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Under the online kamagra prescription how to use kamagra 100mg oral jelly stewardship of the MidMichigan Health Foundation, this year, 23 area students will received scholarship awards from the Tolfree Scholarship, the Dr. George Schaiberger, online kamagra prescription Sr., Dr. Howard VanOosten and Dr. Lloyd Wiegerink Medical Scholarship, and the online kamagra prescription Paul A. Poling Memorial Scholarship.Awardees receiving the Dr.

George Schaiberger, online kamagra prescription Sr., Dr. Howard VanOosten and Dr. Lloyd Wiegerink Medical Staff Memorial online kamagra prescription Scholarship are. Allie Morand, Camden Groff, Nicholas Morse, Anna Erickson, Emily Terry, Brooke Chenette, Tyler Walters, Austin Raymond, Jordan Williams, Andrew Waack, Rylie Alward, online kamagra prescription Nicholas Thomas and Madison Nachtrieb. Those receiving the Tolfree Scholarship are.

Allie Morand, online kamagra prescription Nicholas Morse, Anna Erickson, Emily Terry and Andrew Waack. Lastly, awardees receiving the Paul A.Poling Memorial Scholarship are Emily Terry, Anna Erickson, Nicholas Morse, Allie Morand and Andrew Waack.“The intent of our generous donors in creating these scholarships is to provide our rural counties, particularly those served by MidMichigan Medical Center – West Branch, with future generations of excellent health care professionals,” said Nicole Potter, director, MidMichigan Health Foundation. €œWe congratulate online kamagra prescription all of this year’s recipients, as well as the parents and teachers who help them arrive at this major milestone in these students’ lives. We wish each one of them the best of success and hope to see them back again in a few years serving the people of their own hometown.”Examples of the health professions being pursued by these individuals include physical therapy, pre-medicine, nursing, health administration, sports medicine, neuroscience and human biology.Applications for the 2021-2022 school year will be accepted from Dec. 1, 2020, through March 1, online kamagra prescription 2021.

Those interested in reviewing the eligibility guidelines, including a scholarship application, may visit www.midmichigan.org/scholarships or call (989) 343-3694.Growers donate produce to staff and patients at MidMichigan Health Park – Bay.Residents in the Bay area have an additional opportunity to embrace healthy online kamagra prescription lifestyles near MidMichigan Health Park – Bay. Produce by the Park, a community garden that began late last year with a donation from MidMichigan Health Foundation, is flourishing, allowing patients, friends and neighbors to literally enjoy the fruits of their labor.Brenda Turner, director, MidMichigan Physicians Group, has a farming background and dreamt of a garden for her community for years. When the Health Park was built with ample property behind and support from the Foundation, that dream was brought to life.“We are so pleased to be able to support this project as it represents very well MidMichigan Health’s purpose of building healthy communities – together,” said Denise O’Keefe, executive director, MidMichigan Health Foundation.Other local organizations online kamagra prescription came on board to offer help. Tri-County Equipment of Saginaw donated dirt, and the Agriscience classes at John Glenn High School volunteered to get plots prepared for gardening. The Building Trades program online kamagra prescription at Bay Arenac ISD built and installed a tool shed.

Woodchips from Weiler Tree Service were donated to cut down on weeding, and Nature’s Own Landscaping and Irrigation hooked up a spigot in a central location so that all gardeners could access it easily.“During our first season, we had just a few plots of our two-acre garden assigned and less than ten participants,” said Ashleigh Palmer, practice manager, MidMichigan Health Park – Bay. €œThis year, we online kamagra prescription have all plots filled with more than 40 participants. We have couples, families and individuals who share online kamagra prescription their experience, produce and recipes with each other. It’s a lot of fun to see the friendships that have developed among our gardeners. The ground is fertile, so produce is thriving, and excess vegetables are being donated to patients of the facility.”Jarod Morse, 21, online kamagra prescription saw the garden information on Facebook and is excited to be participating.

€œMy whole family - brother, sister and her fiancé, mom, and Papa - are working on the garden together,” Morse stated. A few of online kamagra prescription the items they are growing are cabbage, cauliflower and a variety of peppers. €œThe best part,” he added, “is getting to share knowledge and smiles with other members of the garden.”Rows of produce growing in the community garden, Produce by the Park.MidMichigan Health staffers Shelby Kuch and Kellie Picard do much of the organizing, serving as “garden ambassadors.” They are excited to see it thriving.“It has been fun to see how each person has their own unique approach to gardening and harvesting,” said Kuch. €œThere are so many things being grown online kamagra prescription. Cabbage, corn, potatoes, broccoli, online kamagra prescription tomatoes, and beautiful sunflowers.

You wouldn’t believe the variety and the willingness to share what is harvested with other gardeners, members of the community and patients.”Picard is pleased to see elderly residents becoming involved. €œMany don’t have the room to plant where they live,” online kamagra prescription she explained. €œThis place gives them a chance to be outside, grow their own food, socialize with others and get some exercise. It’s inspiring to see their work pay off in so many ways.”Those who are online kamagra prescription interested in securing a plot must fill out an application and waiver, and agree to the terms set by Produce by the Park. All skill levels are welcome and there is no cost associated with securing a plot.“Our goal has evolved,” said Palmer.

€œWe hope to build upon this year’s successes to increase food security by providing access to online kamagra prescription fresh, healthy foods while reinforcing ties to the environment and encouraging community members to work together. I think we are well on our way.”Those interested in more information on the Produce by the Park or to request an application may visit www.midmichigan.org/bay/garden or contact Palmer at (989) 778-2888 or ashleigh.palmer@midmichigan.org..

Under the stewardship of the MidMichigan kamagra thailand price Health Foundation, this year, 23 area students will received scholarship awards from the Tolfree Scholarship, the Dr. George Schaiberger, kamagra thailand price Sr., Dr. Howard VanOosten and Dr. Lloyd Wiegerink Medical Scholarship, kamagra thailand price and the Paul A.

Poling Memorial Scholarship.Awardees receiving the Dr. George Schaiberger, Sr., Dr kamagra thailand price. Howard VanOosten and Dr. Lloyd Wiegerink Medical Staff Memorial Scholarship kamagra thailand price are.

Allie Morand, Camden Groff, Nicholas Morse, Anna Erickson, Emily Terry, Brooke Chenette, Tyler Walters, Austin Raymond, Jordan Williams, Andrew Waack, Rylie Alward, Nicholas Thomas and Madison Nachtrieb kamagra thailand price. Those receiving the Tolfree Scholarship are. Allie Morand, kamagra thailand price Nicholas Morse, Anna Erickson, Emily Terry and Andrew Waack. Lastly, awardees receiving the Paul A.Poling Memorial Scholarship are Emily Terry, Anna Erickson, Nicholas Morse, Allie Morand and Andrew Waack.“The intent of our generous donors in creating these scholarships is to provide our rural counties, particularly those served by MidMichigan Medical Center – West Branch, with future generations of excellent health care professionals,” said Nicole Potter, director, MidMichigan Health Foundation.

€œWe congratulate all of kamagra thailand price this year’s recipients, as well as the parents and teachers who help them arrive at this major milestone in these students’ lives. We wish each one of them the best of success and hope to see them back again in a few years serving the people of their own hometown.”Examples of the health professions being pursued by these individuals include physical therapy, pre-medicine, nursing, health administration, sports medicine, neuroscience and human biology.Applications for the 2021-2022 school year will be accepted from Dec. 1, 2020, through March 1, kamagra thailand price 2021. Those interested in reviewing the eligibility guidelines, including a scholarship application, may visit www.midmichigan.org/scholarships or call (989) 343-3694.Growers donate produce to staff and patients at MidMichigan Health Park – Bay.Residents in the Bay area have an additional opportunity to embrace healthy kamagra thailand price lifestyles near MidMichigan Health Park – Bay.

Produce by the Park, a community garden that began late last year with a donation from MidMichigan Health Foundation, is flourishing, allowing patients, friends and neighbors to literally enjoy the fruits of their labor.Brenda Turner, director, MidMichigan Physicians Group, has a farming background and dreamt of a garden for her community for years. When the Health Park was built with ample property behind and support from the Foundation, kamagra thailand price that dream was brought to life.“We are so pleased to be able to support this project as it represents very well MidMichigan Health’s purpose of building healthy communities – together,” said Denise O’Keefe, executive director, MidMichigan Health Foundation.Other local organizations came on board to offer help. Tri-County Equipment of Saginaw donated dirt, and the Agriscience classes at John Glenn High School volunteered to get plots prepared for gardening. The Building Trades program at Bay Arenac ISD built and installed a tool kamagra thailand price shed.

Woodchips from Weiler Tree Service were donated to cut down on weeding, and Nature’s Own Landscaping and Irrigation hooked up a spigot in a central location so that all gardeners could access it easily.“During our first season, we had just a few plots of our two-acre garden assigned and less than ten participants,” said Ashleigh Palmer, practice manager, MidMichigan Health Park – Bay. €œThis year, we have all plots filled with kamagra thailand price more than 40 participants. We have couples, families and individuals who share their experience, produce and recipes with kamagra thailand price each other. It’s a lot of fun to see the friendships that have developed among our gardeners.

The ground is fertile, so produce is thriving, and excess vegetables are being donated to patients of the facility.”Jarod Morse, 21, saw the garden information on Facebook kamagra thailand price and is excited to be participating. €œMy whole family - brother, sister and her fiancé, mom, and Papa - are working on the garden together,” Morse stated. A few of the items they are growing are cabbage, kamagra thailand price cauliflower and a variety of peppers. €œThe best part,” he added, “is getting to share knowledge and smiles with other members of the garden.”Rows of produce growing in the community garden, Produce by the Park.MidMichigan Health staffers Shelby Kuch and Kellie Picard do much of the organizing, serving as “garden ambassadors.” They are excited to see it thriving.“It has been fun to see how each person has their own unique approach to gardening and harvesting,” said Kuch.

€œThere are so many kamagra thailand price things being grown. Cabbage, corn, kamagra thailand price potatoes, broccoli, tomatoes, and beautiful sunflowers. You wouldn’t believe the variety and the willingness to share what is harvested with other gardeners, members of the community and patients.”Picard is pleased to see elderly residents becoming involved. €œMany don’t have the room to plant kamagra thailand price where they live,” she explained.

€œThis place gives them a chance to be outside, grow their own food, socialize with others and get some exercise. It’s inspiring to see their work pay off in so many ways.”Those who are interested in securing a plot must fill out an application and waiver, and agree to the terms set kamagra thailand price by Produce by the Park. All skill levels are welcome and there is no cost associated with securing a plot.“Our goal has evolved,” said Palmer. €œWe hope to build upon this year’s successes to increase food security by providing access to fresh, healthy foods while reinforcing ties to the environment and encouraging community members kamagra thailand price to work together.

I think we are well on our way.”Those interested in more information on the Produce by the Park or to request an application may visit www.midmichigan.org/bay/garden or contact Palmer at (989) 778-2888 or ashleigh.palmer@midmichigan.org..

What should I tell my health care provider before I take Kamagra?

They need to know if you have any of these conditions:

  • eye or vision problems, including a rare inherited eye disease called retinitis pigmentosa
  • heart disease, angina, high or low blood pressure, a history of heart attack, or other heart problems
  • kidney disease
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  • stroke
  • an unusual or allergic reaction to sildenafil, other medicines, foods, dyes, or preservatives

Does kamagra jelly work

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There’s a does kamagra jelly work reason for that, too. For the past few weeks I’ve seen Facebook posts daily from former nursing colleagues in metro Detroit, one of the hardest hit areas in the country, as they provide front-line care to patients with COVID-19. It makes me very proud to call these nurses my friends. As a former emergency does kamagra jelly work department nurse, I recall the feeling of satisfaction knowing that I’ve helped someone on the worst day of their life. One of the best parts of being a nurse is knowing you matter to the only person in health care that truly matters.

The patient. Several years ago I made does kamagra jelly work the difficult decision to no longer perform bedside nursing and become a nurse administrator. The biggest loss from my transition is the feeling that what I do matters to the patient. COVID-19 has forced a lot of us to rethink the role we play in health care and what the real priority should be. Things that does kamagra jelly work were top priorities three months ago have been rightfully cast aside to either care for patients in a pandemic or prepare for the unknown future of, “When is our turn?.

€ For me, COVID-19 has reignited the feeling that what I do matters as virtual care has become a powerful tool on the forefront of care during this crisis. It has also shown that many of the powerful rules and regulations that limit virtual care are not needed and should be discarded permanently. When I became the director of virtual care at does kamagra jelly work our organization in 2015 I knew nothing about telehealth. Sure, I had seen a stroke robot in some Emergency Departments, and I had some friends that told me their insurance company lets them FaceTime a doctor for free (spoiler alert. It’s not FaceTime).

I was tech-savvy from a consumer perspective and a does kamagra jelly work tech novice from an IT perspective. Nevertheless, my team and I spent the next few years learning as we built one of the higher volume virtual care networks in the state of Michigan. We discovered a lot of barriers that keep virtual care from actually making the lives of patients and providers better and we also became experts in working around those barriers. But, there were two obstacles does kamagra jelly work that we could not overcome. Government regulation and insurance provider willingness to cover virtual visits.

