another good option — although, with hundreds of wildfires burning across California, it may be challenging to drive far enough away to avoid fire and smoke. If you do camp, try to find a site away from wooded areas.

And think twice before using group bathrooms.Is an evacuation center safe?. Many counties have implemented new precautions at emergency shelters to prevent the spread of the coronavirus. In Santa Cruz, for example, officials are scaling back the capacity in each shelter to allow for social distancing, providing tents for people to use as shielding inside and allowing camping in the parking lots.Still, staying in a shelter should probably not be your first choice.

In terms of COVID risk, deciding between a hotel and a friend’s house is “nipping at the edges,” said Dr. John Swartzberg, a clinical professor emeritus at the UC-Berkeley School of Public Health, while “being in a congregate setting is only better than being completely exposed to the elements.”If an evacuation shelter is your best immediate option, again, do not hesitate. €œYou have these standards you want to practice for yourselves,” Swartzberg said, “but when something worse comes along, it trumps how careful we can be with COVID because the need for shelter is greater.” You can lower your risk of infection by wearing a mask, washing hands frequently and sanitizing surfaces.Smith’s partner, Grant Whipple, walks with their children in Big Sur on March 7.

That was their last camping trip before the COVID-19 pandemic hit, Smith says. That area is now under threat from wildfire. (Amanda Smith)If you aren’t in a fire zone, should you invite friends and family to stay with you?.

Deciding whether to open your home to friends who are evacuating is an intensely personal decision and may depend on whether anyone in your family has a preexisting condition.“I guess it depends on how good a friend they are and how desperate they are,” said Swartzberg. It may also depend on how much space you have. If your guests can have their own bedroom and bathroom, it might be safer.If you do offer your home, experts advise against simply considering yourself a new pod with your guests.

Instead, take steps to lower your chances of infection.“It might not be pleasant, but wearing a mask anytime you’re not in your own bedroom is the safest way to go,” said Solomon. Stay outside as much as possible, she added, and consider eating meals outdoors or eating in shifts to avoid being maskless with those outside your family unit. Sanitize surfaces and wash hands frequently.

If air quality permits, keep the windows open to improve airflow.If you’re in a region with hazardous smoke conditions, should you leave?. If your area has dense smoke but no imminent fire risk, the thought of heading somewhere else may be appealing, especially if you have respiratory issues. But in most cases, Wilkes said, it would be safer not to leave your COVID bubble.

And given the expanse of California’s fires, anywhere you flee could end up having lousy air quality by the time you arrive.“The better part of rationality,” Wilkes said, “would be to stay at home, not exercise [outdoors], stay inside as much as you can, turn on the air conditioning.”California Healthline senior correspondent Anna Maria Barry-Jester contributed to this report. Jenny Gold. jgold@kff.org, @JennyAGold Related Topics California Public Health States COVID-19 Environmental Health Natural DisastersIn the 2014 elections, Republicans rode a wave of anti-Affordable Care Act sentiment to pick up nine Senate seats, the largest gain for either party since 1980.

Newly elected Republicans such as Cory Gardner in Colorado and Steve Daines in Montana had hammered their Democratic opponents over the health care law during the campaign and promised to repeal it.Six years later, those senators are up for reelection. Not only is the law still around, but it’s gaining in popularity. What was once a winning strategy has become a political liability.Public sentiment about the ACA, also known as Obamacare, has shifted considerably during the Trump administration after Republicans tried but failed to repeal it.

Now, in the midst of the COVID-19 pandemic and the ensuing economic crisis, which has led to the loss of jobs and health insurance for millions of people, health care again looks poised to be a key issue for voters this election. Don't Miss A Story Subscribe to KHN’s free Weekly Edition newsletter. With competitive races in Colorado, Montana, Arizona, North Carolina and Iowa pitting Republican incumbents who voted to repeal the ACA against Democratic challengers promising to protect it, attitudes surrounding the health law could help determine control of the Senate.

Republicans hold a slim three-vote majority in the Senate but are defending 23 seats in the Nov. 3 election. Only one Democratic Senate seat — in Alabama, where incumbent Doug Jones is up against former Auburn University football coach Tommy Tuberville — is considered in play for Republicans.“The fall election will significantly revolve around people’s belief about what [candidates] will do for their health coverage,” said Dr.

