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OCI works with other agencies across the Department to help employers understand how to comply with our laws and regulations and buy glucovance canada help workers understand their rights. The goal is to ultimately reduce violations, which frees the Department up to focus its enforcement resources on the truly bad actors.As we reflect on OCI’s second anniversary, here are five highlights of what we’ve accomplished working with agency partners at the Department. Hosted, supported, and promoted 6,000+ events in fiscal year 2019 to educate employers glucovance tablet about their responsibilities and to gather feedback about how the Department can support them.

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We heard from many stakeholders that they needed an easy-to-use web tool to understand employer coverage and worker eligibility under the new law. We turned this innovative idea into the Wage and Hour Division’s interactive Paid Leave Eligibility Tool, which helps workers determine if they qualify for buy glucovance canada leave for reasons related to the coronavirus. The web tool already has more than 111,000 views since its launch in late June.

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Only official editions of buy glucovance online usa the Federal Register provide legal notice to the public and judicial notice to the courts under 44 U.S.C. 1503 & buy glucovance online usa. 1507.

Learn more here.Start Preamble buy glucovance online usa Centers for Medicare &. Medicaid Services buy glucovance online usa (CMS), HHS. Final rule.

Correction. This document corrects technical errors that appeared in the final rule published in the Federal Register on June 2, 2020 entitled “Medicare Program. Contract Year 2021 Policy and Technical Changes to the Medicare Advantage Program, Medicare Prescription Drug Benefit Program, and Medicare Cost Plan Program.” Effective date.

This correcting document is effective on October 13, 2020. Start Further Info Cali Diehl, (410) 786-4053 or Christopher McClintick, (410) 786-4682—General Questions. Kimberlee Levin, (410) 786-2549—Part C Issues.

Stacy Davis, (410) 786-7813—Part C and D Payment Issues. Melissa Seeley, (212) 616-2329—D-SNP Issues. End Further Info End Preamble Start Supplemental Information I.

Background In FR Doc. 2020-11342 of June 2, 2020 (85 FR 33796), there were a number of technical errors that are identified and corrected in this correcting document. The provisions in this correction document are effective as if they had been included in the document published June 2, 2020.

Accordingly, the corrections are effective August 3, 2020. II. Summary of Errors On page 33820, in our discussion of dual eligible special needs plans, we inadvertently included a disclaimer that was not applicable to the published final rule.

On pages 33876 and 33877, in our discussion of the information collection requirements regarding Special Supplemental Benefits for the Chronically Ill (SSBCI), we inadvertently identified the wrong Paperwork Reduction Act package in our narrative and omitted several Office of Management and Budget (OMB) control numbers from Table 3. On page 33881, in our discussion of the information collection requirements regarding medical savings account (MSA) medical loss ratio (MLR), we made inadvertent errors the amount of time it would take beneficiaries to complete an enrollment form. On page 33883, in the table that provides a summary of the annual information collection burden (Table 6), we made the following typographical errors.

In the table title, we included the term “requirements” instead of “burden”.Start Printed Page 64402 In the SSBCI entries there were errors in the identification numbers in the “OMB Control No.” column. In the MSA MLR entries, there were errors in the values and numbers for the “Regulatory citation”, “OMB Control No.”, “Total number of respondents”, and the “Total number of responses”. On pages 33889 and 33890, in the table that displays the per-year calculations regarding kidney acquisition costs (Table 11), we made inadvertent errors in the table title (we omitted “s” in the term “costs”).

Additionally, on page 33890, the column headings are listed for the years 2013 to 2020 instead of 2021 to 2030. III. Waiver of Proposed Rulemaking Under 5 U.S.C.

553(b) of the Administrative Procedure Act (APA), the agency is required to publish a notice of the proposed rule in the Federal Register before the provisions of a rule take effect. Similarly, section 1871(b)(1) of the Act requires the Secretary to provide for notice of the proposed rule in the Federal Register and provide a period of not less than 60 days for public comment. In addition, section 553(d) of the APA, and section 1871(e)(1)(B)(i) of the Act mandate a 30-day delay in effective date after issuance or publication of a rule.

Sections 553(b)(B) and 553(d)(3) of the APA provide for exceptions from the notice and comment and delay in effective date APA requirements. In cases in which these exceptions apply, sections 1871(b)(2)(C) and 1871(e)(1)(B)(ii) of the Act provide exceptions from the notice and 60-day comment period and delay in effective date requirements of the Act as well. Section 553(b)(B) of the APA and section 1871(b)(2)(C) of the Act authorize an agency to dispense with normal rulemaking requirements for good cause if the agency makes a finding that the notice and comment process are impracticable, unnecessary, or contrary to the public interest.

In addition, both section 553(d)(3) of the APA and section 1871(e)(1)(B)(ii) of the Act allow the agency to avoid the 30-day delay in effective date where such delay is contrary to the public interest and an agency includes a statement of support. Section 553(d) of the APA ordinarily requires a 30-day delay in effective date of final rules after the date of their publication in the Federal Register. This 30-day delay in effective date can be waived, however, if an agency finds for good cause that the delay is impracticable, unnecessary, or contrary to the public interest, and the agency incorporates a statement of the findings and its reasons in the rule issued.

We believe that this correcting document does not constitute a rule that would be subject to the notice and comment or delayed effective date requirements of the APA or section 1871 of the Act. This correcting document corrects technical errors in the preamble and regulation text of the final rule but does not make substantive changes to the policies that were adopted in the final rule. As a result, this correcting document is intended to ensure that the information in the final rule accurately reflects the policies adopted in that final rule.

In addition, even if this were a rule to which the notice and comment procedures and delayed effective date requirements applied, we find that there is good cause to waive such requirements. Undertaking further notice and comment procedures to incorporate the corrections in this document into the final rule or delaying the effective date would be contrary to the public interest because it is in the public's interest to ensure that final rule accurately reflects our policies. Furthermore, such procedures would be unnecessary, as we are not altering payment eligibility or benefit methodologies or policies, but rather, simply implementing correctly the policies that we previously proposed, received comment on, and subsequently finalized.

This correcting document is intended solely to ensure that the final rule accurately reflects these policies. Therefore, we believe we have good cause to waive the notice and comment and effective date requirements. IV.

Correction of Errors In FR Doc. 2020-11342 of June 2, 2020 (85 FR 33796), make the following corrections. 1.

On page 33820, lower third of the page, the text box that includes the phrase “DISCLAIMER. Based on the tight time constraints and the need to expedite” is corrected by removing the text box. 2.