These two barriers effectively cripple most legitimate attempts to provide value-added direct-to-consumer virtual care, which I define as using virtual care technologies to provide care outside of our brick-and-mortar facilities, most commonly in the patient home. The need to social distance, cancel appointments, close provider offices, keep does kamagra jelly work from overloading emergency departments and urgent cares and shelter in place created instant demand for direct-to-consumer virtual care. In all honesty, I’ve always considered direct-to-consumer virtual care to be the flashy, must-have holiday gift of the year that organizations are convinced will be the way of the future. If a health system wants to provide on-demand access to patients for low-complexity acute conditions, they will easily find plenty of vendors that will sell them their app and their doctors and put the health system’s logo on it. What a health system will struggle with is to find is does kamagra jelly work enough patient demand to cover the high cost.

Remember my friends from earlier that told me about the app their insurance gave them?. Nearly all of them followed that up by telling me they’ve never actually used it. I am fortunate that I work for an organization that understands this and instead focuses on how can does kamagra jelly work we provide care that our patients actually want and need from the doctors they want to see. Ironically, this fiscal year we had a corporate top priority around direct-to-consumer virtual care. We wanted to expand what we thought were some successful pilots and perform 500 direct-to-consumer visits.

This year has been one of the hardest of my leadership career because, frankly, up until a month ago I was about does kamagra jelly work to fail on this top priority. With only four months left, we were only about halfway there. The biggest problem we ran into was that every great idea a physician brought to me was instantly dead in the water because practically no insurance company would pay for it. There are (prior to COVID-19) a plethora of rules around virtual care billing but the simplest way to summarize it is that most virtual care does kamagra jelly work will only be paid if it happens in a rural location and inside of a health care facility. It is extremely limited what will be paid for in the patient home and most of it is so specific that the average patient isn’t eligible to get any in-home virtual care.

Therefore, most good medical uses for direct-to-consumer care would be asking the patient to pay cash or the physician to forgo reimbursement for a visit that would be covered if it happened in office. Add to that the massive capital and operating expenses does kamagra jelly work it takes to build a virtual care network and you can see why these programs don’t exist. A month ago I was skeptical we’d have a robust direct-to-consumer program any time soon and then COVID-19 hit. When COVID-19 started to spread rapidly in the United States, regulations and reimbursement rules were being stripped daily. The first change that had major impact is when the Centers for Medicare and Medicaid does kamagra jelly work Services (CMS) announced that they would temporarily begin reimbursing for virtual visits conducted in the patient’s home for COVID-19 and non-COVID related visits.

We were already frantically designing a virtual program to handle the wave of COVID-19 screening visits that were overloading our emergency departments and urgent cares. We were having plenty of discussions around reimbursement for this clinic. Do we attempt to bill insurances knowing they will likely deny, do we do a cash clinic model or do we do this as a community benefit and eat does kamagra jelly work the cost?. The CMS waiver gave us hope that we would be compensated for diverting patients away from reimbursed visits to a virtual visit that is more convenient for the patient and aligns with the concept of social distancing. Realistically we don’t know if we will be paid for any of this.

We are holding all of the bills for at least 90 days while the industry sorts out the rules does kamagra jelly work. I was excited by the reimbursement announcement because I knew we had eliminated one of the biggest direct-to-consumer virtual care barriers. However, I was quickly brought back to reality when I was reminded that HIPAA (Health Insurance Portability and Accountability Act) still existed. I had this crazy idea that during a pandemic we should make it as easy as possible for people to receive virtual care and that the best way to do that was to meet the patient on the device they are most comfortable with and the application does kamagra jelly work (FaceTime, Facebook, Skype, etc.) that they use every day. The problem is nearly every app the consumer uses on a daily basis is banned by HIPAA because “it’s not secure.” I’m not quite sure what a hacker stands to gain by listening into to my doctor and me talk about how my kids yet again gave me strep throat but apparently the concern is great enough to stifle the entire industry.

Sure, not every health care discussion is as low-key as strep throat and a patient may want to protect certain topics from being discussed over a “non-secure” app but why not let the patient decide through informed consent?. Regulators could also abandon this all-or-nothing approach and lighten regulations surrounding specific does kamagra jelly work health conditions. The idea that regulations change based on medical situation is not new. For example, in my home state of Michigan, adolescents are essentially considered emancipated if it involves sexual health, mental health or substance abuse. Never mind that this same information is freely given over the phone by does kamagra jelly work every office around the country daily without issue, but I digress.

While my job is to innovate new pathways for care, our lawyer’s job is to protect the organization and he, along with IT security, rightfully shot down my consumer applications idea. A few days later I legitimately screamed out loud in joy when the Department of Health and Human Services announced that it would use discretion on enforcing HIPAA compliance rules and specifically allowed for use of consumer applications. The elimination of billing restrictions does kamagra jelly work and HIPAA regulations changed what is possible for health care organizations to offer virtually. Unfortunately both changes are listed as temporary and will likely be removed when the pandemic ends. Six days after the HIPAA changes were announced, we launched a centralized virtual clinic for any patient that wanted a direct-to-consumer video visit to be screened by a provider for COVID-19.

It allows patients to call in without a referral and most patients are on-screen within five minutes of clicking the does kamagra jelly work link we text them. They don’t have to download an app, create an account or even be an established patient of our health system. It saw over 900 patients in the first 12 days it was open. That is 900 real patients that received care from a physician or advanced practice provider without risking personal exposure and does kamagra jelly work without going to an already overwhelmed ED or urgent care. To date, 70 percent of the patients seen by the virtual clinic did not meet CDC testing criteria for COVID-19.

I don’t believe we could have reached even half of these patients had the consumer application restrictions been kept. A program like this almost certainly wouldn’t exist if not for the regulations being lifted and even if it did, it would have taken six to 12 months does kamagra jelly work to navigate barriers and implement in normal times. Sure, the urgency of a pandemic helps but the impact of provider, patients, regulators and payors being on the same page is what fueled this fire. During the virtual clinic’s first two weeks, my team turned its attention to getting over 300 providers across 60+ offices virtual so they could see their patients at home. Imagine being an immunocompromised cancer patient right now and being asked to does kamagra jelly work leave your home and be exposed to other people in order to see your oncologist.

Direct-to-consumer virtual care is the best way to safely care for these patients and without these temporary waivers it wouldn’t be covered by insurance even if you did navigate the clunky apps that are HIPAA compliant. Do we really think the immunocompromised cancer patient feels any more comfortable every normal flu season?. Is it any more appropriate does kamagra jelly work to ask them to risk exposure to the flu than it is to COVID-19?. And yet we deny them this access in normal times and it quite possibly will be stripped away from them when this crisis is over. Now 300 to 400 patients per day in our health system are seen virtually by their own primary care doctor or specialist for non-COVID related visits.

Not a single one of these would does kamagra jelly work have been reimbursed one month ago and I am highly skeptical I would have gotten approval to use the software that connects us to the patient. Lastly, recall that prior to COVID-19, our system had only found 250 total patients that direct-to-consumer care was value-added and wasn’t restricted by regulation or reimbursement. COVID-19 has been a wake-up call to the whole country and health care is no exception. It has put priorities in perspective and shined a light on what is truly does kamagra jelly work value-added. For direct-to-consumer virtual care it has shown us what is possible when we get out of our own way.

If a regulation has to be removed to allow for care during a crisis then we must question why it exists in the first place. HIPAA regulation cannot go back to its antiquated practices if we are truly going to shift does kamagra jelly work the focus to patient wellness. CMS and private payors must embrace value-added direct-to-consumer virtual care and allow patients the access they deserve. COVID-19 has forced this industry forward, we cannot allow it to regress and be forgotten when this is over. Tom Wood is the director of trauma and virtual care for MidMichigan Health, a non-profit health system headquartered in Midland, Michigan, does kamagra jelly work affiliated with Michigan Medicine, the health care division of the University of Michigan.

The views and opinions expressed in this commentary are his own.When dealing with all of the aspects of diabetes, it’s easy to let your feel fall to the bottom of the list. But daily care and evaluation is one of the best ways to prevent foot complications. It’s important does kamagra jelly work to identify your risk factors and take the proper steps in limiting your complications. Two of the biggest complications with diabetes are peripheral neuropathy and ulcer/amputation. Symptoms of peripheral neuropathy include numbness, tingling and/or burning in your feet and legs.

You can slow the progression of developing neuropathy by making it a point to does kamagra jelly work manage your blood sugars and keep them in the normal range. If you are experiencing these symptoms, it is important to establish and maintain a relationship with a podiatrist. Your podiatrist can make sure things are looking healthy and bring things to your attention to monitor and keep a close eye on. Open wounds does kamagra jelly work or ulcers can develop secondary to trauma, pressure, diabetes, neuropathy or poor circulation. If ulcerations do develop, it’s extremely important to identify the cause and address it.

Ulcers can get worse quickly, so it’s necessary to seek immediate medical treatment if you find yourself or a loved one dealing with this complication. Untreated ulcerations often lead to amputation and can be avoided if does kamagra jelly work proper medical attention is sought right away. There are important things to remember when dealing with diabetic foot care. It’s very important to inspect your feet daily, especially if you have peripheral neuropathy. You may have a cut or a sore on your feet that you can’t feel, so your body does kamagra jelly work doesn’t alarm you to check your feet.

Be gentle when bathing your feet. Moisturize your feet, but not between your toes. Do not treat calluses or corns on your does kamagra jelly work own. Wear clean, dry socks. Never walk barefoot, and consider socks and shoes made specifically for patients with diabetes.

Kristin Raleigh, D.P.M., is a podiatrist who sees patients at Foot &.

There’s a reason for that, can u buy kamagra over the counter too kamagra thailand price. For the past few weeks I’ve seen Facebook posts daily from former nursing colleagues in metro Detroit, one of the hardest hit areas in the country, as they provide front-line care to patients with COVID-19. It makes me very proud to call these nurses my friends.

As a former emergency department nurse, I recall the feeling of kamagra thailand price satisfaction knowing that I’ve helped someone on the worst day of their life. One of the best parts of being a nurse is knowing you matter to the only person in health care that truly matters. The patient.

Several years ago I made the difficult kamagra thailand price decision to no longer perform bedside nursing and become a nurse administrator. The biggest loss from my transition is the feeling that what I do matters to the patient. COVID-19 has forced a lot of us to rethink the role we play in health care and what the real priority should be.

Things that were top priorities three months ago have been rightfully cast kamagra thailand price aside to either care for patients in a pandemic or prepare for the unknown future of, “When is our turn?. € For me, COVID-19 has reignited the feeling that what I do matters as virtual care has become a powerful tool on the forefront of care during this crisis. It has also shown that many of the powerful rules and regulations that limit virtual care are not needed and should be discarded permanently.

When I became the director of virtual care at our organization in kamagra thailand price 2015 I knew nothing about telehealth. Sure, I had seen a stroke robot in some Emergency Departments, and I had some friends that told me their insurance company lets them FaceTime a doctor for free (spoiler alert. It’s not FaceTime).

I was tech-savvy from a consumer perspective and a kamagra thailand price tech novice from an IT perspective. Nevertheless, my team and I spent the next few years learning as we built one of the higher volume virtual care networks in the state of Michigan. We discovered a lot of barriers that keep virtual care from actually making the lives of patients and providers better and we also became experts in working around those barriers.

But, kamagra thailand price there were two obstacles that we could not overcome. Government regulation and insurance provider willingness to cover virtual visits. These two barriers effectively cripple most legitimate attempts to provide value-added direct-to-consumer virtual care, which I define as using virtual care technologies to provide care outside of our brick-and-mortar facilities, most commonly in the patient home.

The need to social distance, cancel appointments, close provider offices, keep from overloading emergency departments and urgent cares and shelter in place created instant kamagra thailand price demand for direct-to-consumer virtual care. In all honesty, I’ve always considered direct-to-consumer virtual care to be the flashy, must-have holiday gift of the year that organizations are convinced will be the way of the future. If a health system wants to provide on-demand access to patients for low-complexity acute conditions, they will easily find plenty of vendors that will sell them their app and their doctors and put the health system’s logo on it.

What a health system will struggle with is to find is enough patient demand to kamagra thailand price cover the high cost. Remember my friends from earlier that told me about the app their insurance gave them?. Nearly all of them followed that up by telling me they’ve never actually used it.

I am fortunate that I work for an organization that understands this and instead focuses on how can we provide care that our patients actually want and need kamagra thailand price from the doctors they want to see. Ironically, this fiscal year we had a corporate top priority around direct-to-consumer virtual care. We wanted to expand what we thought were some successful pilots and perform 500 direct-to-consumer visits.

This year has been one of the hardest of my leadership career because, frankly, up until a month ago I was about kamagra thailand price to fail on this top priority. With only four months left, we were only about halfway there. The biggest problem we ran into was that every great idea a physician brought to me was instantly dead in the water because practically no insurance company would pay for it.

There are (prior to COVID-19) a plethora of rules around virtual care billing but the simplest way to summarize it is that most virtual care will only be paid kamagra thailand price if it happens in a rural location and inside of a health care facility. It is extremely limited what will be paid for in the patient home and most of it is so specific that the average patient isn’t eligible to get any in-home virtual care. Therefore, most good medical uses for direct-to-consumer care would be asking the patient to pay cash or the physician to forgo reimbursement for a visit that would be covered if it happened in office.

Add to that the massive capital and operating expenses it takes to kamagra thailand price build a virtual care network and you can see why these programs don’t exist. A month ago I was skeptical we’d have a robust direct-to-consumer program any time soon and then COVID-19 hit. When COVID-19 started to spread rapidly in the United States, regulations and reimbursement rules were being stripped daily.