Daniel Derksen, a professor of public health at the University of Arizona.The Affordable Care Act has been a wedge issue since it was signed into law in 2010. Because it then took four years to enact, its opponents talked for years about how bad the not-yet-created marketplace for insurance would be, said Joe Hanel, spokesperson for the Colorado Health Institute, a nonpartisan nonprofit focused on health policy analysis. And they continued to attack the law as it took full effect in 2014.Gardner, for example, ran numerous campaign ads that year criticizing the ACA and, in particular, President Barack Obama’s assertion that “if you like your health care plan, you’ll be able to keep your health care plan.”But now, Hanel said, the ACA’s policies have become much more popular in Colorado as the costs of health exchange plans have dropped.

Thus, political messaging has changed, too.“This time it’s the opposite,” Hanel said. €œThe people bringing up the Affordable Care Act are the Democrats.”Despite Gardner’s multiple votes to repeal the ACA, he has largely avoided talking about the measure during the 2020 campaign. He even removed his pro-repeal position from his campaign website.Democratic attack ads in July blasted Gardner for repeatedly dodging questions in an interview with Colorado Public Radio about his stance on a lawsuit challenging the ACA.His opponent, Democrat John Hickenlooper, fully embraced the law when he was Colorado governor, using the measure to expand Medicaid eligibility to more low-income people and to create a state health insurance exchange.

Now, he’s campaigning on that record, with promises to expand health care access even further.Polling DataPolling conducted by KFF for the past 10 years shows a shift in public opinion has occurred nationwide. (KHN is an editorially independent program of KFF, the Kaiser Family Foundation.)“Since Trump won the election in 2016, we now have consistently found that a larger share of the public holds favorable views” of the health law, said Ashley Kirzinger, associate director of public opinion and survey research for the foundation. €œThis really solidified in 2017 after the failed repeal in the Senate.”The foundation’s polling found that, in July 2014, 55% of voters opposed the law, while 36% favored it.

By July 2020, that had flipped, with 51% favoring the law and 38% opposing it. A shift was seen across all political groups, though 74% of Republicans still viewed it unfavorably in the latest poll.Public support for individual provisions of the ACA — such as protections for people with preexisting conditions or allowing young adults to stay on their parents’ health plans until age 26 — have proved even more popular than the law as a whole. And the provision that consistently polled unfavorably — the mandate that those without insurance must pay a fine — was eliminated in 2017.“We’re 10 years along and the sky hasn’t caved in,” said Sabrina Corlette, a health policy professor at Georgetown University.Political MessagingFollowing the passage of the ACA, Democrats didn’t reference the law in their campaigns, said Erika Franklin Fowler, a government professor at Wesleyan University and the director of the Wesleyan Media Project, which tracks political advertising.“They ran on any other issue they could find,” Fowler said.Republicans, she said, kept promising to “repeal and replace” but weren’t able to do so.Then, in the 2018 election, Democrats seized on the shift in public opinion, touting the effects of the law and criticizing Republicans for their attempts to overturn it.“In the decade I have been tracking political advertising, there wasn’t a single-issue topic that was as prominent as health care was in 2018,” she said.As the global health crisis rages, health care concerns again dominate political ads in the 2020 races, Fowler said, although most ads haven’t explicitly focused on the ACA.

Many highlight Republicans’ support for the lawsuit challenging preexisting condition protections or specific provisions of the ACA that their votes would have overturned. Republicans say they, too, will protect people with preexisting conditions but otherwise have largely avoided talking about the ACA.“Cory Gardner has been running a lot on his environmental bills and conservation funding,” Fowler said. €œIt’s not difficult to figure out why he’s doing that.

It’s easier for him to tout that in a state like Colorado than it is to talk about health care.”Similar dynamics are playing out in other key Senate races. In Arizona, Republican Sen. Martha McSally was one of the more vocal advocates of repealing the ACA while she served in the House of Representatives.

She publicly acknowledged those votes may have hurt her 2018 Senate bid.“I did vote to repeal and replace Obamacare,” McSally said on conservative pundit Sean Hannity’s radio show during the 2018 campaign. €œI’m getting my ass kicked for it right now.”She indeed lost but was appointed to fill the seat of Sen. Jon Kyl after he resigned at the end of 2018.