On page 33876, lower three-fourths of the page (after the table), second column, sixth full paragraph, lines 6 and 7, the reference to “control number 0938-0763 (CMS-R-262)” is corrected to read “control number 0938-0753 (CMS-R-267)”. 3. On page 33877, lower third of the page, the table titled “TABLE 3—SUMMARY OF BURDEN FOR SSBCI AT § 422.102” is corrected by correcting the third column (OMB Control No.) for the listed entries (SSBCI provisions) to read as follows.

ProvisionRegulatory citationOMB Control No.SubjectNumber of respondentsTotal number of responsesTime per response (hr)Total time (hr)Labor cost ($/hr)Annual cost ($)SSBCI§ 422.102(f)(3)(i)0938-0753SSBCI. Criteria (Initial Software)2341122808103.3396,717SSBCI§ 422.102(f)(3)(i)0938-0753SSBCI. Criteria (Physician review)2341368424193.71,631,729SSBCI§ 422.102(f)(3)(i)0938-0753SSBCI.

Criteria (Software updates)23415117085.2699,754SSBCI§ 422.102(f)(3)(ii)0938-0753Written criteria2341246856.3426,367SSBCI§ 422.102(f)(3)(iii)0938-0753Enrollee eligibility23419210686.95179,465 4. On page 33881, first column, fourth full paragraph, line 8, the phrase “0.5 hours at $25.72/hr” is corrected to read “0.3333 hours at $25.72/hr” 5. On page 33883, in the table titled “TABLE 6—ANNUAL INFORMATION COLLECTION REQUIREMENTS” the table is corrected by— a.

Correcting the table title “TABLE 6—ANNUAL INFORMATION COLLECTION REQUIREMENTS” to read “TABLE 6—ANNUAL INFORMATION COLLECTION BURDEN”. B. Correcting the second (Regulatory citation), third (OMB Control No.), sixth (Total number of respondents), and seventh columns (Total number of responses) for the listed entry (third row the first MSA MLR provision) to read as follows:Start Printed Page 64403 ProvisionRegulatory citationOMB Control No.Respondent typeResponse summaryTotal number of respondentsTotal number of responsesTime per response (hr)Total annual time (hr)Labor cost ($/hr)Total annual cost ($)MSA MLR§ 422.24400938-NEWEnrolleesMSA MLR.

Filling out enrollment forms.2,7652,7650.333392225.7223,705 c. Correcting the identification numbers in third column (OMB Control No.) for the listed entries (SSBCI provisions) to read as follows. ProvisionRegulatory citationOMB Control No.Respondent typeResponse summaryTotal number of respondentsTotal number of responsesTime per response (hr)Total annual time (hr)Labor cost ($/hr)Total annual cost ($)SSCBI§ 422.102(f)(3)(i)0938-0753MA PlansSSBCI.

Criteria (initial software update)2341122808103.3396,717SSCBI§ 422.102(f)(3)(i)0938-0753MA PlansSSBCI. Criteria (Annual physician review)2341368424193.71,631,729SSCBI§ 422.102(f)(3)(i)0938-0753MA PlansSSBCI. Criteria (Software updates)23415117085.2699,754SSCBI§ 422.102(f)(3)(ii)0938-0753MA PlansSSBCI.

Documentation2341246856.3426,367SSCBI§ 422.102(f)(3)(iii)0938-0753MA PlansSSBCI. Enrollee records2341970286.9561,039 d. Correcting the second (Regulatory citation) and seventh columns (Total number of responses) for the listed entries (the specified MSA MLR provisions) to read as follows.

ProvisionRegulatory citationOMB Control No.Respondent typeResponse summaryTotal number of respondentsTotal number of responsesTime per response (hr)Total annual time (hr)Labor cost ($/hr)Total annual cost ($)MSA MLR§ 422.24400938-0753MA PlansMSA MLR. Notify enrollees82,7650.01674677.143,548MSA MLR§ 422.24400938-0753MA PlansMSA MLR. Submit to CMS82,7650.01674677.143,548MSA MLR§ 422.24400938-0753MA PlansMSA MLR.

Archive82,7650.083323036.828,481 e. Correcting column 2 (Regulatory citation) for the listed entry (the specified MSA MLR provision) to read as follows. ProvisionRegulatory citationOMB Control No.Respondent typeResponse summaryTotal number of respondentsTotal number of responsesTime per response (hr)Total annual time (hr)Labor cost ($/hr)Total annual cost ($)MSA MLR§ 422.24400938-1252MA PlansMSA MLR.

Calculation of the deductible factor880.08330.6664116.3278 6. On pages 33889 and 33890, in the table titled “Table 11, Per-Year Calculations, Representing the Pre-Statute Baseline Based on Medicare FFS Coverage of Kidney Acquisition Cost”, the table title and table are corrected to read as follows. Table 11—Per-Year Calculations, Representing the Pre-Statute Baseline Based on Medicare FFS Coverage of Kidney Acquisition Costs 20132014201520162017201820192020   Kidney Acquisition Costs (PMPM):1.721.821.952.082.202.342.492.65 20212022202320242025202620272028202920302021-2030Kidney Acquisition Costs (PMPM):2.823.003.203.403.623.854.104.364.644.94Medicare Advantage Enrollment Projection (000's):24,69025,62426,50827,38028,23729,07029,86130,60731,31332,035Gross Savings ($Millions):836.2923.51,016.61,117.41,226.31,343.41,468.41,601.71,743.71,898.413,175.6Average government share of Gross Savings:83.0%83.0%83.0%83.1%83.2%83.2%83.2%83.4%83.4%83.4%Net of Part B Premium:85.6%85.6%85.5%85.4%85.3%85.2%85.0%84.9%84.9%84.9%Net Savings ($Millions):594.1655.7721.5792.3869.5951.71,038.91,134.11,235.91,345.69,339.3 Start Signature Start Printed Page 64404 Dated.

October 1, 2020. Wilma M. Robinson, Deputy Executive Secretary to the Department, Department of Health and Human Services.

End Signature End Supplemental Information [FR Doc. 2020-22481 Filed 10-8-20. 8:45 am]BILLING CODE 4120-01-P.

This document get glucovance online is unpublished buy glucovance canada. It is scheduled to be published on 10/16/2020 buy glucovance canada. Once it is published it will be available on this page in an official form. Until then, you can download the unpublished PDF version buy glucovance canada. Although we make a concerted effort to buy glucovance canada reproduce the original document in full on our Public Inspection pages, in some cases graphics may not be displayed, and non-substantive markup language may appear alongside substantive text.

If you are using public inspection listings for legal research, you should verify the contents of documents against a final, official edition of the Federal Register. Only official editions of the Federal Register provide legal notice to the public and judicial buy glucovance canada notice to the courts under 44 U.S.C. 1503 & buy glucovance canada. 1507. Learn more here.Start Preamble Centers for Medicare & buy glucovance canada.