The first change that had major impact is when the Centers for Medicare and Medicaid Services (CMS) announced that they would temporarily begin reimbursing kamagra thailand price for virtual visits conducted in the patient’s home for COVID-19 and non-COVID related visits. We were already frantically designing a virtual program to handle the wave of COVID-19 screening visits that were overloading our emergency departments and urgent cares. We were having plenty of discussions around reimbursement for this clinic.

Do we kamagra thailand price attempt to bill insurances knowing they will likely deny, do we do a cash clinic model or do we do this as a community benefit and eat the cost?. The CMS waiver gave us hope that we would be compensated for diverting patients away from reimbursed visits to a virtual visit that is more convenient for the patient and aligns with the concept of social distancing. Realistically we don’t know if we will be paid for any of this.

We are holding all of the bills for at least 90 days while the industry sorts out the rules kamagra thailand price. I was excited by the reimbursement announcement because I knew we had eliminated one of the biggest direct-to-consumer virtual care barriers. However, I was quickly brought back to reality when I was reminded that HIPAA (Health Insurance Portability and Accountability Act) still existed.

I had this crazy kamagra thailand price idea that during a pandemic we should make it as easy as possible for people to receive virtual care and that the best way to do that was to meet the patient on the device they are most comfortable with and the application (FaceTime, Facebook, Skype, etc.) that they use every day. The problem is nearly every app the consumer uses on a daily basis is banned by HIPAA because “it’s not secure.” I’m not quite sure what a hacker stands to gain by listening into to my doctor and me talk about how my kids yet again gave me strep throat but apparently the concern is great enough to stifle the entire industry. Sure, not every health care discussion is as low-key as strep throat and a patient may want to protect certain topics from being discussed over a “non-secure” app but why not let the patient decide through informed consent?.

Regulators could also abandon this all-or-nothing approach and lighten regulations surrounding specific kamagra thailand price health conditions. The idea that regulations change based on medical situation is not new. For example, in my home state of Michigan, adolescents are essentially considered emancipated if it involves sexual health, mental health or substance abuse.

Never mind that this same information is freely given over the phone by every office around the country daily without issue, but kamagra thailand price I digress. While my job is to innovate new pathways for care, our lawyer’s job is to protect the organization and he, along with IT security, rightfully shot down my consumer applications idea. A few days later I legitimately screamed out loud in joy when the Department of Health and Human Services announced that it would use discretion on enforcing HIPAA compliance rules and specifically allowed for use of consumer applications.

The elimination of billing restrictions and HIPAA regulations changed what is possible for health care kamagra thailand price organizations to offer virtually. Unfortunately both changes are listed as temporary and will likely be removed when the pandemic ends. Six days after the HIPAA changes were announced, we launched a centralized virtual clinic for any patient that wanted a direct-to-consumer video visit to be screened by a provider for COVID-19.

It allows patients to call in without a referral and kamagra thailand price most patients are on-screen within five minutes of clicking the link we text them. They don’t have to download an app, create an account or even be an established patient of our health system. It saw over 900 patients in the first 12 days it was open.

That is 900 real patients that received care from a kamagra thailand price physician or advanced practice provider without risking personal exposure and without going to an already overwhelmed ED or urgent care. To date, 70 percent of the patients seen by the virtual clinic did not meet CDC testing criteria for COVID-19. I don’t believe we could have reached even half of these patients had the consumer application restrictions been kept.

A program like this almost certainly wouldn’t exist if not for the regulations being kamagra thailand price lifted and even if it did, it would have taken six to 12 months to navigate barriers and implement in normal times. Sure, the urgency of a pandemic helps but the impact of provider, patients, regulators and payors being on the same page is what fueled this fire. During the virtual clinic’s first two weeks, my team turned its attention to getting over 300 providers across 60+ offices virtual so they could see their patients at home.

Imagine being an immunocompromised cancer patient right now and being asked to leave your home and be exposed to other people in order to kamagra thailand price see your oncologist. Direct-to-consumer virtual care is the best way to safely care for these patients and without these temporary waivers it wouldn’t be covered by insurance even if you did navigate the clunky apps that are HIPAA compliant. Do we really think the immunocompromised cancer patient feels any more comfortable every normal flu season?.

Is it any more appropriate kamagra thailand price to ask them to risk exposure to the flu than it is to COVID-19?. And yet we deny them this access in normal times and it quite possibly will be stripped away from them when this crisis is over. Now 300 to 400 patients per day in our health system are seen virtually by their own primary care doctor or specialist for non-COVID related visits.

Not a single one of these would have been reimbursed one month ago and I am highly skeptical kamagra thailand price I would have gotten approval to use the software that connects us to the patient. Lastly, recall that prior to COVID-19, our system had only found 250 total patients that direct-to-consumer care was value-added and wasn’t restricted by regulation or reimbursement. COVID-19 has been a wake-up call to the whole country and health care is no exception.

It has put priorities in perspective and shined a light on kamagra thailand price what is truly value-added. For direct-to-consumer virtual care it has shown us what is possible when we get out of our own way. If a regulation has to be removed to allow for care during a crisis then we must question why it exists in the first place.

HIPAA regulation kamagra thailand price cannot go back to its antiquated practices if we are truly going to shift the focus to patient wellness. CMS and private payors must embrace value-added direct-to-consumer virtual care and allow patients the access they deserve. COVID-19 has forced this industry forward, we cannot allow it to regress and be forgotten when this is over.

Tom Wood is the director of trauma and virtual care for MidMichigan Health, kamagra thailand price a non-profit health system headquartered in Midland, Michigan, affiliated with Michigan Medicine, the health care division of the University of Michigan. The views and opinions expressed in this commentary are his own.When dealing with all of the aspects of diabetes, it’s easy to let your feel fall to the bottom of the list. But daily care and evaluation is one of the best ways to prevent foot complications.

It’s important to identify your risk factors and kamagra thailand price take the proper steps in limiting your complications. Two of the biggest complications with diabetes are peripheral neuropathy and ulcer/amputation. Symptoms of peripheral neuropathy include numbness, tingling and/or burning in your feet and legs.

You can slow the progression of developing neuropathy by making it a point to manage kamagra thailand price your blood sugars and keep them in the normal range. If you are experiencing these symptoms, it is important to establish and maintain a relationship with a podiatrist. Your podiatrist can make sure things are looking healthy and bring things to your attention to monitor and keep a close eye on.

Open wounds or kamagra thailand price ulcers can develop secondary to trauma, pressure, diabetes, neuropathy or poor circulation. If ulcerations do develop, it’s extremely important to identify the cause and address it. Ulcers can get worse quickly, so it’s necessary to seek immediate medical treatment if you find yourself or a loved one dealing with this complication.

Untreated ulcerations often lead to kamagra thailand price amputation and can be avoided if proper medical attention is sought right away. There are important things to remember when dealing with diabetic foot care. It’s very important to inspect your feet daily, especially if you have peripheral neuropathy.

You may have a cut or a sore on your feet that you can’t feel, so your body doesn’t alarm you to check your feet kamagra thailand price. Be gentle when bathing your feet. Moisturize your feet, but not between your toes.

Do not treat calluses kamagra thailand price or corns on your own. Wear clean, dry socks. Never walk barefoot, and consider socks and shoes made specifically for patients with diabetes.

Kristin Raleigh, D.P.M., is a podiatrist who sees patients at Foot &.

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Only individuals with proper training, equipment and experience kamagra gold vs kamagra should conduct recovery and cleanup activities. Protective measures after a weather disaster should include. Evaluating the work area for hazards. Assessing the kamagra gold vs kamagra stability of structures and walking surfaces.

Ensuring fall protection when working on elevated surfaces. Assuming all kamagra gold vs kamagra power lines are live. Keeping portable generators outside. Operating chainsaws, ladders and other equipment properly.

And Using personal protective equipment, such as gloves, hard hats kamagra gold vs kamagra and hearing, foot and eye protection. "A range of safety and health hazards exist following storms," said OSHA Dallas Regional Administrator Eric Harbin. "Implementing safe work practices, using appropriate kamagra gold vs kamagra personal protective equipment, and ensuring workers are properly trained can help minimize the risk of injuries and fatalities during storm cleanup operations." OSHA maintains a comprehensive webpage on hurricane preparedness and response with safety tips to help employers and workers, including an alert on keeping workers safe during flood cleanup. Individuals involved in response and recovery efforts may call OSHA's toll-free hotline at 800-321-OSHA (6742).

Under the Occupational Safety and Health Act of 1970, employers are responsible for providing safe and healthful workplaces for their employees. OSHA's role is to help ensure these conditions for American working kamagra gold vs kamagra men and women by setting and enforcing standards, and providing training, education and assistance. For more information, visit http://www.osha.gov. The mission of the Department of Labor is to foster, promote and develop the welfare of the kamagra gold vs kamagra wage earners, job seekers and retirees of the United States.

Improve working conditions. Advance opportunities for profitable employment. And assure kamagra gold vs kamagra work-related benefits and rights. # # # Media Contact.

Chauntra Rideaux, kamagra gold vs kamagra 972-850-4710, rideaux.chauntra.D@dol.gov Release Number. 20-1674-DAL U.S. Department of Labor news kamagra gold vs kamagra materials are accessible at http://www.dol.gov. The Department's Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print.

For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay).August 31, 2020U.S. Department of Labor Urges Workers and PublicTo Be Aware of kamagra gold vs kamagra Hazards After Hurricane Laura BATON ROUGE, LA – The U.S. Department of Labor's Occupational Safety and Health Administration (OSHA) urges response crews and residents in areas affected by Hurricane Laura to be aware of hazards created by flooding, power loss, structural damage, fallen trees and storm debris. Recovery efforts after the storm may involve hazards related to restoring electricity and communications, kamagra gold vs kamagra removing debris, repairing water damage, repairing or replacing roofs, and trimming trees.

Only individuals with proper training, equipment and experience should conduct recovery and cleanup activities. Protective measures after a weather disaster should include. Evaluating the work kamagra gold vs kamagra area for hazards. Assessing the stability of structures and walking surfaces.

Ensuring fall protection kamagra gold vs kamagra when working on elevated surfaces. Assuming all power lines are live. Keeping portable generators outside. Operating chainsaws, kamagra gold vs kamagra ladders and other equipment properly.

And Using personal protective equipment, such as gloves, hard hats and hearing, foot, and eye protection. "A range of safety and health hazards exist following storms," said OSHA Dallas Regional Administrator Eric Harbin kamagra gold vs kamagra. "Implementing safe work practices, using appropriate personal protective equipment, and ensuring workers are properly trained can help minimize the risk of injuries and fatalities during storm cleanup operations." OSHA maintains a comprehensive webpage on hurricane preparedness and response with safety tips to help employers and workers, including an alert on keeping workers safe during flood cleanup. Individuals involved in response and recovery efforts may call OSHA’s toll-free hotline at 800-321-OSHA (6742).

Under the kamagra gold vs kamagra Occupational Safety and Health Act of 1970, employers are responsible for providing safe and healthful workplaces for their employees. OSHA’s role is to help ensure these conditions for American working men and women by setting and enforcing standards, and providing training, education and assistance. For more information, visit https://www.osha.gov The mission of the Department of Labor is kamagra gold vs kamagra to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions.

Advance opportunities for profitable employment. And assure kamagra gold vs kamagra work-related benefits and rights. # # # Media Contact. Chauntra Rideaux, 972-850-4710, rideaux.chauntra.d@dol.gov kamagra gold vs kamagra Release Number.

20-1640-DAL U.S. Department of Labor news materials are accessible kamagra gold vs kamagra at http://www.dol.gov. The Department’s Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print. For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay).Hopefully, summer won’t end the way it began.

Memorial Day celebrations helped set off a wave of kamagra gold vs kamagra coronavirus infections across much of the South and West. Gatherings around the Fourth of July seemed to keep those hot spots aflame. And kamagra gold vs kamagra now Labor Day arrives as those regions are cooling off from COVID-19. Dr.

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, warned Wednesday that Americans should be cautious to avoid another surge in infection rates. But travelers are also weary of staying home — and tourist destinations are starved for cash.“Just getting away for an hour up the street and staying at a hotel is like a vacation, for real,” says Kimberly Michaels, who works for NASA in Huntsville, Alabama, and traveled to kamagra gold vs kamagra Nashville, Tennessee, with her boyfriend to celebrate his birthday last weekend.Lifting Restrictions for Summer’s EndIn time for the tail end of summer, many local governments are lifting restrictions to resuscitate tourism activity and rescue small businesses.Nashville, for instance, gave the green light to pedal taverns this week, allowing the human-powered bars-on-wheels to take to the streets again. €œThey’re not Nashville’s favorite group, frankly. But fairness requires kamagra gold vs kamagra this protocol change to take place,” Mayor John Cooper said, noting the city’s dramatic reduction in new cases.

This week, the city also raised the attendance cap on weddings, funerals and other ceremonies. Email Sign-Up Subscribe to California Healthline’s free Daily Edition. Elsewhere, Virginia Beach tried to get some leniency for its struggling restaurants over kamagra gold vs kamagra the holiday weekend. But Virginia Gov.

Ralph Northam rejected pleas from the mayor, at the encouragement of Fauci kamagra gold vs kamagra. The country’s top health official has encouraged governors to keep restrictions in place to avoid another holiday-related surge.“Sometimes, as we start to lift restrictions, the impression that people get is ‘Oh, that must mean it’s safe,’” says epidemiologist Melissa McPheeters of Vanderbilt University. €œWe want to make sure we don’t give that impression, because this disease has not gone anywhere.”Some communities have gone the other direction and reimposed restrictions, especially for the three-day weekend. Santa Barbara, California, has banned sunbathing to avoid another surge in cases.Schooling Screws Up COVID CirclesOn a Sunday afternoon, out-of-towners walk kamagra gold vs kamagra the tourist district in Nashville, where many attractions have reopened — with restrictions.