Now McSally is in a tight race with Democratic challenger Mark Kelly, an astronaut and the husband of former Rep. Gabby Giffords.“Kelly doesn’t have a track record of voting one way or another, but certainly in his campaign this is one of his top speaking points. What he would do to expand coverage and reassure people that coverage won’t be taken away,” said Derksen, the University of Arizona professor.The ACA has proved a stumbling block for Republican Sens.

Thom Tillis of North Carolina and Joni Ernst of Iowa. In Maine, GOP Sen. Susan Collins cast a key vote that prevented the repeal of the law but cast other votes that weakened it.

She now also appears vulnerable — but more for her vote to confirm Brett Kavanaugh’s nomination to the Supreme Court and for not doing more to oppose President Donald Trump.In Montana, Daines, who voted to repeal the ACA, is trying to hold on to his seat against Democratic Gov. Steve Bullock, who used the law to expand the state’s Medicaid enrollment in 2015. At its peak, nearly 1 in 10 Montanans were covered through the expansion.As more Montanans now face the high cost of paying for health care on their own amid pandemic-related job losses, Montana State University political science professor David Parker said he expects Democrats to talk about Daines’ votes to repeal cost-saving provisions of the ACA.“People are losing jobs, and their jobs bring health care with them,” Parker said.

€œI don’t think it’s a good space for Daines to be right now.” Markian Hawryluk. MarkianH@kff.org, @MarkianHawryluk Related Topics Elections Health Care Costs Health Care Reform Insurance States Arizona Colorado Montana North Carolina Obamacare Plans.

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Before that date, people enrolled in a Medicaid managed care plan obtained all of their health care through the plan, but used their regular Medicaid buy biaxin online canada card to access any drug available on the state formulary on a "fee for service" basis without needing to utilize a restricted pharmacy network or comply with managed care plan rules. COMING IN April 2021 - In the NYS Budget enacted in April 2020, the pharmacy benefit was "carved out" of "mainstream" Medicaid managed care plans. That means that members of managed care plans will access their drugs outside their plan, unlike the rest of their medical care, which is accessed from in-network providers. How Prescription Drugs are Obtained through Managed Care plans No - Until April 2020 buy biaxin online canada HOW DO MANAGED CARE PLANS DEFINE THE PHARMACY BENEFIT FOR CONSUMERS?.

The Medicaid pharmacy benefit includes all FDA approved prescription drugs, as well as some over-the-counter drugs and medical supplies. Under Medicaid managed care. Plan formularies buy biaxin online canada will be comparable to but not the same as the Medicaid formulary. Managed care plans are required to have drug formularies that are “comparable” to the Medicaid fee for service formulary.

Plan formularies do not have to include all drugs covered listed on the fee for service formulary, but they must include generic or therapeutic equivalents of all Medicaid covered drugs. The Pharmacy buy biaxin online canada Benefit will vary by plan. Each plan will have its own formulary and drug coverage policies like prior authorization and step therapy. Pharmacy networks can also differ from plan to plan.

Prescriber Prevails applies buy biaxin online canada in certain drug classes. Prescriber prevails applys to medically necessary precription drugs in the following classes. atypical antipsychotics, anti-depressants, anti-retrovirals, anti-rejection, seizure, epilepsy, endocrine, hemotologic and immunologic therapeutics. Prescribers buy biaxin online canada will need to demonstrate reasonable profession judgment and supply plans witht requested information and/or clinical documentation.

Pharmacy Benefit Information Website -- http://mmcdruginformation.nysdoh.suny.edu/-- This website provides very helpful information on a plan by plan basis regarding pharmacy networks and drug formularies. The Department of Health plans to build capacity for interactive searches allowing for comparison of coverage across plans in the near future. Standardized Prior buy biaxin online canada Autorization (PA) Form -- The Department of Health worked with managed care plans, provider organizations and other state agencies to develop a standard prior authorization form for the pharmacy benefit in Medicaid managed care. The form will be posted on the Pharmacy Information Website in July of 2013.