Medicaid Services buy glucovance canada (CMS), HHS. Final rule. Correction. This document corrects technical errors that appeared in the final rule published in the Federal Register on June 2, 2020 entitled “Medicare Program. Contract Year 2021 Policy and Technical Changes to the Medicare Advantage Program, Medicare Prescription Drug Benefit Program, and Medicare Cost Plan Program.” Effective date.

This correcting document is effective on October 13, 2020. Start Further Info Cali Diehl, (410) 786-4053 or Christopher McClintick, (410) 786-4682—General Questions. Kimberlee Levin, (410) 786-2549—Part C Issues. Stacy Davis, (410) 786-7813—Part C and D Payment Issues. Melissa Seeley, (212) 616-2329—D-SNP Issues.

End Further Info End Preamble Start Supplemental Information I. Background In FR Doc. 2020-11342 of June 2, 2020 (85 FR 33796), there were a number of technical errors that are identified and corrected in this correcting document. The provisions in this correction document are effective as if they had been included in the document published June 2, 2020. Accordingly, the corrections are effective August 3, 2020.

II. Summary of Errors On page 33820, in our discussion of dual eligible special needs plans, we inadvertently included a disclaimer that was not applicable to the published final rule. On pages 33876 and 33877, in our discussion of the information collection requirements regarding Special Supplemental Benefits for the Chronically Ill (SSBCI), we inadvertently identified the wrong Paperwork Reduction Act package in our narrative and omitted several Office of Management and Budget (OMB) control numbers from Table 3. On page 33881, in our discussion of the information collection requirements regarding medical savings account (MSA) medical loss ratio (MLR), we made inadvertent errors the amount of time it would take beneficiaries to complete an enrollment form. On page 33883, in the table that provides a summary of the annual information collection burden (Table 6), we made the following typographical errors.

In the table title, we included the term “requirements” instead of “burden”.Start Printed Page 64402 In the SSBCI entries there were errors in the identification numbers in the “OMB Control No.” column. In the MSA MLR entries, there were errors in the values and numbers for the “Regulatory citation”, “OMB Control No.”, “Total number of respondents”, and the “Total number of responses”. On pages 33889 and 33890, in the table that displays the per-year calculations regarding kidney acquisition costs (Table 11), we made inadvertent errors in the table title (we omitted “s” in the term “costs”). Additionally, on page 33890, the column headings are listed for the years 2013 to 2020 instead of 2021 to 2030. III.

Waiver of Proposed Rulemaking Under 5 U.S.C. 553(b) of the Administrative Procedure Act (APA), the agency is required to publish a notice of the proposed rule in the Federal Register before the provisions of a rule take effect. Similarly, section 1871(b)(1) of the Act requires the Secretary to provide for notice of the proposed rule in the Federal Register and provide a period of not less than 60 days for public comment. In addition, section 553(d) of the APA, and section 1871(e)(1)(B)(i) of the Act mandate a 30-day delay in effective date after issuance or publication of a rule. Sections 553(b)(B) and 553(d)(3) of the APA provide for exceptions from the notice and comment and delay in effective date APA requirements.

In cases in which these exceptions apply, sections 1871(b)(2)(C) and 1871(e)(1)(B)(ii) of the Act provide exceptions from the notice and 60-day comment period and delay in effective date requirements of the Act as well. Section 553(b)(B) of the APA and section 1871(b)(2)(C) of the Act authorize an agency to dispense with normal rulemaking requirements for good cause if the agency makes a finding that the notice and comment process are impracticable, unnecessary, or contrary to the public interest. In addition, both section 553(d)(3) of the APA and section 1871(e)(1)(B)(ii) of the Act allow the agency to avoid the 30-day delay in effective date where such delay is contrary to the public interest and an agency includes a statement of support. Section 553(d) of the APA ordinarily requires a 30-day delay in effective date of final rules after the date of their publication in the Federal Register. This 30-day delay in effective date can be waived, however, if an agency finds for good cause that the delay is impracticable, unnecessary, or contrary to the public interest, and the agency incorporates a statement of the findings and its reasons in the rule issued.

We believe that this correcting document does not constitute a rule that would be subject to the notice and comment or delayed effective date requirements of the APA or section 1871 of the Act. This correcting document corrects technical errors in the preamble and regulation text of the final rule but does not make substantive changes to the policies that were adopted in the final rule. As a result, this correcting document is intended to ensure that the information in the final rule accurately reflects the policies adopted in that final rule. In addition, even if this https://www.cityreal.lv/can-you-buy-over-the-counter-glucovance/ were a rule to which the notice and comment procedures and delayed effective date requirements applied, we find that there is good cause to waive such requirements. Undertaking further notice and comment procedures to incorporate the corrections in this document into the final rule or delaying the effective date would be contrary to the public interest because it is in the public's interest to ensure that final rule accurately reflects our policies.

Furthermore, such procedures would be unnecessary, as we are not altering payment eligibility or benefit methodologies or policies, but rather, simply implementing correctly the policies that we previously proposed, received comment on, and subsequently finalized. This correcting document is intended solely to ensure that the final rule accurately reflects these policies. Therefore, we believe we have good cause to waive the notice and comment and effective date requirements. IV. Correction of Errors In FR Doc.

2020-11342 of June 2, 2020 (85 FR 33796), make the following corrections. 1. On page 33820, lower third of the page, the text box that includes the phrase “DISCLAIMER. Based on the tight time constraints and the need to expedite” is corrected by removing the text box. 2.

On page 33876, lower three-fourths of the page (after the table), second column, sixth full paragraph, lines 6 and 7, the reference to “control number 0938-0763 (CMS-R-262)” is corrected to read “control number 0938-0753 (CMS-R-267)”. 3. On page 33877, lower third of the page, the table titled “TABLE 3—SUMMARY OF BURDEN FOR SSBCI AT § 422.102” is corrected by correcting the third column (OMB Control No.) for the listed entries (SSBCI provisions) to read as follows. ProvisionRegulatory citationOMB Control No.SubjectNumber of respondentsTotal number of responsesTime per response (hr)Total time (hr)Labor cost ($/hr)Annual cost ($)SSBCI§ 422.102(f)(3)(i)0938-0753SSBCI. Criteria (Initial Software)2341122808103.3396,717SSBCI§ 422.102(f)(3)(i)0938-0753SSBCI.