All dance floors are closed and restaurants and bars must close by 10:30 p.m. (Blake Farmer/WLPN)There’s also a new kamagra gold vs kamagra X-factor with summer’s last holiday weekend. In many states, schools have resumed in-person classes. So families and friends meeting up are now more likely to expose each other to the virus, even if they tried to keep a tight circle over the summer.“If those bubbles now have kids that went back to school and are interacting with others or they’ve gone back to sports and the bubble has since expanded, that ability to be safely together in a gathering is probably less likely,” says epidemiologist Bertha Hidalgo of the University of Alabama-Birmingham.And yet, getting together safely — preferably outdoors — is still worth a try, Hidalgo says.

She says people’s mental health needs a boost to get through the next few months.“If you can do the safe things now before winter hits and that cold weather hits, then you’ll be more resilient to get through any bad kamagra gold vs kamagra times that may come,” she says.In drivable destinations like Nashville that have welcomed visitors throughout the pandemic, tourism has not bounced back entirely. But on some weekend nights, the neon-soaked tourist district can draw a crowd.This week, Vaj Vemulapalli and his girlfriend, of Dallas, turned back to their hotel after feeling uncomfortable with how tightly people were packed together.“We crave the social interaction, the going out to bars and everything,” he says. €œBut at the end of the day, our general stance is it’s not worth getting kamagra gold vs kamagra [COVID-19] just to get a drink.”Kimberly Michaels and Marcus Robinson of Huntsville, Alabama, drove to Nashville, Tennessee, for a night to celebrate Robinson’s birthday. The streets were crowded when they arrived and then quickly cleared as establishments closed at 10:30 p.m.

(Blake Farmer/WLPN)(Blake Farmer/WLPN)Those crowds have limits, though, as Kimberly Michaels kamagra gold vs kamagra and birthday boy Marcus Robinson discovered. They arrived in Nashville fashionably late, masked up and ready to responsibly party. But after they checked into their hotel, they discovered that everything has to shut down by 10:30.“It’s crazy. It was kamagra gold vs kamagra like the twilight zone,” Robinson says.

€œWe went in [to the hotel], the streets were full. Got dressed, come downstairs kamagra gold vs kamagra. Like, where did everybody go?. Like, did something happen?.

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So you can’t live your life in fear, either.”Ourso has a trip to the beach planned for later in the month.This story is part of a partnership that includes Nashville Public Radio, NPR and Kaiser Health News, an editorially independent program of the Kaiser Family Foundation. Related Topics Insight Public Health States COVID-19 TennesseeAbout Insight kamagra gold vs kamagra Insight provides an in-depth look at health care issues in and affecting California.Have a story suggestion?. Let us know. Although the coronavirus pandemic shut down many organizations and businesses across the nation, KHN kamagra gold vs kamagra has never been busier ― and health coverage has never been more vital.

We’ve revamped our Behind the Byline YouTube series and brought it to Instagram TV.Journalists and producers from across KHN’s newsrooms take you behind the scenes in these bite-size videos to show the ways they are following the story, connecting with sources and sorting through facts — all while staying safe.Heidi de Marco – “At Least I Got the Shot” Photojournalist Heidi de Marco’s stunning images transport viewers to two California hospitals near the U.S.-Mexico border where the influx of patients with COVID-19 overwhelmed local intensive care units in late May. To capture these scenes at El Centro Regional Medical Center in Imperial County and Scripps Mercy Hospital Chula Vista in San Diego County, de Marco donned personal protective equipment and followed each facility’s safety guidelines. Still, she kamagra gold vs kamagra acknowledges, the work increased her risk of exposure to the coronavirus. She also risked bringing the virus home to her family.

For her it was worth the risk, in order to give readers a window on health care in the midst of a pandemic — and to share her work with the world. Heidi de Marco. heidid@kff.org, @Heidi_deMarco Related Topics Insight Multimedia Public Health States Behind The Byline COVID-19.

September 2, https://www.cityreal.lv/kamagra-tablets/ 2020U.S kamagra thailand price. Department of Labor Urges Workers and PublicTo Be Aware of Hazards After Hurricane Laura HOUSTON, TX – The U.S. Department of Labor's Occupational Safety and Health Administration (OSHA) urges response crews and residents in areas kamagra thailand price affected by Hurricane Laura to be aware of hazards created by flooding, power loss, structural damage, fallen trees and storm debris.

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Evaluating the work area for hazards. Assessing the stability of structures and kamagra thailand price walking surfaces. Ensuring fall protection when working on elevated surfaces.

Assuming all power kamagra thailand price lines are live. Keeping portable generators outside. Operating chainsaws, ladders and other equipment properly.

And Using personal protective equipment, such as gloves, hard kamagra thailand price hats and hearing, foot and eye protection. "A range of safety and health hazards exist following storms," said OSHA Dallas Regional Administrator Eric Harbin. "Implementing safe work practices, using appropriate personal protective equipment, and ensuring workers are properly trained can help minimize kamagra thailand price the risk of injuries and fatalities during storm cleanup operations." OSHA maintains a comprehensive webpage on hurricane preparedness and response with safety tips to help employers and workers, including an alert on keeping workers safe during flood cleanup.

Individuals involved in response and recovery efforts may call OSHA's toll-free hotline at 800-321-OSHA (6742). Under the Occupational Safety and Health Act of 1970, employers are responsible for providing safe and healthful workplaces for their employees. OSHA's role is to help ensure these conditions for American working men kamagra thailand price and women by setting and enforcing standards, and providing training, education and assistance.

For more information, visit http://www.osha.gov. The mission of the Department of Labor is to foster, kamagra thailand price promote and develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions.

Advance opportunities for profitable employment. And assure work-related kamagra thailand price benefits and rights. # # # Media Contact.

Chauntra Rideaux, 972-850-4710, kamagra thailand price rideaux.chauntra.D@dol.gov Release Number. 20-1674-DAL U.S. Department of Labor news materials are accessible at kamagra thailand price http://www.dol.gov.

The Department's Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print. For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay).August 31, 2020U.S. Department of Labor Urges Workers kamagra thailand price and PublicTo Be Aware of Hazards After Hurricane Laura BATON ROUGE, LA – The U.S.

Department of Labor's Occupational Safety and Health Administration (OSHA) urges response crews and residents in areas affected by Hurricane Laura to be aware of hazards created by flooding, power loss, structural damage, fallen trees and storm debris. Recovery efforts kamagra thailand price after the storm may involve hazards related to restoring electricity and communications, removing debris, repairing water damage, repairing or replacing roofs, and trimming trees. Only individuals with proper training, equipment and experience should conduct recovery and cleanup activities.

Protective measures after a weather disaster should include. Evaluating the work area for kamagra thailand price hazards. Assessing the stability of structures and walking surfaces.

Ensuring fall protection when working kamagra thailand price on elevated surfaces. Assuming all power lines are live. Keeping portable generators outside.

Operating chainsaws, kamagra thailand price ladders and other equipment properly. And Using personal protective equipment, such as gloves, hard hats and hearing, foot, and eye protection. "A range of safety kamagra thailand price and health hazards exist following storms," said OSHA Dallas Regional Administrator Eric Harbin.

"Implementing safe work practices, using appropriate personal protective equipment, and ensuring workers are properly trained can help minimize the risk of injuries and fatalities during storm cleanup operations." OSHA maintains a comprehensive webpage on hurricane preparedness and response with safety tips to help employers and workers, including an alert on keeping workers safe during flood cleanup. Individuals involved in response and recovery efforts may call OSHA’s toll-free hotline at 800-321-OSHA (6742). Under the Occupational Safety and Health Act of 1970, employers kamagra thailand price are responsible for providing safe and healthful workplaces for their employees.

OSHA’s role is to help ensure these conditions for American working men and women by setting and enforcing standards, and providing training, education and assistance. For more information, visit https://www.osha.gov The mission of the Department of Labor is to foster, promote and kamagra thailand price develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions.

Advance opportunities for profitable employment. And assure kamagra thailand price work-related benefits and rights. # # # Media Contact.

Chauntra Rideaux, kamagra thailand price 972-850-4710, rideaux.chauntra.d@dol.gov Release Number Discover More. 20-1640-DAL U.S. Department of Labor kamagra thailand price news materials are accessible at http://www.dol.gov.

The Department’s Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print. For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay).Hopefully, summer won’t end the way it began. Memorial Day celebrations helped set off a wave of coronavirus infections kamagra thailand price across much of the South and West.

Gatherings around the Fourth of July seemed to keep those hot spots aflame. And now Labor Day kamagra thailand price arrives as those regions are cooling off from COVID-19. Dr.

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, warned Wednesday that Americans should be cautious to avoid another surge in infection rates. But travelers are also weary of staying home — and kamagra thailand price tourist destinations are starved for cash.“Just getting away for an hour up the street and staying at a hotel is like a vacation, for real,” says Kimberly Michaels, who works for NASA in Huntsville, Alabama, and traveled to Nashville, Tennessee, with her boyfriend to celebrate his birthday last weekend.Lifting Restrictions for Summer’s EndIn time for the tail end of summer, many local governments are lifting restrictions to resuscitate tourism activity and rescue small businesses.Nashville, for instance, gave the green light to pedal taverns this week, allowing the human-powered bars-on-wheels to take to the streets again. €œThey’re not Nashville’s favorite group, frankly.

But fairness requires this protocol change to take place,” Mayor John kamagra thailand price Cooper said, noting the city’s dramatic reduction in new cases. This week, the city also raised the attendance cap on weddings, funerals and other ceremonies. Email Sign-Up Subscribe to California Healthline’s free Daily Edition.

Elsewhere, Virginia Beach tried to get some leniency kamagra thailand price for its struggling restaurants over the holiday weekend. But Virginia Gov. Ralph Northam kamagra thailand price rejected pleas from the mayor, at the encouragement of Fauci.

The country’s top health official has encouraged governors to keep restrictions in place to avoid another holiday-related surge.“Sometimes, as we start to lift restrictions, the impression that people get is ‘Oh, that must mean it’s safe,’” says epidemiologist Melissa McPheeters of Vanderbilt University. €œWe want to make sure we don’t give that impression, because this disease has not gone anywhere.”Some communities have gone the other direction and reimposed restrictions, especially for the three-day weekend. Santa Barbara, California, has banned sunbathing to avoid another surge in cases.Schooling Screws Up COVID CirclesOn a Sunday afternoon, out-of-towners walk kamagra thailand price the tourist district in Nashville, where many attractions have reopened — with restrictions.

All dance floors are closed and restaurants and bars must close by 10:30 p.m. (Blake Farmer/WLPN)There’s also kamagra thailand price a new X-factor with summer’s last holiday weekend. In many states, schools have resumed in-person classes.

So families and friends meeting up are now more likely to expose each other to the virus, even if they tried to keep a tight circle over the summer.“If those bubbles now have kids that went back to school and are interacting with others or they’ve gone back to sports and the bubble has since expanded, that ability to be safely together in a gathering is probably less likely,” says epidemiologist Bertha Hidalgo of the University of Alabama-Birmingham.And yet, getting together safely — preferably outdoors — is still worth a try, Hidalgo says. She says people’s mental health needs a boost to get through the next few months.“If you can do the safe things now before winter hits and that cold weather hits, then you’ll be more resilient to get through kamagra thailand price any bad times that may come,” she says.In drivable destinations like Nashville that have welcomed visitors throughout the pandemic, tourism has not bounced back entirely. But on some weekend nights, the neon-soaked tourist district can draw a crowd.This week, Vaj Vemulapalli and his girlfriend, of Dallas, turned back to their hotel after feeling uncomfortable with how tightly people were packed together.“We crave the social interaction, the going out to bars and everything,” he says.

€œBut at the end of the day, our general stance is it’s not worth getting [COVID-19] just to get a drink.”Kimberly Michaels and Marcus Robinson of Huntsville, Alabama, drove to kamagra thailand price Nashville, Tennessee, for a night to celebrate Robinson’s birthday. The streets were crowded when they arrived and then quickly cleared as establishments closed at 10:30 p.m. (Blake Farmer/WLPN)(Blake Farmer/WLPN)Those crowds have limits, though, kamagra thailand price as Kimberly Michaels and birthday boy Marcus Robinson discovered.

They arrived in Nashville fashionably late, masked up and ready to responsibly party. But after they checked into their hotel, they discovered that everything has to shut down by 10:30.“It’s crazy. It was kamagra thailand price like the twilight zone,” Robinson says.

€œWe went in [to the hotel], the streets were full. Got dressed, kamagra thailand price come downstairs. Like, where did everybody go?.

Like, did something happen?. But we didn’t know, because we’re not from here.”Still, as time goes by, some travelers are willing to take more risks to get back to activities that feel normal.Suzette Ourso kamagra thailand price lives outside New Orleans and flew to Nashville for her first out-of-town trip since the pandemic hit. She says she’s cautious, wearing her mask whenever near anyone else.“I keep hand sanitizer in my purse now.

That’s something I’ve never really done before,” kamagra thailand price she says. €œBut you can die tomorrow riding in your vehicle. So you can’t live your life in fear, either.”Ourso has a trip to the beach planned for later in the month.This story is part of a partnership that includes Nashville Public Radio, NPR and Kaiser Health News, an editorially independent program of the Kaiser Family Foundation.