Mail Order Drugs -- Medicaid managed care members can obtain mail order/specialty drugs at any retail network pharmacy, as long as that retail network pharmacy agrees to a price that is comparable to the mail order/specialty pharmacy price. CAN CONSUMERS SWITCH PLANS IN buy biaxin online canada ORDER TO GAIN ACCESS TO DRUGS?. Changing plans is often an effective strategy for consumers eligible for both Medicaid and Medicare (dual eligibles) who receive their pharmacy service through Medicare Part D, because dual eligibles are allowed to switch plans at any time. Medicaid consumers will have this option only in the limited circumstances during the first year of enrollment in managed care.

Medicaid managed care enrollees can only leave and join another plan within buy biaxin online canada the first 90 days of joining a health plan. After the 90 days has expired, enrollees are “locked in” to the plan for the rest of the year. Consumers can switch plans during the “lock in” period only for good cause. The pharmacy benefit changes buy biaxin online canada are not considered good cause.

After the first 12 months of enrollment, Medicaid managed care enrollees can switch plans at any time. STEPS CONSUMERS CAN TAKE WHEN A MANAGED CARE PLAM DENIES ACCESS TO A NECESSARY DRUG As a first step, consumers should try to work with their providers to satisfy plan requirements for prior authorization or step therapy or any other utilization control requirements. If the plan still denies access, consumers can pursue review processes specific to managed buy biaxin online canada care while at the same time pursuing a fair hearing. All plans are required to maintain an internal and external review process for complaints and appeals of service denials.

Some plans may develop special procedures for drug denials. Information on these procedures should be buy biaxin online canada provided in member handbooks. Beginning April 1, 2018, Medicaid managed care enrollees whose plan denies prior approval of a prescription drug, or discontinues a drug that had been approved, will receive an Initial Adverse Determination notice from the plan - See Model Denial IAD Notice and IAD Notice to Reduce, Suspend or Stop Services The enrollee must first request an internal Plan Appeal and wait for the Plan's decision. An adverse decision is called a 'FInal Adverse Determination" or FAD.

See model Denial FAD Notice and FAD Notice buy biaxin online canada to Reduce, Suspend or Stop Services. The enroll has the right to request a fair hearing to appeal an FAD. The enrollee may only request a fair hearing BEFORE receiving the FAD if the plan fails to send the FAD in the required time limit, which is 30 calendar days in standard appeals, and 72 hours in expedited appeals. The plan may extend the time to decide both standard and expedited appeals by up to 14 days if more information buy biaxin online canada is needed and it is in the enrollee's interest.

AID CONTINUING -- If an enrollee requests a Plan Appeal and then a fair hearing because access to a drug has been reduced or terminated, the enrollee has the right to aid continuing (continued access to the drug in question) while waiting for the Plan Appeal and then the fair hearing. The enrollee must request the Plan Appeal and then the Fair Hearing before the effective date of the IAD and FAD notices, which is a very short time - only 10 days including mailing time. See more about the changes in Managed Care appeals here buy biaxin online canada. Even though that article is focused on Managed Long Term Care, the new appeals requirements also apply to Mainstream Medicaid managed care.

Enrollees who are in the first 90 days of enrollment, or past the first 12 months of enrollment also have the option of switching plans to improve access to their medications. Consumers who experience problems with access to buy biaxin online canada prescription drugs should always file a complaint with the State Department of Health’s Managed Care Hotline, number listed below. ACCESSING MEDICAID'S PHARMACY BENEFIT IN FEE FOR SERVICE MEDICAID For those Medicaid recipients who are not yet in a Medicaid Managed Care program, and who do not have Medicare Part D, the Medicaid Pharmacy program covers most of their prescription drugs and select non-prescription drugs and medical supplies for Family Health Plus enrollees. Certain drugs/drug categories require the prescribers to obtain prior authorization.

These include brand name drugs that have a generic alternative under New York's mandatory generic drug program or prescribed drugs that are not on New York's preferred buy biaxin online canada drug list. The full Medicaid formulary can be searched on the eMedNY website. Even in fee for service Medicaid, prescribers must obtain prior authorization before prescribing non-preferred drugs unless otherwise indicated. Prior authorization is required buy biaxin online canada for original prescriptions, not refills.