Criteria (Physician review)2341368424193.71,631,729SSBCI§ 422.102(f)(3)(i)0938-0753SSBCI. Criteria (Software updates)23415117085.2699,754SSBCI§ 422.102(f)(3)(ii)0938-0753Written criteria2341246856.3426,367SSBCI§ 422.102(f)(3)(iii)0938-0753Enrollee eligibility23419210686.95179,465 4. On page 33881, first column, fourth full paragraph, line 8, the phrase “0.5 hours at $25.72/hr” is corrected to read “0.3333 hours at $25.72/hr” 5. On page 33883, in the table titled “TABLE 6—ANNUAL INFORMATION COLLECTION REQUIREMENTS” the table is corrected by— a. Correcting the table title “TABLE 6—ANNUAL INFORMATION COLLECTION REQUIREMENTS” to read “TABLE 6—ANNUAL INFORMATION COLLECTION BURDEN”.

B. Correcting the second (Regulatory citation), third (OMB Control No.), sixth (Total number of respondents), and seventh columns (Total number of responses) for the listed entry (third row the first MSA MLR provision) to read as follows:Start Printed Page 64403 ProvisionRegulatory citationOMB Control No.Respondent typeResponse summaryTotal number of respondentsTotal number of responsesTime per response (hr)Total annual time (hr)Labor cost ($/hr)Total annual cost ($)MSA MLR§ 422.24400938-NEWEnrolleesMSA MLR. Filling out enrollment forms.2,7652,7650.333392225.7223,705 c. Correcting the identification numbers in third column (OMB Control No.) for the listed entries (SSBCI provisions) to read as follows. ProvisionRegulatory citationOMB Control No.Respondent typeResponse summaryTotal number of respondentsTotal number of responsesTime per response (hr)Total annual time (hr)Labor cost ($/hr)Total annual cost ($)SSCBI§ 422.102(f)(3)(i)0938-0753MA PlansSSBCI.

Criteria (initial software update)2341122808103.3396,717SSCBI§ 422.102(f)(3)(i)0938-0753MA PlansSSBCI. Criteria (Annual physician review)2341368424193.71,631,729SSCBI§ 422.102(f)(3)(i)0938-0753MA PlansSSBCI. Criteria (Software updates)23415117085.2699,754SSCBI§ 422.102(f)(3)(ii)0938-0753MA PlansSSBCI. Documentation2341246856.3426,367SSCBI§ 422.102(f)(3)(iii)0938-0753MA PlansSSBCI. Enrollee records2341970286.9561,039 d.

Correcting the second (Regulatory citation) and seventh columns (Total number of responses) for the listed entries (the specified MSA MLR provisions) to read as follows. ProvisionRegulatory citationOMB Control No.Respondent typeResponse summaryTotal number of respondentsTotal number of responsesTime per response (hr)Total annual time (hr)Labor cost ($/hr)Total annual cost ($)MSA MLR§ 422.24400938-0753MA PlansMSA MLR. Notify enrollees82,7650.01674677.143,548MSA MLR§ 422.24400938-0753MA PlansMSA MLR. Submit to CMS82,7650.01674677.143,548MSA MLR§ 422.24400938-0753MA PlansMSA MLR. Archive82,7650.083323036.828,481 e.

Correcting column 2 (Regulatory citation) for the listed entry (the specified MSA MLR provision) to read as follows. ProvisionRegulatory citationOMB Control No.Respondent typeResponse summaryTotal number of respondentsTotal number of responsesTime per response (hr)Total annual time (hr)Labor cost ($/hr)Total annual cost ($)MSA MLR§ 422.24400938-1252MA PlansMSA MLR. Calculation of the deductible factor880.08330.6664116.3278 6. On pages 33889 and 33890, in the table titled “Table 11, Per-Year Calculations, Representing the Pre-Statute Baseline Based on Medicare FFS Coverage of Kidney Acquisition Cost”, the table title and table are corrected to read as follows. Table 11—Per-Year Calculations, Representing the Pre-Statute Baseline Based on Medicare FFS Coverage of Kidney Acquisition Costs 20132014201520162017201820192020   Kidney Acquisition Costs (PMPM):1.721.821.952.082.202.342.492.65 20212022202320242025202620272028202920302021-2030Kidney Acquisition Costs (PMPM):2.823.003.203.403.623.854.104.364.644.94Medicare Advantage Enrollment Projection (000's):24,69025,62426,50827,38028,23729,07029,86130,60731,31332,035Gross Savings ($Millions):836.2923.51,016.61,117.41,226.31,343.41,468.41,601.71,743.71,898.413,175.6Average government share of Gross Savings:83.0%83.0%83.0%83.1%83.2%83.2%83.2%83.4%83.4%83.4%Net of Part B Premium:85.6%85.6%85.5%85.4%85.3%85.2%85.0%84.9%84.9%84.9%Net Savings ($Millions):594.1655.7721.5792.3869.5951.71,038.91,134.11,235.91,345.69,339.3 Start Signature Start Printed Page 64404 Dated.

October 1, 2020. Wilma M. Robinson, Deputy Executive Secretary to the Department, Department of Health and Human Services. End Signature End Supplemental Information [FR Doc. 2020-22481 Filed 10-8-20.

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It makes where to buy glucovance online me very proud to call these nurses my friends. As a former emergency 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 where to buy glucovance online. Several years ago I made 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 where to buy glucovance online play in health care and what the real priority should be. Things that 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 where to buy glucovance online 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 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 where to buy glucovance online FaceTime). I was tech-savvy from a consumer perspective and a 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online. We are holding all of the bills for at least 90 days while the industry sorts out the rules. 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 where to buy glucovance online. 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 (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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online days it was open. That is 900 real patients that received care from a 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 where to buy glucovance online 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 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 where to buy glucovance online 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 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 where to buy glucovance online normal flu season?.

Is it any more appropriate 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 where to buy glucovance online visits. Not a single one of these would 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 where to buy glucovance online care is no exception. It has put priorities in perspective and shined a light on 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 where to buy glucovance online 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 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 where to buy glucovance online 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, 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 where to buy glucovance online foot complications.

It’s important 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, where to buy glucovance online tingling and/or burning in your feet and legs. You can slow the progression of developing neuropathy by making it a point to 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 where to buy glucovance online things to your attention to monitor and keep a close eye on. Open wounds 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 where to buy glucovance online 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 proper medical attention is sought right away.

There are important things to remember when dealing with diabetic foot care. It’s very where to buy glucovance online 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. Be gentle when bathing your feet. Moisturize your feet, but not between your toes.

Do not treat calluses 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 &. Ankle Specialists of Mid-Michigan in Midland.

Those who would like to make an appointment may contact her office at (989) 488-6355..