Related Topics Insight Public Health States COVID-19 TennesseeAbout Insight Insight provides kamagra thailand price an in-depth look at health care issues in and affecting California.Have a story suggestion?. Let us know. Although the coronavirus pandemic shut down many organizations and businesses across the nation, KHN has never been busier ― and health coverage has never been more vital kamagra thailand price.

We’ve revamped our Behind the Byline YouTube series and brought it to Instagram TV.Journalists and producers from across KHN’s newsrooms take you behind the scenes in these bite-size videos to show the ways they are following the story, connecting with sources and sorting through facts — all while staying safe.Heidi de Marco – “At Least I Got the Shot” Photojournalist Heidi de Marco’s stunning images transport viewers to two California hospitals near the U.S.-Mexico border where the influx of patients with COVID-19 overwhelmed local intensive care units in late May. To capture these scenes at El Centro Regional Medical Center in Imperial County and Scripps Mercy Hospital Chula Vista in San Diego County, de Marco donned personal protective equipment and followed each facility’s safety guidelines. Still, she kamagra thailand price acknowledges, the work increased her risk of exposure to the coronavirus.

She also risked bringing the virus home to her family. For her it was worth the risk, in order to give readers a window on health care in the midst of a pandemic — and to share her work with kamagra thailand price the world. Heidi de Marco.

heidid@kff.org, @Heidi_deMarco Related Topics Insight Multimedia Public Health States Behind The Byline COVID-19.

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("Health Catalyst", https://www.cityreal.lv/kamagra-fast-next-day-delivery/ Nasdaq where can you get kamagra. HCAT), a leading provider of data and analytics technology and services to healthcare organizations, today announced that Patrick Nelli, Chief Financial Officer, and Adam Brown, Senior Vice President, Investor Relations, will participate in the 2020 Cantor Global Virtual Healthcare Conference on Tuesday, September 15, 2020, which will include a fireside chat presentation at 1:20 p.m. ET. A live audio webcast and replay of this presentation will be available at https://ir.healthcatalyst.com/investor-relations.About Health CatalystHealth Catalyst is a leading provider of data and analytics technology and services to healthcare organizations committed to being the catalyst for massive, measurable, data-informed where can you get kamagra healthcare improvement. Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial, and operational improvements.

Health Catalyst envisions a future in which all healthcare decisions are data informed.Health Catalyst Investor Relations Contact:Adam BrownSenior Vice President, Investor Relations+1 (855)-309-6800ir@healthcatalyst.comHealth Catalyst Media Contact:Kristen BerryVice President, Public Relations+1 (617) 234-4123+1 (774) 573-0455 (m)kberry@we-worldwide.com Source. Health Catalyst, Inc.SALT where can you get kamagra LAKE CITY, Sept. 8, 2020 /PRNewswire/ -- Health Catalyst, Inc. ("Health Catalyst," Nasdaq. HCAT), a leading provider of data and analytics technology and services to healthcare organizations, where can you get kamagra today announced that it has completed its seventh annual and first ever virtual Healthcare Analytics Summit (HAS), with record registration of more than 3,500 attendees.

Keynotes included Dr. Amy Abernethy, Principal Deputy Commissioner and Acting CIO of the U.S. Food and Drug Administration, Michael Dowling, CEO of where can you get kamagra Northwell Health, Vice Admiral Raquel Bono, MD, and many others. Other business updates include:The Vitalware, LLC ("VitalWare"), transaction has closed, and integration is underway of the Yakima, Washington-based provider of revenue workflow optimization and analytics SaaS technology solutions for health organizations. This is another example of Health Catalyst's ability to scale software on top of its cloud-based Data Operating System (DOS™).

DOS will further enhance the analytics insights made where can you get kamagra available by Vitalware's technology by combining charge and revenue data with claims, cost, and quality data. Vitalware's flagship offering is a Best in KLAS chargemaster management solution that delivers results for the complex regulatory and compliance functions needed by all healthcare provider systems. "As announced on August 11, 2020, we entered into an acquisition agreement to acquire Vitalware and expected to close the acquisition in Q3 or Q4 of 2020. We are pleased to announce that we closed where can you get kamagra the acquisition on September 1, 2020. We are thrilled to formalize the combination of our solutions for the benefit of our customers and the industry," said CEO Dan Burton.

On its upcoming Q3 2020 earnings call, Health Catalyst will share the impact of Vitalware on its Q3 2020 financial performance, which will not be significant given the timing of the acquisition, as well as update its full year 2020 guidance to include the impact of Vitalware. Health Catalyst Co-Founder where can you get kamagra Steve Barlow has returned from his three-year full-time volunteer mission for the Church of Jesus Christ of Latter-Day Saints, having served as Mission President of the Ecuador Quito Mission. He has rejoined Health Catalyst's companywide Leadership Team as a Senior Vice President, responsible for some of the company's largest customer relationships. Dan Burton said, "We couldn't be more excited about Steve's return to Health Catalyst. His energy, dedication and commitment where can you get kamagra to transforming healthcare launched our journey and will continue to make us better and stronger.

Steve is leading and overseeing all aspects of our partnerships with some of our largest and longest-standing customers. Steve's extraordinary experience and capability enable him to be a critical partner and leader in enabling these customers' continued improvement and success." "My experience over the past three years in Ecuador reinforced for me how fortunate I am to be in a country with high-quality healthcare," said Barlow. "It has been invigorating to return to Health Catalyst and witness the incredible growth and where can you get kamagra expansion that has occurred over the past few years. We are better positioned than ever before to achieve our mission of being the catalyst for massive, measurable, data-informed healthcare improvement. I am grateful to be reunited with our longstanding team members and customers, and I'm thrilled to get to know and work alongside our new customers and teammates in this critical work." Effective October 1, 2020, Chief Technology Officer Dale Sanders will be transitioning to a Senior Advisor role with Health Catalyst, and the company is pleased to announce that one of Dale's longtime protégés and colleagues, Bryan Hinton, will serve as Health Catalyst's next Chief Technology Officer.

Hinton joined Health Catalyst in 2012 and currently serves as the Senior Vice President and where can you get kamagra General Manager of the DOS Platform Business. He will continue to lead this business in addition to assuming the responsibilities of CTO. He has been instrumental in the development and integration of DOS and has been working directly with Dale and other technology leaders at Health Catalyst for many years. His experience prior to joining Health Catalyst includes four years with the .NET Development Center of Excellence at The Church where can you get kamagra of Jesus Christ of Latter-Day Saints, where he established the architectural guidance of all .NET projects. Previously, at Intel, he was responsible for the development and implementation of Intel's factory data warehouse product installed at Intel global factories.

Hinton graduated from Brigham Young University with a BS in Computer Science. "Dale where can you get kamagra has been central to Health Catalyst's growth and success and we are grateful to him for his many years of service to our company and to the broader healthcare industry," said Dan Burton, CEO of Health Catalyst. "Thanks to Dale's vision, passion, innovative thinking and broad-based industry experience and perspective, Health Catalyst has grown from a handful of clients to a large number of organizations relying on us as their digital transformation partner, helping the healthcare ecosystem to constantly learn and improve. Dale's technology leadership was critical to the company's overall maturation, and I am convinced that we could not have grown and scaled as we have without Dale's foundational leadership and contributions. We are grateful to continue our association with Dale in the months and years ahead in his next role as a Senior Advisor to the company." Burton added, "We are thrilled to see Bryan Hinton take on this added role after having demonstrated his technology leadership prowess during the course of his tenure at Health Catalyst and having been mentored by where can you get kamagra Dale for many years.

Bryan is well-prepared and ready for this additional responsibility, and we extend our congratulations to him." "I feel like a parent saying goodbye to my kids at their college graduation," said Dale Sanders. "Many of the concepts we first developed and applied over 20 years ago at Intermountain and then later refined during my tenure as CIO at Northwestern had a big influence on our technology and products at Health Catalyst. The vision where can you get kamagra of the Data Operating System and its application ecosystem originated in the real-world healthcare operations and research trenches of Northwestern. At Health Catalyst, I had the wonderful opportunity to lead the teams who made that vision a reality for the benefit of the entire industry. None of it would have been possible without Bryan Hinton leading the DOS team and Eric Just and Dan Unger leading the application development teams.

We've been working side-by-side for many years to make the where can you get kamagra vision real. Bryan is the consummate modern CTO from outside of healthcare that healthcare needs. I've always described Eric as having a manufacturing engineer's mindset with a healthcare data and software engineer's skills, with Dan Unger leveraging his deep domain expertise in financial transformation to oversee the development of meaningful applications and solutions so relevant for CFOs. I'm honored and thrilled to step aside and turn the future over to their very where can you get kamagra capable hands. Under their leadership, the best is yet to come for Health Catalyst's technology." About Health CatalystHealth Catalyst is a leading provider of data and analytics technology and services to healthcare organizations, and is committed to being the catalyst for massive, measurable, data-informed healthcare improvement.

Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial and operational improvements. Health Catalyst envisions a future in which all healthcare decisions are data informed.Health Catalyst Media Contact:Kristen BerrySenior Vice President, Public Relations+1 (617) 234-4123HealthCatalyst@we-worldwide.com View original content to download multimedia:http://www.prnewswire.com/news-releases/health-catalyst-completes-hosting-of-the-largest-ever-healthcare-analytics-summit-and-announces-the-close-of-the-vitalware-acquisition-301125125.htmlSOURCE Health CatalystPeople who have never tried intense interval training might be surprised to find that the workouts can be more appealing than they anticipate, according to an interesting new study of people’s emotional reactions where can you get kamagra to different types of workouts.The study, which involved inactive adults sampling intervals and other types of exercise, often for the first time, found that some — although not all — of them preferred the intense efforts to gentler workouts. The findings challenge common assumptions about the disagreeableness of high-intensity exercise and also suggest that the best way to decide which workout might entice you is to play the exercise field.Almost anyone with a passing interest in fitness is familiar, by now, with the concept of high-intensity interval training. Consisting of brief, repeated bursts of strenuous exercise interspersed with periods of rest, H.I.I.T. Has become a trendy if controversial way to work out.Past studies show that even a few minutes of interval training improve fitness and where can you get kamagra health as much as hours of milder exercise.

But in some cautionary psychological studies, novice exercisers report disliking such intense training, which would seem to limit the workouts’ long-term allure.Few of these past studies have directly compared people’s feelings about intense and moderate exercise in head-to-head, in-depth exercise matchups, however. So, for the new study, which was published in August in Psychology of Sport &. Exercise, researchers at the University of British Columbia, in Kelowna, recruited 30 sedentary but otherwise healthy young men and women who said that they had not tried where can you get kamagra intense interval training before. (The new study expands on preliminary findings first published in 2018.)The researchers invited the men and women to the lab and talked to them there, at some length, about what they had heard about interval training and more-traditional exercise, including whether they thought they would be able to complete such workouts and enjoy them, or not.In general, the volunteers expressed knowledge of but also trepidation about interval training. Most worried that such workouts would be beyond them, physically, and would feel awful.Then the researchers asked the volunteers to exercise.

On one visit to the lab, each completed a standard, moderate workout, riding a stationary bicycle for 45 where can you get kamagra minutes at a sustainable pace. During another visit, they all tried H.I.I.T. For the first time, pedaling strenuously for one minute, resting for a minute, and repeating the sequence 10 times. During a third session, where can you get kamagra they were introduced to super-short intervals, consisting of three repetitions of 20-second, all-out pedaling spurts, with two minutes of rest between each interval.During and after each workout, the researchers asked the volunteers how they felt. In general, most gasped that they were not having fun during the interval sessions.

But afterward, reflecting on the experience, many told the researchers that maybe those workouts had been tolerable, after all. Surprised and pleased they had where can you get kamagra gotten through the intervals, a majority of the volunteers reported, in fact, that they now considered the longer H.I.I.T. Session to have been the most pleasant of all of the workouts.Supervised lab sessions are not a good reflection of real-life exercise, however. So, as a final step in the study, the researchers asked the volunteers to go home and work out on their own for a month, keeping exercise logs, then return to the lab to talk at length with the researchers again.This month of do-it-yourself workouts proved to be revealing. Almost everyone where can you get kamagra remained active, with most completing frequent, moderate exercise sessions, like the 45-minute bike rides at the lab.

But many also threaded some sort of interval training into their weekly workouts, although few of these sessions replicated the structured intervals from the lab. Instead, people tended to sprint up and down stairs or grunted through some quick burpees and other body weight exercises.Most interesting, during their subsequent, prolonged interviews with the researchers, the volunteers who interval trained on their own said they felt more engaged and motivated during those workouts than in the longer, continuous-intensity sessions, even when the intervals were physically draining.The upshot of the study data would seem to be that many of us might want to consider H.I.I.T., if we have not already, says Matthew Stork, a postdoctoral fellow at the University of British Columbia, who led the new study. We might surprise ourselves by liking the workouts.But, he points out, some volunteers continued to prefer the familiar, less-intense exercise, and almost everyone completed more of those sessions than of intervals.“What the data really show is that where can you get kamagra there is no one-size-fits-all way to work out,” Dr. Stork says. The best exercise will be the one each of us ultimately relishes most, he says.

It may require some experimentation, though, for us to settle on our particular, preferred workouts.Of course, this where can you get kamagra study involved healthy young adults and followed them for a month. Whether people who are older or have health concerns will respond similarly to intervals and whether anyone will stick to their chosen workouts for more than four weeks remain uncertain. Also, people who have not exercised in some time should generally consult a physician before tackling a new exercise routine.Alexis Block was worried that the robot she’d built was malfunctioning. She was testing the optimal hug where can you get kamagra duration for her “HuggieBot 1.0,” a purple-furred, on-demand squeeze machine. Ms.