A prior authorization is effective for the original dispensing and up to five refills of that prescription within the next six months. Click here for more information on NY's prior authorization process. The New York State buy biaxin online canada Board of Pharmacy publishes an annual list of the 150 most frequently prescribed drugs, in the most common quantities. The State Department of Health collects retail price information on these drugs from pharmacies that participate in the Medicaid program.

Click here to search for a specific drug from the most frequently prescribed drug list and this site can also provide you with the locations of pharmacies that provide this drug as well as their costs. Click here to view New York State Medicaid’s Pharmacy Provider buy biaxin online canada Manual. WHO YOU CAN CALL FOR HELP Community Health Advocates Hotline. 1-888-614-5400 NY State Department of Health's Managed Care Hotline.

1-800-206-8125 buy biaxin online canada (Mon. - Fri. 8:30 am - 4:30 pm) NY State Department of Insurance. 1-800-400-8882 NY State Attorney General's Health buy biaxin online canada Care Bureau.

1-800-771-7755Haitian individuals and immigrants from some other countries who have applied for Temporary Protected Status (TPS) may be eligible for public health insurance in New York State. 2019 updates - The Trump administration has taken steps to end TPS status. Two courts have temporarily enjoined the termination of buy biaxin online canada TPS, one in New York State in April 2019 and one in California in October 2018. The California case was argued in an appeals court on August 14, 2019, which the LA Times reported looked likely to uphold the federal action ending TPS.

See US Immigration Website on TPS - General TPS website with links to status in all countries, including HAITI. See also Pew buy biaxin online canada Research March 2019 article. Courts Block Changes in Public charge rule- See updates on the Public Charge rule here, blocked by federal court injunctions in October 2019. Read more about this change in public charge rules here.

What is Temporary Protected buy biaxin online canada Status?. TPS is a temporary immigration status granted to eligible individuals of a certain country designated by the Department of Homeland Security because serious temporary conditions in that country, such as armed conflict or environmental disaster, prevents people from that country to return safely. On January 21, 2010 the United States determined that individuals from Haiti warranted TPS because of the devastating earthquake that occurred there on January 12. TPS gives undocumented Haitian residents, who buy biaxin online canada were living in the U.S.

On January 12, 2010, protection from forcible deportation and allows them to work legally. It is important to note that the U.S. Grants TPS to individuals from other countries, as well, including individuals buy biaxin online canada from El Salvador, Honduras, Nicaragua, Somalia and Sudan. TPS and Public Health Insurance TPS applicants residing in New York are eligible for Medicaid and Family Health Plus as long as they also meet the income requirements for these programs.

In New York, applicants for TPS are considered PRUCOL immigrants (Permanently Residing Under Color of Law) for purposes of medical assistance eligibility and thus meet the immigration status requirements for Medicaid, Family Health Plus, and the Family Planning Benefit Program. Nearly all children in New York remain eligible for Child Health Plus including TPS applicants and buy biaxin online canada children who lack immigration status. For more information on immigrant eligibility for public health insurance in New York see 08 GIS MA/009 and the attached chart. Where to Apply What to BringIndividuals who have applied for TPS will need to bring several documents to prove their eligibility for public health insurance.

Individuals will need to buy biaxin online canada bring. 1) Proof of identity. 2) Proof of residence in New York. 3) Proof of income.

4) Proof of application for TPS. 5) Proof that U.S. Citizenship and Immigration Services (USCIS) has received the application for TPS. Free Communication Assistance All applicants for public health insurance, including Haitian Creole speakers, have a right to get help in a language they can understand.

All Medicaid offices and enrollers are required to offer free translation and interpretation services to anyone who cannot communicate effectively in English. A bilingual worker or an interpreter, whether in-person or over the telephone, must be provided in all interactions with the office. Important documents, such as Medicaid applications, should be translated either orally or in writing. Interpreter services must be offered free of charge, and applicants requiring interpreter services must not be made to wait unreasonably longer than English speaking applicants.

An applicant must never be asked to bring their own interpreter. Related Resources on TPS and Public Health Insurance o The New York Immigration Coalition (NYIC) has compiled a list of agencies, law firms, and law schools responding to the tragedy in Haiti and the designation of Haiti for Temporary Protected Status. A copy of the list is posted at the NYIC’s website at http://www.thenyic.org. o USCIS TPS website with links to status in all countries, including HAITI.