There’s a buy glucovance online usa reason buy glucovance canada 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 department nurse, I recall the feeling of satisfaction knowing that I’ve helped buy glucovance canada 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 decision to no longer perform bedside nursing and become buy glucovance canada 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 buy glucovance canada 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 our organization in 2015 I knew nothing about telehealth buy glucovance canada. 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 buy glucovance canada tech-savvy from a consumer perspective and a 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 that we could buy glucovance canada 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 buy glucovance canada 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 buy glucovance canada find is 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 buy glucovance canada understands this and instead focuses on how can 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 buy glucovance canada was about 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 buy glucovance canada the simplest way to summarize it is that most virtual care 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 it takes to build a virtual care network buy glucovance canada 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 buy glucovance canada impact is when the Centers for Medicare and Medicaid 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 buy glucovance canada 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 buy glucovance canada the rules. 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 buy glucovance canada 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 buy glucovance canada surrounding specific 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 buy glucovance canada by 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 and HIPAA regulations changed what is possible for buy glucovance canada 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 buy glucovance canada 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 physician or advanced practice provider without risking personal exposure and without going to an already overwhelmed buy glucovance canada 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 buy glucovance canada 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 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 buy glucovance canada an immunocompromised cancer patient right now and being asked to 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 to ask them to risk exposure to buy glucovance canada 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 I would have gotten approval to buy glucovance canada 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 buy glucovance canada 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 the focus to buy glucovance canada 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 buy glucovance canada 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 buy glucovance canada 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 manage your blood sugars and keep them in the buy glucovance canada 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 ulcers buy glucovance canada 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 proper medical attention is sought right buy glucovance canada 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 buy glucovance canada 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 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 &.

Glucovance cost

The human connectionWhen writing this primary survey under the cloud of COVID-19, it is encouraging to see so many excellent papers being submitted to EMJ knowing that glucovance cost many of these have been written and re written in a time of adversity and the greatest challenge our specialty has faced. This issue has papers that cover the wide range of emergency medicine all of which are informative and interesting, but, for me the most moving and poignant paper of all is ‘The View from Here’ written by Landry and Ouchi in Boston. They describe glucovance cost how one doctor used her phone to make a brief video which allowed an elderly dying patient to say a last few precious words of love to his family who could not be with him because of the virus. She then sent the video to his family.

It was, in her own words ‘a desire to provide connection in a deeply difficult time and to preserve the patient’s final conscious moments, she didn’t want these intensely emotional moments and thoughts to belong only to glucovance cost her, she wanted to offer them to his loved ones as well’. This doctor’s empathy and deep compassion for this dying man and his family epitomises true humanity and the great privilege we have as clinicians sharing such moments in our patients’ lives. The silver lining of this cruel virus is that it has brought to the fore the very best in healthcare staff where there have been countless examples of extraordinary acts of human kindness that have helped lighten the burden and sadness that is COVID-19. Many of us have been touched personally by tragedy and sadness during this time and we have been encouraged and inspired by the glucovance cost compassion and fortitude demonstrated by our colleagues.

We can be confident that our specialty irrespective of future challenges will be underpinned by kindness and the human connection. Do read glucovance cost this paper, it is humbling, but also reassuring in times of such anxiety and upheaval. Most of all, it is an important human account for posterity.Under triaging the older patientUnder triage in the older patient is an ongoing concern, as major trauma in older patients is on the increase it is worrying that serious injury might not always be recognised in this group. Hoyle and colleagues in the glucovance cost UK undertook a retrospective review of the Trauma Audit&.

Research Network (TARN) data of a 3 month period from 2014 to investigate this concern. Their findings give some substance to these concerns as they found mortality higher in older patients despite a lower median ISS. Older patients were significantly less likely to have the attention of a consultant first attender or trauma team and similar trends were also seen on subgroup analysis by mechanism glucovance cost of injury or number of injured body areas. While more recent interventions and awareness focusing on the older patient in the ED may have improved initial assessment there is little room for complacency, older patients deserve the same urgency as younger patients.

Do read glucovance cost this paper even if this has not been your experience the findings are a reminder of the need for equitable care.Two other papers among the many worthy of mention in this issue relate to common presentations in the ED, Headache and Colles’fracture.Editors’s choiceHeadache, a common presentations in the ED can be a high risk consultation. Many physicians use an IV fluid bolus as part of a cocktail of treatments for patients presenting with headaches even though the benefit of this treatment is less than clear. Zitek and colleagues undertook a randomised single -blinded clinical trial on patients from the age of glucovance cost 10 years to 65 years who presented to a single ED in Nevada USA to determine if an IV fluid bolus would help reduce pain or improve other outcomes for those with a benign headache. All patients received Prochlorperazine and Diphenhydramine and they were randomised to receive either 20 mL/kg up to 1000 ML of normal saline (the fluid bolus group) or 5 mL (the control group).

Perhaps, surprisingly, the patients that received the fluid bolus for their headache had similar improvement in their pain and other outcomes as those who did not. So it seems fluid is not the cure.Fixing broken bonesIn the UK, Colles’ fractures account glucovance cost for nearly one sixth of all fractures presenting to the ED. Learning how to manipulate a Colles’ fracture usually under a haematoma block is a rite of passage for most trainees but we rarely get to hear how these patients fare afterwards or how effective our management has been. It was interesting therefore to glucovance cost read a paper by Malik and colleagues in this issue.

In response to a local audit that suggested a high proportion of these injuries often need surgical fixation, they conducted a multicentre observational study in 16 Emergency departments in February and March 2019 of all patients who underwent manipulation of a Colles’ fracture in the ED. Of the 328 patients who presented with a distal radius fracture during the study period, 83 underwent fracture manipulation and were eligible for the study. Of these 83 cases 41% required glucovance cost surgical fixation. Younger patients were more likely to have surgical fixation but the ED anaesthetic used did not affect the subsequent need for surgery in this sample.

The authors suggest these findings merit further research particularly in glucovance cost terms of rationalising repeat procedures.The first confirmed cases of COVID-19 in the UK were recorded on the 29 January 2020. 3 days later, the UK government declared a level 4 incident, allowing for an extraordinary increase in powers and control. Similar severe measures happened all around glucovance cost the world. The first UK death happened 6 days after the first recorded cases and many tens of thousands of deaths rapidly followed.

EDs around the world underwent rapid reconfiguration as national strategies moved from containment to mitigation. The Emergency Medicine Journal has led the way in quickly and usefully reporting these changes with the ‘Reports from the Front’ series.1 The overarching aim of these reconfigurations was to increase capacity for an expected surge in seriously ill patients and to provide glucovance cost a safe working environment for patients and staff. Staff rotas were rewritten, allocating staff to acute areas and increasing senior presence. It proved impossible to predict how many staff would be off sick or need to self-isolate, and many of us were blindsided by the apparent vindictiveness of glucovance cost the virus to older men, diabetics and those from a non-white background.

Processes and protocols had to be all modified to answer the question ‘what if this patient has suspected COVID-19?. €™. Simple working arrangements suddenly became more complex and routine clinical tasks became much more effortful.Many hospitals gave welcome extra space to the emergency medicine service. Quick rebuilding jobs were carried out to increase the amount of space where potentially infectious cases could be seen.