Block had built pressure sensors into the machine’s torso, so if the human tester tapped or squeezed the robot on the back, it let go. But this hug was going on where can you get kamagra and on. €œI worried that the pressure sensors were malfunctioning,” she said.Her palms began to sweat (getting stuck in the clutches of a giant robot is no one’s idea of a good time). But then, the hug ended, and the HuggieBot released its test subject. When Ms where can you get kamagra.

Block, who is working toward her Ph.D. At the Max Planck ETH Center for Learning Systems in both Stuttgart, Germany and Zurich, Switzerland, asked the subject if something had gone wrong, he surprised her by explaining that he had wanted the hug to last a long time. €œHe said, ‘I just needed it, and the robot wasn’t going to judge me.’”As the weeks of coronavirus quarantine stretched into months, hugs are among the many things isolated people where can you get kamagra found themselves aching for. Hugs are good for humans — perhaps more valuable than many of us realized, until we found ourselves missing them.Research has shown that hugs can lower our cortisol levels during stressful situations, and can raise oxytocin levels and maybe even lower our blood pressure. A 2015 paper published in Psychological Science even found that study subjects who got more hugs were less likely to get sick when exposed to a cold virus than those who weren’t hugged as often.“The need for human contact is extremely profound,” said Judith Hall, a psychology professor emerita at Northeastern University who researched interpersonal touch at the university’s Social Interaction Lab.

But whether to hug someone or not sometimes seems where can you get kamagra fraught. #styln-briefing-block { font-family. Nyt-franklin,helvetica,arial,sans-serif. Background-color. #ffffff.

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09, 2020 (GLOBE how to get kamagra online NEWSWIRE) kamagra thailand price -- Health Catalyst, Inc. ("Health Catalyst", Nasdaq. HCAT), a leading provider of data and analytics technology and services to healthcare organizations, today announced that Patrick Nelli, Chief Financial Officer, and Adam Brown, Senior Vice President, Investor Relations, will participate in the 2020 Cantor Global Virtual Healthcare Conference on Tuesday, September 15, 2020, which will include a fireside chat presentation at 1:20 p.m. ET.

A live audio webcast and replay of this presentation will be available at https://ir.healthcatalyst.com/investor-relations.About Health CatalystHealth Catalyst is a leading provider of data and analytics technology and services to healthcare organizations committed to being the catalyst for massive, measurable, data-informed healthcare improvement. Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial, and operational improvements. Health Catalyst envisions a future in which all healthcare decisions are data informed.Health Catalyst Investor Relations Contact:Adam BrownSenior Vice President, Investor Relations+1 (855)-309-6800ir@healthcatalyst.comHealth Catalyst Media Contact:Kristen BerryVice President, Public Relations+1 (617) 234-4123+1 (774) 573-0455 (m)kberry@we-worldwide.com Source. Health Catalyst, Inc.SALT LAKE CITY, Sept.

8, 2020 /PRNewswire/ -- Health Catalyst, Inc. ("Health Catalyst," Nasdaq. HCAT), a leading provider of data and analytics technology and services to healthcare organizations, today announced that it has completed its seventh annual and first ever virtual Healthcare Analytics Summit (HAS), with record registration of more than 3,500 attendees. Keynotes included Dr.

Amy Abernethy, Principal Deputy Commissioner and Acting CIO of the U.S. Food and Drug Administration, Michael Dowling, CEO of Northwell Health, Vice Admiral Raquel Bono, MD, and many others. Other business updates include:The Vitalware, LLC ("VitalWare"), transaction has closed, and integration is underway of the Yakima, Washington-based provider of revenue workflow optimization and analytics SaaS technology solutions for health organizations. This is another example of Health Catalyst's ability to scale software on top of its cloud-based Data Operating System (DOS™).

DOS will further enhance the analytics insights made available by Vitalware's technology by combining charge and revenue data with claims, cost, and quality data. Vitalware's flagship offering is a Best in KLAS chargemaster management solution that delivers results for the complex regulatory and compliance functions needed by all healthcare provider systems. "As announced on August 11, 2020, we entered into an acquisition agreement to acquire Vitalware and expected to close the acquisition in Q3 or Q4 of 2020. We are pleased to announce that we closed the acquisition on September 1, 2020.

We are thrilled to formalize the combination of our solutions for the benefit of our customers and the industry," said CEO Dan Burton. On its upcoming Q3 2020 earnings call, Health Catalyst will share the impact of Vitalware on its Q3 2020 financial performance, which will not be significant given the timing of the acquisition, as well as update its full year 2020 guidance to include the impact of Vitalware. Health Catalyst Co-Founder Steve Barlow has returned from his three-year full-time volunteer mission for the Church of Jesus Christ of Latter-Day Saints, having served as Mission President of the Ecuador Quito Mission. He has rejoined Health Catalyst's companywide Leadership Team as a Senior Vice President, responsible for some of the company's largest customer relationships.

Dan Burton said, "We couldn't be more excited about Steve's return to Health Catalyst. His energy, dedication and commitment to transforming healthcare launched our journey and will continue to make us better and stronger. Steve is leading and overseeing all aspects of our partnerships with some of our largest and longest-standing customers. Steve's extraordinary experience and capability enable him to be a critical partner and leader in enabling these customers' continued improvement and success." "My experience over the past three years in Ecuador reinforced for me how fortunate I am to be in a country with high-quality healthcare," said Barlow.

"It has been invigorating to return to Health Catalyst and witness the incredible growth and expansion that has occurred over the past few years. We are better positioned than ever before to achieve our mission of being the catalyst for massive, measurable, data-informed healthcare improvement. I am grateful to be reunited with our longstanding team members and customers, and I'm thrilled to get to know and work alongside our new customers and teammates in this critical work." Effective October 1, 2020, Chief Technology Officer Dale Sanders will be transitioning to a Senior Advisor role with Health Catalyst, and the company is pleased to announce that one of Dale's longtime protégés and colleagues, Bryan Hinton, will serve as Health Catalyst's next Chief Technology Officer. Hinton joined Health Catalyst in 2012 and currently serves as the Senior Vice President and General Manager of the DOS Platform Business.

He will continue to lead this business in addition to assuming the responsibilities of CTO. He has been instrumental in the development and integration of DOS and has been working directly with Dale and other technology leaders at Health Catalyst for many years. His experience prior to joining Health Catalyst includes four years with the .NET Development Center of Excellence at The Church of Jesus Christ of Latter-Day Saints, where he established the architectural guidance of all .NET projects. Previously, at Intel, he was responsible for the development and implementation of Intel's factory data warehouse product installed at Intel global factories.

Hinton graduated from Brigham Young University with a BS in Computer Science. "Dale has been central to Health Catalyst's growth and success and we are grateful to him for his many years of service to our company and to the broader healthcare industry," said Dan Burton, CEO of Health Catalyst. "Thanks to Dale's vision, passion, innovative thinking and broad-based industry experience and perspective, Health Catalyst has grown from a handful of clients to a large number of organizations relying on us as their digital transformation partner, helping the healthcare ecosystem to constantly learn and improve. Dale's technology leadership was critical to the company's overall maturation, and I am convinced that we could not have grown and scaled as we have without Dale's foundational leadership and contributions.

We are grateful to continue our association with Dale in the months and years ahead in his next role as a Senior Advisor to the company." Burton added, "We are thrilled to see Bryan Hinton take on this added role after having demonstrated his technology leadership prowess during the course of his tenure at Health Catalyst and having been mentored by Dale for many years. Bryan is well-prepared and ready for this additional responsibility, and we extend our congratulations to him." "I feel like a parent saying goodbye to my kids at their college graduation," said Dale Sanders. "Many of the concepts we first developed and applied over 20 years ago at Intermountain and then later refined during my tenure as CIO at Northwestern had a big influence on our technology and products at Health Catalyst. The vision of the Data Operating System and its application ecosystem originated in the real-world healthcare operations and research trenches of Northwestern.

At Health Catalyst, I had the wonderful opportunity to lead the teams who made that vision a reality for the benefit of the entire industry. None of it would have been possible without Bryan Hinton leading the DOS team and Eric Just and Dan Unger leading the application development teams. We've been working side-by-side for many years to make the vision real. Bryan is the consummate modern CTO from outside of healthcare that healthcare needs.

I've always described Eric as having a manufacturing engineer's mindset with a healthcare data and software engineer's skills, with Dan Unger leveraging his deep domain expertise in financial transformation to oversee the development of meaningful applications and solutions so relevant for CFOs. I'm honored and thrilled to step aside and turn the future over to their very capable hands. Under their leadership, the best is yet to come for Health Catalyst's technology." About Health CatalystHealth Catalyst is a leading provider of data and analytics technology and services to healthcare organizations, and is committed to being the catalyst for massive, measurable, data-informed healthcare improvement. Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial and operational improvements.

Health Catalyst envisions a future in which all healthcare decisions are data informed.Health Catalyst Media Contact:Kristen BerrySenior Vice President, Public Relations+1 (617) 234-4123HealthCatalyst@we-worldwide.com View original content to download multimedia:http://www.prnewswire.com/news-releases/health-catalyst-completes-hosting-of-the-largest-ever-healthcare-analytics-summit-and-announces-the-close-of-the-vitalware-acquisition-301125125.htmlSOURCE Health CatalystPeople who have never tried intense interval training might be surprised to find that the workouts can be more appealing than they anticipate, according to an interesting new study of people’s emotional reactions to different types of workouts.The study, which involved inactive adults sampling intervals and other types of exercise, often for the first time, found that some — although not all — of them preferred the intense efforts to gentler workouts. The findings challenge common assumptions about the disagreeableness of high-intensity exercise and also suggest that the best way to decide which workout might entice you is to play the exercise field.Almost anyone with a passing interest in fitness is familiar, by now, with the concept of high-intensity interval training. Consisting of brief, repeated bursts of strenuous exercise interspersed with periods of rest, H.I.I.T. Has become a trendy if controversial way to work out.Past studies show that even a few minutes of interval training improve fitness and health as much as hours of milder exercise.

But in some cautionary psychological studies, novice exercisers report disliking such intense training, which would seem to limit the workouts’ long-term allure.Few of these past studies have directly compared people’s feelings about intense and moderate exercise in head-to-head, in-depth exercise matchups, however. So, for the new study, which was published in August in Psychology of Sport &. Exercise, researchers at the University of British Columbia, in Kelowna, recruited 30 sedentary but otherwise healthy young men and women who said that they had not tried intense interval training before. (The new study expands on preliminary findings first published in 2018.)The researchers invited the men and women to the lab and talked to them there, at some length, about what they had heard about interval training and more-traditional exercise, including whether they thought they would be able to complete such workouts and enjoy them, or not.In general, the volunteers expressed knowledge of but also trepidation about interval training.

Most worried that such workouts would be beyond them, physically, and would feel awful.Then the researchers asked the volunteers to exercise. On one visit to the lab, each completed a standard, moderate workout, riding a stationary bicycle for 45 minutes at a sustainable pace. During another visit, they all tried H.I.I.T. For the first time, pedaling strenuously for one minute, resting for a minute, and repeating the sequence 10 times.

During a third session, they were introduced to super-short intervals, consisting of three repetitions of 20-second, all-out pedaling spurts, with two minutes of rest between each interval.During and after each workout, the researchers asked the volunteers how they felt. In general, most gasped that they were not having fun during the interval sessions. But afterward, reflecting on the experience, many told the researchers that maybe those workouts had been tolerable, after all. Surprised and pleased they had gotten through the intervals, a majority of the volunteers reported, in fact, that they now considered the longer H.I.I.T.

Session to have been the most pleasant of all of the workouts.Supervised lab sessions are not a good reflection of real-life exercise, however. So, as a final step in the study, the researchers asked the volunteers to go home and work out on their own for a month, keeping exercise logs, then return to the lab to talk at length with the researchers again.This month of do-it-yourself workouts proved to be revealing. Almost everyone remained active, with most completing frequent, moderate exercise sessions, like the 45-minute bike rides at the lab. But many also threaded some sort of interval training into their weekly workouts, although few of these sessions replicated the structured intervals from the lab.

Instead, people tended to sprint up and down stairs or grunted through some quick burpees and other body weight exercises.Most interesting, during their subsequent, prolonged interviews with the researchers, the volunteers who interval trained on their own said they felt more engaged and motivated during those workouts than in the longer, continuous-intensity sessions, even when the intervals were physically draining.The upshot of the study data would seem to be that many of us might want to consider H.I.I.T., if we have not already, says Matthew Stork, a postdoctoral fellow at the University of British Columbia, who led the new study. We might surprise ourselves by liking the workouts.But, he points out, some volunteers continued to prefer the familiar, less-intense exercise, and almost everyone completed more of those sessions than of intervals.“What the data really show is that there is no one-size-fits-all way to work out,” Dr. Stork says. The best exercise will be the one each of us ultimately relishes most, he says.

It may require some experimentation, though, for us to settle on our particular, preferred workouts.Of course, this study involved healthy young adults and followed them for a month. Whether people who are older or have health concerns will respond similarly to intervals and whether anyone will stick to their chosen workouts for more than four weeks remain uncertain. Also, people who have not exercised in some time should generally consult a physician before tackling a new exercise routine.Alexis Block was worried that the robot she’d built was malfunctioning. She was testing the optimal hug duration for her “HuggieBot 1.0,” a purple-furred, on-demand squeeze machine.