O For information on eligibility for public health insurance programs call The Legal Aid Society’s Benefits Hotline 1-888-663-6880 Tuesdays, Wednesdays and Thursdays. 9:30 am - 12:30 pm FOR IMMIGRATION HELP. CONTACT THE New York State New Americans Hotline for a referral to an organization to advise you. 212-419-3737 Monday-Friday, from 9:00 a.m.

To 8:00 p.m.Saturday-Sunday, from 9:00 a.m. To 5:00 p.m. Or call toll-free in New York State at 1-800-566-7636 Please see these fact sheets and web sites of national organizations for more information about the new PUBLIC CHARGE rules. Printable Fact Sheets for Distribution This article was co-authored by the New York Immigration Coalition, Empire Justice Center and the Health Law Unit of the Legal Aid Society.

Heads Up - Changes Coming April 2021 Once again, NYS is changing the way where to get biaxin pills people without Medicare access prescription drugs. Since October 2011, most people who do not have Medicare obtained their drugs throug their Medicaid managed care plan. At that time, this drug benefit was "carved into" the Medicaid managed care benefit package.

Before that date, people enrolled in a Medicaid managed care plan obtained all of their health care through where to get biaxin pills the plan, but used their regular Medicaid card to access any drug available on the state formulary on a "fee for service" basis without needing to utilize a restricted pharmacy network or comply with managed care plan rules. COMING IN April 2021 - In the NYS Budget enacted in April 2020, the pharmacy benefit was "carved out" of "mainstream" Medicaid managed care plans. That means that members of managed care plans will access their drugs outside their plan, unlike the rest of their medical care, which is accessed from in-network providers.

How Prescription Drugs are Obtained through Managed Care plans No - Until April 2020 where to get biaxin pills HOW DO MANAGED CARE PLANS DEFINE THE PHARMACY BENEFIT FOR CONSUMERS?. The Medicaid pharmacy benefit includes all FDA approved prescription drugs, as well as some over-the-counter drugs and medical supplies. Under Medicaid managed care.

Plan formularies will be comparable to but not the same as the where to get biaxin pills Medicaid formulary. Managed care plans are required to have drug formularies that are “comparable” to the Medicaid fee for service formulary. Plan formularies do not have to include all drugs covered listed on the fee for service formulary, but they must include generic or therapeutic equivalents of all Medicaid covered drugs.

The Pharmacy Benefit will where to get biaxin pills vary by plan. Each plan will have its own formulary and drug coverage policies like prior authorization and step therapy. Pharmacy networks can also differ from plan to plan.

Prescriber Prevails where to get biaxin pills applies in certain drug classes. Prescriber prevails applys to medically necessary precription drugs in the following classes. atypical antipsychotics, anti-depressants, anti-retrovirals, anti-rejection, seizure, epilepsy, endocrine, hemotologic and immunologic therapeutics.

Prescribers will need where to get biaxin pills to demonstrate reasonable profession judgment and supply plans witht requested information and/or clinical documentation. Pharmacy Benefit Information Website -- http://mmcdruginformation.nysdoh.suny.edu/-- This website provides very helpful information on a plan by plan basis regarding pharmacy networks and drug formularies. The Department of Health plans to build capacity for interactive searches allowing for comparison of coverage across plans in the near future.

Standardized Prior Autorization (PA) Form -- The Department of Health worked with managed care plans, provider organizations and other state agencies where to get biaxin pills to develop a standard prior authorization form for the pharmacy benefit in Medicaid managed care. The form will be posted on the Pharmacy Information Website in July of 2013. Mail Order Drugs -- Medicaid managed care members can obtain mail order/specialty drugs at any retail network pharmacy, as long as that retail network pharmacy agrees to a price that is comparable to the mail order/specialty pharmacy price.

CAN CONSUMERS SWITCH PLANS IN ORDER TO GAIN ACCESS where to get biaxin pills TO DRUGS?. Changing plans is often an effective strategy for consumers eligible for both Medicaid and Medicare (dual eligibles) who receive their pharmacy service through Medicare Part D, because dual eligibles are allowed to switch plans at any time. Medicaid consumers will have this option only in the limited circumstances during the first year of enrollment in managed care.