Many changes have been implemented very quickly, and the normal safeguards to ensure they work as intended may be missing. In these cases, it is important to evaluate the changes carefully and adapt where necessary. Some changes may have been harmful, and it is important we are alert to how these might affect our patients.Inpatient capacity improved dramatically, so that many hospitals regularly had extraordinarily better bed states. This was due to a combination of fewer ‘medically fit’ patients remaining in hospital, acceptance of different admission and discharge thresholds, improvements in pathways within hospitals and reductions in elective surgery.

This illustrates that delayed transfers of care and the resulting exit block is not an insoluble problem and can be fixed where there is a political, financial, managerial and clinical will. Patient flow improved, and many EDs are less crowded as result of all these changes.Our community and inpatient colleagues underwent a paradigm shift in providing care by video conference. Our departments were confronted by the full spectrum of disease severity that the COVID-19 can cause. Initially large proportions of other patients stayed away from our EDs in March and April.

Some of this will have been serious cases, but a lot more will have been the lower acuity presentations that previously congested our departments. There are multiple, complicated reasons why this happened, some of this will have been from the obvious result of lockdown. Understanding this will keep health service researchers and policy makers busy for a while, but this has been the most extraordinary behavioural intervention of our generation, and it would be a wasted opportunity not to analyse this properly.2 As we move from a pandemic to an endemic state, delivery of care must also change to ensure this—and similar diseases—can be managed safely, alongside regular emergency care, within our departments and wider healthcare systems. Past reorganisations and reform of healthcare delivery have put increased pressure on EDs as they are perceived to be ‘safe places’ by the public and other parts of the system and become the default option for all healthcare needs.

This has contributed to unsustainable overcrowding and corridor care in EDs.3 We must learn from this response and make changes to our future operations. As we progress beyond the peak of this outbreak, we must act now to ensure patient safety is never jeopardised again through poor infection control, design, physical crowding, inadequate staff protection and corridor care.It is also important that the public, who pay for and use these services, are meaningfully consulted as to how EDs need to change. However, EDs should return to their original core purpose. The rapid assessment and emergency stabilisation of seriously ill and injured patients.

They can no longer be used to pick up the pieces where community, ‘out of hours’ or specialist care has struggled, or chosen not, to cope. Our colleagues in primary care must be able to safely offer face-to-face consultations and physical examination.As some form of order (and our patients) return, there is a need to consider how things must change in the future. The COVID-19 is likely to circulate for the immediate future, and this will influence how EDs operate. The Royal College of Emergency Medicine, along with a number of other emergency medicine professional bodies around the world, has published a position statement, ‘COVID-19.

Resetting Emergency Department Care’.4–6 The position statement makes a series of radical recommendations about how ED care needs to change, and these have gained support from regulators (see box 1).Box 1 Royal College of Emergency Medicine recommendations for resetting emergency careImproved infection control,Reducing crowding and improving safety.Patients under the care of specialist teams.Physical ED redesign.Using COVID-19 testing for best care.Metrics to support reduced crowding.Improved infection control means that our departments need to be cleaner and bigger, staff need to be provided with appropriate levels of Personal Protective Equipmentand staff need to be trained how to minimise nosocomial infections. The need for social distancing means that we need to establish maximum occupancy thresholds for each area of our department, and this may mean the end of the traditional waiting room as we know it. The link between high inpatient bed capacity and poor infection control is well accepted, and our inpatient areas need to not exceed capacity.There is a moral imperative to ensure our EDs never become crowded again. If we are crowded, we cannot protect patients and staff.

Crowding has long been associated with avoidable mortality, and COVID-19 reinforces and multiplies this risk. It is important to consolidate alternative routes of access for lower acuity patients while maintaining access for those who need the services of EDs and hospitals. Some crowding can be reduced by better integration of community, ambulance and hospital information systems. Experience from Denmark and the Netherlands has shown that primary care and advice lines can have an effective role in providing alternative services and that this can reduce ED attendances.7 8 Lower acuity patients should be offered responsive alternatives to ED care.

In England, there is a programme to develop ‘same day emergency care’ that aims to offer definitive care without hospital admission. This would both ensure the best possible outcomes and lower nosocomial infection risk for patients and staff. The response of the public in complying with the social isolation imposed by lockdown has been impressive and effective. The pandemic has driven use of NHS 111 and other advice lines in a way that had previously not been realised.

Ambulance services have focused heavily on prioritisation and need for conveyance. Primary care and other services have undergone a paradigm shift in how consultations are conducted, and community work is undertaken. There has been a welcome transformation in the way that many specialties have delivered care to their most vulnerable patients to minimise their risk of nosocomial infection by increasing the use of telemedicine and remote consultations. Major changes have been made to the way patients are cared for throughout the system to effectively respond to the pandemic.

Some of these changes are welcome such as increased use of virtual fracture clinics and remote clinics, telemedicine and careful consideration around the value of hospital admissions for very elderly patients and improved end-of-life care. Our role as emergency physicians will have to change as we focus on shortening the length of stay for our patients and reducing overall occupancy. This might involve restricting some areas of practice.Patients with complicated healthcare problems under the care of specialist teams pose particular challenges for emergency care in the pandemic. There need to be realistic and accessible alternative pathways of care so that an immunocompromised patient is not exposed to an avoidable risk of nosocomial infection by waiting in a crowded ED.Many departments are simply not built in a way that promotes good infection prevention control and patient flow.

Some EDs need to be rebuilt with more siderooms.Testing for COVID-19 should not impede patient flow, particularly while turnaround times are long and testing capacity is limited. Until turnaround times improve, hospitals will need to provide cohort areas where patients can wait for test results after their evaluation in the ED.Metrics and performance measures should support reduced crowding. A number of countries have used time based targets for several years, notably the 4-hour access standard in the UK and the National Emergency Access Target in Australia.9–12 Now is the time to introduce metrics that reduce crowding. The Royal College of Emergency Medicine has proposed that this includes a maximum occupancy and a marker for infection control.Many of these actions require action from senior leaders, both inside and outside hospitals.

Our political leaders need to have honest conversations with the public about the limitations of what can be offered in an ED.The College welcomes signs of recovery from the first wave of the pandemic but cautions that we are at the beginning of a long period of necessary transformation. Failing to appreciate this minimises the significant prepandemic problems in urgent and emergency care. There is also a concerning risk that subsequent waves may coincide with a seasonal influenza epidemic, creating more pressure. There will be a ‘nosocomial dividend’ from implementing these recommendations, with reduced infections to staff and patients and improved safety and quality of care, not just from COVID-19 but measles, norovirus and influenza.It is imperative that these recommendations are implemented right through the urgent and emergency care pathway.