Ms. Block had built pressure sensors into the machine’s torso, so if the human tester tapped or squeezed the robot on the back, it let go. But this hug was going on and on. €œI worried that the pressure sensors were malfunctioning,” she said.Her palms began to sweat (getting stuck in the clutches of a giant robot is no one’s idea of a good time).

But then, the hug ended, and the HuggieBot released its test subject. When Ms. Block, who is working toward her Ph.D. At the Max Planck ETH Center for Learning Systems in both Stuttgart, Germany and Zurich, Switzerland, asked the subject if something had gone wrong, he surprised her by explaining that he had wanted the hug to last a long time.

€œHe said, ‘I just needed it, and the robot wasn’t going to judge me.’”As the weeks of coronavirus quarantine stretched into months, hugs are among the many things isolated people found themselves aching for. Hugs are good for humans — perhaps more valuable than many of us realized, until we found ourselves missing them.Research has shown that hugs can lower our cortisol levels during stressful situations, and can raise oxytocin levels and maybe even lower our blood pressure. A 2015 paper published in Psychological Science even found that study subjects who got more hugs were less likely to get sick when exposed to a cold virus than those who weren’t hugged as often.“The need for human contact is extremely profound,” said Judith Hall, a psychology professor emerita at Northeastern University who researched interpersonal touch at the university’s Social Interaction Lab. But whether to hug someone or not sometimes seems fraught.

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Buy chewable kamagra

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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 kwik kamagra uk sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this buy chewable kamagra 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 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 buy chewable kamagra 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 buy chewable kamagra 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 buy chewable kamagra 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 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, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for buy chewable kamagra these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the buy chewable kamagra postnatal team and from the paediatric to the adult 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 buy chewable kamagra international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed 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 more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving buy chewable kamagra 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 buy chewable kamagra in English and were identified using a broad range of Medical Subject Headings 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 buy chewable kamagra not open access 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, after having obtained agreement on remaining points of buy chewable kamagra 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 buy chewable kamagra 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 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 buy chewable kamagra 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 buy chewable kamagra 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 buy chewable kamagra 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 time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably buy chewable kamagra 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 findings and the limitations of this technique buy chewable kamagra. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can and cannot buy chewable kamagra 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 buy chewable kamagra 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 continue the pregnancy. Termination of pregnancy can be buy chewable kamagra considered, for instance, in a syndromic form of DSD 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 not knowing exactly what the child’s genitalia will look like and buy chewable kamagra 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 contact person buy chewable kamagra 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 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 buy chewable kamagra 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 buy chewable kamagra 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 buy chewable kamagra 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 https://www.cityreal.lv/how-to-get-kamagra-prescription/. 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 https://www.cityreal.lv/kamagra-online-pharmacy/ 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 multidisciplinary teams that provide care for patients who have a DSD.11 kamagra thailand price 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 elucidation of differences of sex development’ has been a platform kamagra thailand price 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 kamagra thailand price 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.

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 kamagra thailand price 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 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 kamagra thailand price sex development and why this may warrant referral to a specialised 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 kamagra thailand price and from the paediatric to the adult 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 kamagra thailand price 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 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 it is often troublesome to substantiate such guidelines with sufficient evidence due kamagra thailand price 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, 46,XX DSD, 46,XY kamagra thailand price DSD, guideline, multidisciplinary care).

Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that kamagra thailand price were not open access 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 kamagra thailand price was discussed by the writing committee and, 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 kamagra thailand price 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 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 kamagra thailand price 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 kamagra thailand price 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 women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal kamagra thailand price restrictions and/or ethical considerations, the X and Y 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 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 kamagra thailand price 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 findings and the kamagra thailand price limitations of this technique.

The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information kamagra thailand price 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 kamagra thailand price 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 continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the kamagra thailand price 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 not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis kamagra thailand price 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 significant number of kamagra thailand price 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 delivery units should be clearly instructed to use gender-neutral and kamagra thailand price 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 kamagra thailand price particularly common.27 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 completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in kamagra thailand price 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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Aug https://www.cityreal.lv/kamagra-gel-packs/ super kamagra canada. 29, 2020 -- Chadwick Boseman, the star of the 2018 Marvel Studios megahit Black Panther, died of colon cancer Friday. He was super kamagra canada 43.

Boseman, who was diagnosed 4 years ago, had kept his condition a secret. He filmed his recent movies ''during and between countless surgeries and chemotherapy," according to a statement issued on his Twitter account. When the actor was diagnosed in 2016, the cancer was at stage III -- meaning it had already grown through the colon wall -- but then progressed to the more lethal stage IV, meaning it had spread beyond his colon super kamagra canada.

Messages of condolences and the hashtag #Wakandaforever, referring to the fictional African nation in the Black Panther film, flooded social media Friday evening. Oprah tweeted. "What a gentle gifted super kamagra canada SOUL.

Showing us all that Greatness in between surgeries and chemo. The courage, the strength, the Power it takes to do that. This is what Dignity looks super kamagra canada like.

" Marvel Studios tweeted. "Your legacy will live on forever." Boseman was also known for his role as Jackie Robinson in the movie 42. Coincidentally, Friday was Major League super kamagra canada Baseball's Jackie Robinson Day, where every player on every team wears Robinson's number 42 on their jerseys.

Boseman's other starring roles include portraying James Brown in Get on Up and U.S. Supreme Court Justice Thurgood Marshall in Marshall. But his role as King T'Challa in Black Panther, the super hero protagonist, super kamagra canada made him an icon and an inspiration.

About Colon Cancer Boseman's death reflects a troubling recent trend, says Mark Hanna, MD, a colorectal surgeon at City of Hope, a comprehensive cancer center near Los Angeles. "We have noticed an increasing incidence of colorectal cancer in young adults," says Hanna, who did not treat Boseman. "I've seen patients as young as their early 20s." About 104,000 cases of colon cancer will be diagnosed this year, according to American Cancer Society estimates, and another 43,000 cases super kamagra canada of rectal cancer will be diagnosed.

About 12% of those, or 18,000 cases, will be in people under age 50. As the rates have declined in older super kamagra canada adults due to screening, rates in young adults have steadily risen. Younger patients are often diagnosed at a later stage than older adults, Hanna says, because patients and even their doctors don't think about the possibility of colon cancer.

Because it is considered a cancer affecting older adults, many younger people may brush off the symptoms or delay getting medical attention, Hanna says. In a survey of 885 colorectal cancer patients conducted by Colorectal Cancer Alliance earlier this year, 75% said they visited two or more doctors before getting their diagnosis, super kamagra canada and 11% went to 10 or more before finding out. If found early, colon cancer is curable, Hanna says.

About 50% of those with colon cancer will be diagnosed at stage I or II, which is considered localized disease, he says. "The majority have a very super kamagra canada good prognosis." The 5-year survival rate is about 90% for both stage I and II. But when it progresses to stage III, the cancer has begun to grow into surrounding tissues and the lymph nodes, Hanna says, and the survival rate for 5 years drops to 75%.

About 25% of patients are diagnosed at stage III, he says. If the diagnosis is made at stage IV, the 5-year survival super kamagra canada rate drops to about 10% or 15%, he says. Experts have been trying to figure out why more young adults are getting colon cancer and why some do so poorly.

"Traditionally we thought that patients who are older would have a worse outlook," Hanna says, partly because they tend to have other medical conditions too. Some experts say that younger patients might have more ''genetically aggressive disease," super kamagra canada Hanna says. "Our understanding of colorectal cancer is becoming more nuanced, and we know that not all forms are the same." For instance, he says, testing is done for specific genetic mutations that have been tied to colon cancer.

"It's not just about finding the mutations, but finding the drug that targets [that form] best." Paying Attention to Red Flags "If you have any of what we call the red flag signs, do not ignore your symptoms no matter what your age is," Hanna says. Those are super kamagra canada. In 2018, the American Cancer Society changed its guidelines for screening, recommending those at average risk start at age 45, not 50.

The screening can be stool-based testing, such as a fecal occult blood test, or visual, such as a colonoscopy. Hanna says he orders a super kamagra canada colonoscopy if the symptoms suggest colon cancer, regardless of a patient's age. Family history of colorectal cancer is a risk factor, as are being obese or overweight, being sedentary, and eating lots of red meat.

Sources Mark Hanna, MD, colorectal surgeon and assistant clinical professor of surgery, City of Hope, Los Angeles. American Cancer Society super kamagra canada. "Key Statistics for Colorectal Cancer." Twitter statement.

Chadwick Boseman super kamagra canada. American Cancer Society. "Colorectal Cancer Risk Factors." American Cancer Society.

'"Colorectal Cancer Rates Rise in Younger Adults." super kamagra canada American Society of Clinical Oncology annual meeting, May 29-31, 2020. American Cancer Society "Survival Rates for Colorectal Cancer." American Cancer Society. "Colorectal Cancer Facts &.

Figures. 2017-2019." © 2020 WebMD, LLC. All rights reserved.FRIDAY, Aug.

28, 2020 (HealthDay News) -- As many as 20% of Americans don't believe in vaccines, a new study finds. Misinformed vaccine beliefs drive opposition to public vaccine policies even more than politics, education, religion or other factors, researchers say. The findings are based on a survey of nearly 2,000 https://www.cityreal.lv/kamagra-nz/ U.S.

Adults done in 2019, during the largest measles outbreak in 25 years. The researchers, from the Annenberg Public Policy Center (APPC) of the University of Pennsylvania, found that negative misperceptions about vaccinations. reduced the likelihood of supporting mandatory childhood vaccines by 70%, reduced the likelihood of opposing religious exemptions by 66%, reduced the likelihood of opposing personal belief exemptions by 79%.

"There are real implications here for a vaccine for COVID-19," lead author Dominik Stecula said in an APPC news release. He conducted the research while at APPC and is now an assistant professor of political science at Colorado State University. "The negative vaccine beliefs we examined aren't limited only to the measles, mumps and rubella [MMR] vaccine, but are general attitudes about vaccination." Stecula called for an education campaign by public health professionals and journalists, among others, to preemptively correct misinformation and prepare the public to accept a COVID-19 vaccine.

Overall, there was strong support for vaccination policies. 72% strongly or somewhat supported mandatory childhood vaccination, 60% strongly or somewhat opposed religious exemptions, 66% strongly or somewhat opposed vaccine exemptions based on personal beliefs. "On the one hand, these are big majorities.

Well above 50% of Americans support mandatory childhood vaccinations and oppose religious and personal belief exemptions to vaccination," said co-author Ozan Kuru, a former APPC researcher, now an assistant professor of communications at the National University of Singapore. "Still, we need a stronger consensus in the public to bolster pro-vaccine attitudes and legislation and thus achieve community immunity," he added in the release. A previous study from the 2018-2019 measles outbreak found that people who rely on social media were more likely to be misinformed about vaccines.

And a more recent one found that people who got information from social media or conservative news outlets at the start of the COVID-19 pandemic were more likely to be misinformed about how to prevent infection and hold conspiracy theories about it. With the coronavirus pandemic still raging, the number of Americans needed to be vaccinated to achieve community-wide immunity is not known, the researchers said. The findings were recently published online in the American Journal of Public Health.By Robert Preidt HealthDay Reporter FRIDAY, Aug.

28, 2020 (HealthDay News) -- Breastfeeding mothers are unlikely to transmit the new coronavirus to their babies via their milk, researchers say. No cases of an infant contracting COVID-19 from breast milk have been documented, but questions about the potential risk remain. Researchers examined 64 samples of breast milk collected from 18 women across the United States who were infected with the new coronavirus (SARS-CoV-2) that causes COVID-19.

One sample tested positive for coronavirus RNA, but follow-up tests showed that the virus couldn't replicate and therefore, couldn't infect the breastfed infant, according to the study recently published online in the Journal of the American Medical Association. "Detection of viral RNA does not equate to infection. It has to grow and multiply in order to be infectious and we did not find that in any of our samples," said study author Christina Chambers, a professor of pediatrics at the University of California, San Diego.

She is also director of the Mommy's Milk Human Milk Research Biorepository. "Our findings suggest breast milk itself is not likely a source of infection for the infant," Chambers said in a UCSD news release. To prevent transmission of the virus while breastfeeding, wearing a mask, hand-washing and sterilizing pumping equipment after each use are recommended.

"We hope our results and future studies will give women the reassurance needed for them to breastfeed. Human milk provides invaluable benefits to mom and baby," said co-author Dr. Grace Aldrovandi, chief of the Division of Infectious Diseases at UCLA Mattel Children's Hospital in Los Angeles.

WebMD News from HealthDay Sources SOURCE. University of California, San Diego, news release, Aug. 19, 2020 Copyright © 2013-2020 HealthDay.

All rights reserved.Nursing home staff will have to be tested regularly for COVID-19, and facilities that fail to do so will face fines, the Trump administration said Tuesday. Even though they account for less than 1% of the nation's population, long-term care facilities account for 42% of COVID-19 deaths in the United States, the Associated Press reported. There have been more than 70,000 deaths in U.S.

Nursing homes, according to the COVID Tracking Project. It's been months since the White House first urged governors to test all nursing home residents and staff, the AP reported. WebMD News from HealthDay Copyright © 2013-2020 HealthDay.