Medicaid managed care enrollees can only leave where to get biaxin pills and join another plan within the first 90 days of joining a health plan. After the 90 days has expired, enrollees are “locked in” to the plan for the rest of the year. Consumers can switch plans during the “lock in” period only for good cause.

The pharmacy benefit changes are not considered good where to get biaxin pills cause. After the first 12 months of enrollment, Medicaid managed care enrollees can switch plans at any time. STEPS CONSUMERS CAN TAKE WHEN A MANAGED CARE PLAM DENIES ACCESS TO A NECESSARY DRUG As a first step, consumers should try to work with their providers to satisfy plan requirements for prior authorization or step therapy or any other utilization control requirements.

If the plan still denies access, consumers can pursue review processes specific to managed care where to get biaxin pills while at the same time pursuing a fair hearing. All plans are required to maintain an internal and external review process for complaints and appeals of service denials. Some plans may develop special procedures for drug denials.

Information on these procedures where to get biaxin pills should be provided in member handbooks. Beginning April 1, 2018, Medicaid managed care enrollees whose plan denies prior approval of a prescription drug, or discontinues a drug that had been approved, will receive an Initial Adverse Determination notice from the plan - See Model Denial IAD Notice and IAD Notice to Reduce, Suspend or Stop Services The enrollee must first request an internal Plan Appeal and wait for the Plan's decision. An adverse decision is called a 'FInal Adverse Determination" or FAD.

See model Denial FAD Notice and FAD Notice to Reduce, Suspend or Stop where to get biaxin pills Services. The enroll has the right to request a fair hearing to appeal an FAD. The enrollee may only request a fair hearing BEFORE receiving the FAD if the plan fails to send the FAD in the required time limit, which is 30 calendar days in standard appeals, and 72 hours in expedited appeals.

The plan may where to get biaxin pills extend the time to decide both standard and expedited appeals by up to 14 days if more information is needed and it is in the enrollee's interest. AID CONTINUING -- If an enrollee requests a Plan Appeal and then a fair hearing because access to a drug has been reduced or terminated, the enrollee has the right to aid continuing (continued access to the drug in question) while waiting for the Plan Appeal and then the fair hearing. The enrollee must request the Plan Appeal and then the Fair Hearing before the effective date of the IAD and FAD notices, which is a very short time - only 10 days including mailing time.

See more about the changes in Managed Care where to get biaxin pills appeals here. Even though that article is focused on Managed Long Term Care, the new appeals requirements also apply to Mainstream Medicaid managed care. Enrollees who are in the first 90 days of enrollment, or past the first 12 months of enrollment also have the option of switching plans to improve access to their medications.

Consumers who experience problems with access to prescription drugs where to get biaxin pills should always file a complaint with the State Department of Health’s Managed Care Hotline, number listed below. ACCESSING MEDICAID'S PHARMACY BENEFIT IN FEE FOR SERVICE MEDICAID For those Medicaid recipients who are not yet in a Medicaid Managed Care program, and who do not have Medicare Part D, the Medicaid Pharmacy program covers most of their prescription drugs and select non-prescription drugs and medical supplies for Family Health Plus enrollees. Certain drugs/drug categories require the prescribers to obtain prior authorization.

These include brand name drugs that have a generic alternative under New York's mandatory generic drug program or prescribed drugs that are not where to get biaxin pills on New York's preferred drug list. The full Medicaid formulary can be searched on the eMedNY website. Even in fee for service Medicaid, prescribers must obtain prior authorization before prescribing non-preferred drugs unless otherwise indicated.

Prior authorization is required for original prescriptions, not refills where to get biaxin pills. A prior authorization is effective for the original dispensing and up to five refills of that prescription within the next six months. Click here for more information on NY's prior authorization process.

The New York State where to get biaxin pills Board of Pharmacy publishes an annual list of the 150 most frequently prescribed drugs, in the most common quantities. The State Department of Health collects retail price information on these drugs from pharmacies that participate in the Medicaid program. Click here to search for a specific drug from the most frequently prescribed drug list and this site can also provide you with the locations of pharmacies that provide this drug as well as their costs.

Click where to get biaxin pills here to view New York State Medicaid’s Pharmacy Provider Manual. WHO YOU CAN CALL FOR HELP Community Health Advocates Hotline. 1-888-614-5400 NY State Department of Health's Managed Care Hotline.