The end result would be that our patients are cared for in a safer, less crowded EDs. We cannot treat ill and injured people in an environment that does not allow adequate social distancing..

The human connectionWhen writing this primary survey under the cloud of COVID-19, it is encouraging to see so many excellent papers being submitted to EMJ knowing that buy glucovance canada many of these have been written and re written in a time of adversity and the greatest challenge our specialty has faced. This issue has papers that cover the wide range of emergency medicine all of which are informative and interesting, but, for me the most moving and poignant paper of all is ‘The View from Here’ written by Landry and Ouchi in Boston. They describe how one doctor used her phone to make a brief buy glucovance canada video which allowed an elderly dying patient to say a last few precious words of love to his family who could not be with him because of the virus. She then sent the video to his family. It was, in her own words ‘a desire to provide connection in a deeply difficult time and to preserve the patient’s final conscious moments, she didn’t want these intensely buy glucovance canada emotional moments and thoughts to belong only to her, she wanted to offer them to his loved ones as well’.

This doctor’s empathy and deep compassion for this dying man and his family epitomises true humanity and the great privilege we have as clinicians sharing such moments in our patients’ lives. The silver lining of this cruel virus is that it has brought to the fore the very best in healthcare staff where there have been countless examples of extraordinary acts of human kindness that have helped lighten the burden and sadness that is COVID-19. Many of buy glucovance canada us have been touched personally by tragedy and sadness during this time and we have been encouraged and inspired by the compassion and fortitude demonstrated by our colleagues. We can be confident that our specialty irrespective of future challenges will be underpinned by kindness and the human connection. Do read this paper, it is humbling, but also reassuring in times of such anxiety buy glucovance canada and upheaval.

Most of all, it is an important human account for posterity.Under triaging the older patientUnder triage in the older patient is an ongoing concern, as major trauma in older patients is on the increase it is worrying that serious injury might not always be recognised in this group. Hoyle and colleagues in the UK undertook a retrospective review buy glucovance canada of the Trauma Audit&. Research Network (TARN) data of a 3 month period from 2014 to investigate this concern. Their findings give some substance to these concerns as they found mortality higher in older patients despite a lower median ISS. Older patients were significantly less buy glucovance canada likely to have the attention of a consultant first attender or trauma team and similar trends were also seen on subgroup analysis by mechanism of injury or number of injured body areas.

While more recent interventions and awareness focusing on the older patient in the ED may have improved initial assessment there is little room for complacency, older patients deserve the same urgency as younger patients. Do read this paper even if this has not been your experience the findings are a reminder of the need for equitable care.Two other papers buy glucovance canada among the many worthy of mention in this issue relate to common presentations in the ED, Headache and Colles’fracture.Editors’s choiceHeadache, a common presentations in the ED can be a high risk consultation. Many physicians use an IV fluid bolus as part of a cocktail of treatments for patients presenting with headaches even though the benefit of this treatment is less than clear. Zitek and colleagues undertook a randomised single -blinded clinical trial on patients from the age buy glucovance canada of 10 years to 65 years who presented to a single ED in Nevada USA to determine if an IV fluid bolus would help reduce pain or improve other outcomes for those with a benign headache. All patients received Prochlorperazine and Diphenhydramine and they were randomised to receive either 20 mL/kg up to 1000 ML of normal saline (the fluid bolus group) or 5 mL (the control group).

Perhaps, surprisingly, the patients that received the fluid bolus for their headache had similar improvement in their pain and other outcomes as those who did not. So it seems fluid is not the cure.Fixing broken bonesIn the UK, Colles’ buy glucovance canada fractures account for nearly one sixth of all fractures presenting to the ED. Learning how to manipulate a Colles’ fracture usually under a haematoma block is a rite of passage for most trainees but we rarely get to hear how these patients fare afterwards or how effective our management has been. It was buy glucovance canada interesting therefore to read a paper by Malik and colleagues in this issue. In response to a local audit that suggested a high proportion of these injuries often need surgical fixation, they conducted a multicentre observational study in 16 Emergency departments in February and March 2019 of all patients who underwent manipulation of a Colles’ fracture in the ED.

Of the 328 patients who presented with a distal radius fracture during the study period, 83 underwent fracture manipulation and were eligible for the study. Of these 83 cases 41% buy glucovance canada required surgical fixation. Younger patients were more likely to have surgical fixation but the ED anaesthetic used did not affect the subsequent need for surgery in this sample. The authors suggest these findings merit further research particularly in terms of rationalising repeat procedures.The first confirmed cases of COVID-19 in the buy glucovance canada UK were recorded on the 29 January 2020. 3 days later, the UK government declared a level 4 incident, allowing for an extraordinary increase in powers and control.

Similar severe measures happened all buy glucovance canada around the world. The first UK death happened 6 days after the first recorded cases and many tens of thousands of deaths rapidly followed. EDs around the world underwent rapid reconfiguration as national strategies moved from containment to mitigation. The Emergency Medicine Journal has led the way in quickly and usefully reporting these changes with the ‘Reports from the Front’ series.1 The overarching aim of these reconfigurations was to increase capacity for an expected surge in seriously ill patients and to provide a safe working environment for patients and buy glucovance canada staff. Staff rotas were rewritten, allocating staff to acute areas and increasing senior presence.

It proved impossible to predict how many staff would be off buy glucovance canada sick or need to self-isolate, and many of us were blindsided by the apparent vindictiveness of the virus to older men, diabetics and those from a non-white background. Processes and protocols had to be all modified to answer the question ‘what if this patient has suspected COVID-19?. €™. Simple working arrangements suddenly became more complex and routine clinical tasks became much more effortful.Many hospitals gave welcome extra space to the emergency medicine service. Quick rebuilding jobs were carried out to increase the amount of space where potentially infectious cases could be seen.

Many changes have been implemented very quickly, and the normal safeguards to ensure they work as intended may be missing. In these cases, it is important to evaluate the changes carefully and adapt where necessary. Some changes may have been harmful, and it is important we are alert to how these might affect our patients.Inpatient capacity improved dramatically, so that many hospitals regularly had extraordinarily better bed states. This was due to a combination of fewer ‘medically fit’ patients remaining in hospital, acceptance of different admission and discharge thresholds, improvements in pathways within hospitals and reductions in elective surgery. This illustrates that delayed transfers of care and the resulting exit block is not an insoluble problem and can be fixed where there is a political, financial, managerial and clinical will.

Patient flow improved, and many EDs are less crowded as result of all these changes.Our community and inpatient colleagues underwent a paradigm shift in providing care by video conference. Our departments were confronted by the full spectrum of disease severity that the COVID-19 can cause. Initially large proportions of other patients stayed away from our EDs in March and April. Some of this will have been serious cases, but a lot more will have been the lower acuity presentations that previously congested our departments. There are multiple, complicated reasons why this happened, some of this will have been from the obvious result of lockdown.