All rights reserved.August 28, 2020 -- Alcohol-based hand sanitizers that are packaged in containers that look like food items or drinks could cause injury or death if ingested, according to a new warning the FDA issued Thursday. Hand sanitizers are being packaged in beer cans, water bottles, juice bottles, vodka bottles and children’s food pouches, the FDA said. Some sanitizers also contain flavors, such as chocolate or raspberry, which could cause confusion.

€œI am increasingly concerned about hand sanitizer being packaged to appear to be consumable products, such as baby food or beverages,” Stephen Hahn, MD, the FDA commissioner, said in a statement. Accidentally drinking hand sanitizer — even a small amount — is potentially lethal to children. €œThese products could confuse consumers into accidentally ingesting a potentially deadly product,” he said.

€œIt’s dangerous to add scents with food flavors to hand sanitizers which children could think smells like food, eat and get alcohol poisoning.” For example, the FDA received a report about a consumer who purchased a bottle that looked like drinkable water but was actually hand sanitizer. In another report, a retailer informed the agency about a hand sanitizer product that was marketed in a pouch that looks like a children’s snack and had cartoons on it. Meanwhile, the FDA's warning list about dangerous hand sanitizers containing methanol continues to grow as some people are drinking the sanitizers to get an alcohol high.

Others have believed a rumor, circulated online, that drinking the highly potent and toxic alcohol can disinfect the body, protecting them from COVID-19 infection. Earlier this month, the FDA also issued a warning about hand sanitizers contaminated with 1-propanol. Ingesting 1-propanol can cause central nervous system depression, which can be fatal, the agency says.

Symptoms of 1-propanol exposure can include confusion, decreased consciousness, and slowed pulse and breathing. One brand of sanitizer, Harmonic Nature S de RL de MI of Mexico, are labeled to contain ethanol or isopropyl alcohol but have tested positive for 1-propanol contamination. Poison control centers and state health departments have reported an increasing number of adverse events associated with hand sanitizer ingestion, including heart issues, nervous system problems, hospitalizations and deaths, according to the statement.

The FDA encouraged consumers and health care professionals to report issues to the MedWatch Adverse Event Reporting program. The agency is working with manufacturers to recall confusing and dangerous products and is encouraging retailers to remove some products from shelves. The FDA is also updating its list of hand sanitizer products that consumers should avoid.

€œManufacturers should be vigilant about packaging and marketing their hand sanitizers in food or drink packages in an effort to mitigate any potential inadvertent use by consumers,” Hahn said..

Aug. 29, 2020 -- Chadwick Boseman, the star of the 2018 Marvel Studios megahit Black Panther, died of colon cancer Friday. He was 43. Boseman, who was diagnosed 4 years ago, had kept his condition a secret. He filmed his recent movies ''during and between countless surgeries and chemotherapy," according to a statement issued on his Twitter account.

When the actor was diagnosed in 2016, the cancer was at stage III -- meaning it had already grown through the colon wall -- but then progressed to the more lethal stage IV, meaning it had spread beyond his colon. Messages of condolences and the hashtag #Wakandaforever, referring to the fictional African nation in the Black Panther film, flooded social media Friday evening. Oprah tweeted. "What a gentle gifted SOUL. Showing us all that Greatness in between surgeries and chemo.

The courage, the strength, the Power it takes to do that. This is what Dignity looks like. " Marvel Studios tweeted. "Your legacy will live on forever." Boseman was also known for his role as Jackie Robinson in the movie 42. Coincidentally, Friday was Major League Baseball's Jackie Robinson Day, where every player on every team wears Robinson's number 42 on their jerseys.

Boseman's other starring roles include portraying James Brown in Get on Up and U.S. Supreme Court Justice Thurgood Marshall in Marshall. But his role as King T'Challa in Black Panther, the super hero protagonist, made him an icon and an inspiration. About Colon Cancer Boseman's death reflects a troubling recent trend, says Mark Hanna, MD, a colorectal surgeon at City of Hope, a comprehensive cancer center near Los Angeles. "We have noticed an increasing incidence of colorectal cancer in young adults," says Hanna, who did not treat Boseman.

"I've seen patients as young as their early 20s." About 104,000 cases of colon cancer will be diagnosed this year, according to American Cancer Society estimates, and another 43,000 cases of rectal cancer will be diagnosed. About 12% of those, or 18,000 cases, will be in people under age 50. As the rates have declined in older adults due to screening, rates in young adults have steadily risen. Younger patients are often diagnosed at a later stage than older adults, Hanna says, because patients and even their doctors don't think about the possibility of colon cancer. Because it is considered a cancer affecting older adults, many younger people may brush off the symptoms or delay getting medical attention, Hanna says.

In a survey of 885 colorectal cancer patients conducted by Colorectal Cancer Alliance earlier this year, 75% said they visited two or more doctors before getting their diagnosis, and 11% went to 10 or more before finding out. If found early, colon cancer is curable, Hanna says. About 50% of those with colon cancer will be diagnosed at stage I or II, which is considered localized disease, he says. "The majority have a very good prognosis." The 5-year survival rate is about 90% for both stage I and II. But when it progresses to stage III, the cancer has begun to grow into surrounding tissues and the lymph nodes, Hanna says, and the survival rate for 5 years drops to 75%.

About 25% of patients are diagnosed at stage III, he says. If the diagnosis is made at stage IV, the 5-year survival rate drops to about 10% or 15%, he says. Experts have been trying to figure out why more young adults are getting colon cancer and why some do so poorly. "Traditionally we thought that patients who are older would have a worse outlook," Hanna says, partly because they tend to have other medical conditions too. Some experts say that younger patients might have more ''genetically aggressive disease," Hanna says.

"Our understanding of colorectal cancer is becoming more nuanced, and we know that not all forms are the same." For instance, he says, testing is done for specific genetic mutations that have been tied to colon cancer. "It's not just about finding the mutations, but finding the drug that targets [that form] best." Paying Attention to Red Flags "If you have any of what we call the red flag signs, do not ignore your symptoms no matter what your age is," Hanna says. Those are. In 2018, the American Cancer Society changed its guidelines for screening, recommending those at average risk start at age 45, not 50. The screening can be stool-based testing, such as a fecal occult blood test, or visual, such as a colonoscopy.

Hanna says he orders a colonoscopy if the symptoms suggest colon cancer, regardless of a patient's age. Family history of colorectal cancer is a risk factor, as are being obese or overweight, being sedentary, and eating lots of red meat. Sources Mark Hanna, MD, colorectal surgeon and assistant clinical professor of surgery, City of Hope, Los Angeles. American Cancer Society. "Key Statistics for Colorectal Cancer." Twitter statement.

Chadwick Boseman. American Cancer Society. "Colorectal Cancer Risk Factors." American Cancer Society. '"Colorectal Cancer Rates Rise in Younger Adults." American Society of Clinical Oncology annual meeting, May 29-31, 2020. American Cancer Society "Survival Rates for Colorectal Cancer." American Cancer Society.

"Colorectal Cancer Facts &. Figures. 2017-2019." © 2020 WebMD, LLC. All rights reserved.FRIDAY, Aug. 28, 2020 (HealthDay News) -- As many as 20% of Americans don't believe in vaccines, a new study finds.

Misinformed vaccine beliefs drive opposition to public vaccine policies even more than politics, education, religion or other factors, researchers say. The findings are based on a survey of nearly 2,000 U.S. Adults done in 2019, during the largest measles outbreak in 25 years. The researchers, from the Annenberg Public Policy Center (APPC) of the University of Pennsylvania, found that negative misperceptions about vaccinations. reduced the likelihood of supporting mandatory childhood vaccines by 70%, reduced the likelihood of opposing religious exemptions by 66%, reduced the likelihood of opposing personal belief exemptions by 79%.

"There are real implications here for a vaccine for COVID-19," lead author Dominik Stecula said in an APPC news release. He conducted the research while at APPC and is now an assistant professor of political science at Colorado State University. "The negative vaccine beliefs we examined aren't limited only to the measles, mumps and rubella [MMR] vaccine, but are general attitudes about vaccination." Stecula called for an education campaign by public health professionals and journalists, among others, to preemptively correct misinformation and prepare the public to accept a COVID-19 vaccine. Overall, there was strong support for vaccination policies. 72% strongly or somewhat supported mandatory childhood vaccination, 60% strongly or somewhat opposed religious exemptions, 66% strongly or somewhat opposed vaccine exemptions based on personal beliefs.

"On the one hand, these are big majorities. Well above 50% of Americans support mandatory childhood vaccinations and oppose religious and personal belief exemptions to vaccination," said co-author Ozan Kuru, a former APPC researcher, now an assistant professor of communications at the National University of Singapore. "Still, we need a stronger consensus in the public to bolster pro-vaccine attitudes and legislation and thus achieve community immunity," he added in the release. A previous study from the 2018-2019 measles outbreak found that people who rely on social media were more likely to be misinformed about vaccines. And a more recent one found that people who got information from social media or conservative news outlets at the start of the COVID-19 pandemic were more likely to be misinformed about how to prevent infection and hold conspiracy theories about it.

With the coronavirus pandemic still raging, the number of Americans needed to be vaccinated to achieve community-wide immunity is not known, the researchers said. The findings were recently published online in the American Journal of Public Health.By Robert Preidt HealthDay Reporter FRIDAY, Aug. 28, 2020 (HealthDay News) -- Breastfeeding mothers are unlikely to transmit the new coronavirus to their babies via their milk, researchers say. No cases of an infant contracting COVID-19 from breast milk have been documented, but questions about the potential risk remain. Researchers examined 64 samples of breast milk collected from 18 women across the United States who were infected with the new coronavirus (SARS-CoV-2) that causes COVID-19.

One sample tested positive for coronavirus RNA, but follow-up tests showed that the virus couldn't replicate and therefore, couldn't infect the breastfed infant, according to the study recently published online in the Journal of the American Medical Association. "Detection of viral RNA does not equate to infection. It has to grow and multiply in order to be infectious and we did not find that in any of our samples," said study author Christina Chambers, a professor of pediatrics at the University of California, San Diego. She is also director of the Mommy's Milk Human Milk Research Biorepository. "Our findings suggest breast milk itself is not likely a source of infection for the infant," Chambers said in a UCSD news release.

To prevent transmission of the virus while breastfeeding, wearing a mask, hand-washing and sterilizing pumping equipment after each use are recommended. "We hope our results and future studies will give women the reassurance needed for them to breastfeed. Human milk provides invaluable benefits to mom and baby," said co-author Dr. Grace Aldrovandi, chief of the Division of Infectious Diseases at UCLA Mattel Children's Hospital in Los Angeles. WebMD News from HealthDay Sources SOURCE.

University of California, San Diego, news release, Aug. 19, 2020 Copyright © 2013-2020 HealthDay. All rights reserved.Nursing home staff will have to be tested regularly for COVID-19, and facilities that fail to do so will face fines, the Trump administration said Tuesday. Even though they account for less than 1% of the nation's population, long-term care facilities account for 42% of COVID-19 deaths in the United States, the Associated Press reported. There have been more than 70,000 deaths in U.S.

Nursing homes, according to the COVID Tracking Project. It's been months since the White House first urged governors to test all nursing home residents and staff, the AP reported. WebMD News from HealthDay Copyright © 2013-2020 HealthDay. All rights reserved.August 28, 2020 -- Alcohol-based hand sanitizers that are packaged in containers that look like food items or drinks could cause injury or death if ingested, according to a new warning the FDA issued Thursday. Hand sanitizers are being packaged in beer cans, water bottles, juice bottles, vodka bottles and children’s food pouches, the FDA said.

Some sanitizers also contain flavors, such as chocolate or raspberry, which could cause confusion. €œI am increasingly concerned about hand sanitizer being packaged to appear to be consumable products, such as baby food or beverages,” Stephen Hahn, MD, the FDA commissioner, said in a statement. Accidentally drinking hand sanitizer — even a small amount — is potentially lethal to children. €œThese products could confuse consumers into accidentally ingesting a potentially deadly product,” he said. €œIt’s dangerous to add scents with food flavors to hand sanitizers which children could think smells like food, eat and get alcohol poisoning.” For example, the FDA received a report about a consumer who purchased a bottle that looked like drinkable water but was actually hand sanitizer.

In another report, a retailer informed the agency about a hand sanitizer product that was marketed in a pouch that looks like a children’s snack and had cartoons on it. Meanwhile, the FDA's warning list about dangerous hand sanitizers containing methanol continues to grow as some people are drinking the sanitizers to get an alcohol high. Others have believed a rumor, circulated online, that drinking the highly potent and toxic alcohol can disinfect the body, protecting them from COVID-19 infection. Earlier this month, the FDA also issued a warning about hand sanitizers contaminated with 1-propanol. Ingesting 1-propanol can cause central nervous system depression, which can be fatal, the agency says.

Symptoms of 1-propanol exposure can include confusion, decreased consciousness, and slowed pulse and breathing. One brand of sanitizer, Harmonic Nature S de RL de MI of Mexico, are labeled to contain ethanol or isopropyl alcohol but have tested positive for 1-propanol contamination. Poison control centers and state health departments have reported an increasing number of adverse events associated with hand sanitizer ingestion, including heart issues, nervous system problems, hospitalizations and deaths, according to the statement. The FDA encouraged consumers and health care professionals to report issues to the MedWatch Adverse Event Reporting program. The agency is working with manufacturers to recall confusing and dangerous products and is encouraging retailers to remove some products from shelves.

The FDA is also updating its list of hand sanitizer products that consumers should avoid. €œManufacturers should be vigilant about packaging and marketing their hand sanitizers in food or drink packages in an effort to mitigate any potential inadvertent use by consumers,” Hahn said..


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