1-800-206-8125 where to get biaxin pills (Mon. - Fri. 8:30 am - 4:30 pm) NY State Department of Insurance.

1-800-400-8882 NY State Attorney where to get biaxin pills General's Health Care Bureau. 1-800-771-7755Haitian individuals and immigrants from some other countries who have applied for Temporary Protected Status (TPS) may be eligible for public health insurance in New York State. 2019 updates - The Trump administration has taken steps to end TPS status.

Two courts have where to get biaxin pills temporarily enjoined the termination of TPS, one in New York State in April 2019 and one in California in October 2018. The California case was argued in an appeals court on August 14, 2019, which the LA Times reported looked likely to uphold the federal action ending TPS. See US Immigration Website on TPS - General TPS website with links to status in all countries, including HAITI.

See also Pew where to get biaxin pills Research March 2019 article. Courts Block Changes in Public charge rule- See updates on the Public Charge rule here, blocked by federal court injunctions in October 2019. Read more about this change in public charge rules here.

What is where to get biaxin pills Temporary Protected Status?. TPS is a temporary immigration status granted to eligible individuals of a certain country designated by the Department of Homeland Security because serious temporary conditions in that country, such as armed conflict or environmental disaster, prevents people from that country to return safely. On January 21, 2010 the United States determined that individuals from Haiti warranted TPS because of the devastating earthquake that occurred there on January 12.

TPS gives undocumented Haitian residents, who were living in the U.S where to get biaxin pills. On January 12, 2010, protection from forcible deportation and allows them to work legally. It is important to note that the U.S.

Grants TPS to where to get biaxin pills individuals from other countries, as well, including individuals from El Salvador, Honduras, Nicaragua, Somalia and Sudan. TPS and Public Health Insurance TPS applicants residing in New York are eligible for Medicaid and Family Health Plus as long as they also meet the income requirements for these programs. In New York, applicants for TPS are considered PRUCOL immigrants (Permanently Residing Under Color of Law) for purposes of medical assistance eligibility and thus meet the immigration status requirements for Medicaid, Family Health Plus, and the Family Planning Benefit Program.

Nearly all children in New York remain eligible for Child Health Plus including TPS applicants and children where to get biaxin pills who lack immigration status. For more information on immigrant eligibility for public health insurance in New York see 08 GIS MA/009 and the attached chart. Where to Apply What to BringIndividuals who have applied for TPS will need to bring several documents to prove their eligibility for public health insurance.

Individuals will need to bring where to get biaxin pills. 1) Proof of identity. 2) Proof of residence in New York.

3) Proof of income where to get biaxin pills. 4) Proof of application for TPS. 5) Proof that U.S.

Citizenship and Immigration Services (USCIS) has received the application for where to get biaxin pills TPS. Free Communication Assistance All applicants for public health insurance, including Haitian Creole speakers, have a right to get help in a language they can understand. All Medicaid offices and enrollers are required to offer free translation and interpretation services to anyone who cannot communicate effectively in English.

A bilingual worker or an interpreter, whether in-person where to get biaxin pills or over the telephone, must be provided in all interactions with the office. Important documents, such as Medicaid applications, should be translated either orally or in writing. Interpreter services must be offered free of charge, and applicants requiring interpreter services must not be made to wait unreasonably longer than English speaking applicants.

An applicant must never be where to get biaxin pills asked to bring their own interpreter. Related Resources on TPS and Public Health Insurance o The New York Immigration Coalition (NYIC) has compiled a list of agencies, law firms, and law schools responding to the tragedy in Haiti and the designation of Haiti for Temporary Protected Status. A copy of the list is posted at the NYIC’s website at http://www.thenyic.org.

o USCIS TPS website with links to status in all countries, including HAITI. O For information on eligibility for public health insurance programs call The Legal Aid Society’s Benefits Hotline 1-888-663-6880 Tuesdays, Wednesdays and Thursdays. 9:30 am - 12:30 pm FOR IMMIGRATION HELP.

CONTACT THE New York State New Americans Hotline for a referral to an organization to advise you. 212-419-3737 Monday-Friday, from 9:00 a.m. To 8:00 p.m.Saturday-Sunday, from 9:00 a.m.


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