Understanding this will keep health service researchers and policy makers busy for a while, but this has been the most extraordinary behavioural intervention of our generation, and it would be a wasted opportunity not to analyse this properly.2 As we move from a pandemic to an endemic state, delivery of care must also change to ensure this—and similar diseases—can be managed safely, alongside regular emergency care, within our departments and wider healthcare systems. Past reorganisations and reform of healthcare delivery have put increased pressure on EDs as they are perceived to be ‘safe places’ by the public and other parts of the system and become the default option for all healthcare needs. This has contributed to unsustainable overcrowding and corridor care in EDs.3 We must learn from this response and make changes to our future operations. As we progress beyond the peak of this outbreak, we must act now to ensure patient safety is never jeopardised again through poor infection control, design, physical crowding, inadequate staff protection and corridor care.It is also important that the public, who pay for and use these services, are meaningfully consulted as to how EDs need to change. However, EDs should return to their original core purpose.

The rapid assessment and emergency stabilisation of seriously ill and injured patients. They can no longer be used to pick up the pieces where community, ‘out of hours’ or specialist care has struggled, or chosen not, to cope. Our colleagues in primary care must be able to safely offer face-to-face consultations and physical examination.As some form of order (and our patients) return, there is a need to consider how things must change in the future. The COVID-19 is likely to circulate for the immediate future, and this will influence how EDs operate. The Royal College of Emergency Medicine, along with a number of other emergency medicine professional bodies around the world, has published a position statement, ‘COVID-19.

Resetting Emergency Department Care’.4–6 The position statement makes a series of radical recommendations about how ED care needs to change, and these have gained support from regulators (see box 1).Box 1 Royal College of Emergency Medicine recommendations for resetting emergency careImproved infection control,Reducing crowding and improving safety.Patients under the care of specialist teams.Physical ED redesign.Using COVID-19 testing for best care.Metrics to support reduced crowding.Improved infection control means that our departments need to be cleaner and bigger, staff need to be provided with appropriate levels of Personal Protective Equipmentand staff need to be trained how to minimise nosocomial infections. The need for social distancing means that we need to establish maximum occupancy thresholds for each area of our department, and this may mean the end of the traditional waiting room as we know it. The link between high inpatient bed capacity and poor infection control is well accepted, and our inpatient areas need to not exceed capacity.There is a moral imperative to ensure our EDs never become crowded again. If we are crowded, we cannot protect patients and staff. Crowding has long been associated with avoidable mortality, and COVID-19 reinforces and multiplies this risk.

It is important to consolidate alternative routes of access for lower acuity patients while maintaining access for those who need the services of EDs and hospitals. Some crowding can be reduced by better integration of community, ambulance and hospital information systems. Experience from Denmark and the Netherlands has shown that primary care and advice lines can have an effective role in providing alternative services and that this can reduce ED attendances.7 8 Lower acuity patients should be offered responsive alternatives to ED care. In England, there is a programme to develop ‘same day emergency care’ that aims to offer definitive care without hospital admission. This would both ensure the best possible outcomes and lower nosocomial infection risk for patients and staff.

The response of the public in complying with the social isolation imposed by lockdown has been impressive and effective. The pandemic has driven use of NHS 111 and other advice lines in a way that had previously not been realised. Ambulance services have focused heavily on prioritisation and need for conveyance. Primary care and other services have undergone a paradigm shift in how consultations are conducted, and community work is undertaken. There has been a welcome transformation in the way that many specialties have delivered care to their most vulnerable patients to minimise their risk of nosocomial infection by increasing the use of telemedicine and remote consultations.

Major changes have been made to the way patients are cared for throughout the system to effectively respond to the pandemic. Some of these changes are welcome such as increased use of virtual fracture clinics and remote clinics, telemedicine and careful consideration around the value of hospital admissions for very elderly patients and improved end-of-life care. Our role as emergency physicians will have to change as we focus on shortening the length of stay for our patients and reducing overall occupancy. This might involve restricting some areas of practice.Patients with complicated healthcare problems under the care of specialist teams pose particular challenges for emergency care in the pandemic. There need to be realistic and accessible alternative pathways of care so that an immunocompromised patient is not exposed to an avoidable risk of nosocomial infection by waiting in a crowded ED.Many departments are simply not built in a way that promotes good infection prevention control and patient flow.

Some EDs need to be rebuilt with more siderooms.Testing for COVID-19 should not impede patient flow, particularly while turnaround times are long and testing capacity is limited. Until turnaround times improve, hospitals will need to provide cohort areas where patients can wait for test results after their evaluation in the ED.Metrics and performance measures should support reduced crowding. A number of countries have used time based targets for several years, notably the 4-hour access standard in the UK and the National Emergency Access Target in Australia.9–12 Now is the time to introduce metrics that reduce crowding. The Royal College of Emergency Medicine has proposed that this includes a maximum occupancy and a marker for infection control.Many of these actions require action from senior leaders, both inside and outside hospitals. Our political leaders need to have honest conversations with the public about the limitations of what can be offered in an ED.The College welcomes signs of recovery from the first wave of the pandemic but cautions that we are at the beginning of a long period of necessary transformation.

Failing to appreciate this minimises the significant prepandemic problems in urgent and emergency care. There is also a concerning risk that subsequent waves may coincide with a seasonal influenza epidemic, creating more pressure. There will be a ‘nosocomial dividend’ from implementing these recommendations, with reduced infections to staff and patients and improved safety and quality of care, not just from COVID-19 but measles, norovirus and influenza.It is imperative that these recommendations are implemented right through the urgent and emergency care pathway. The end result would be that our patients are cared for in a safer, less crowded EDs. We cannot treat ill and injured people in an environment that does not allow adequate social distancing..

Glucovance price in canada

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the https://www.cityreal.lv/can-you-buy-over-the-counter-glucovance/ composition of the multidisciplinary teams that provide care for patients glucovance price in canada who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science glucovance price in canada 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 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 glucovance price in canada 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 for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration glucovance price in canada 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 glucovance price in canada 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 and from the paediatric to glucovance price in canada 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 international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for glucovance price in canada 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 glucovance price in canada Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and glucovance price in canada 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 glucovance price in canada that 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 was discussed by the writing committee and, after having obtained agreement on remaining points of glucovance price in canada 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 glucovance price in canada 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 glucovance price in canada invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring glucovance price in canada 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 restrictions and/or ethical considerations, the glucovance price in canada 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 should refer the couple to their colleague prenatal specialists working with glucovance price in canada 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 glucovance price in canada findings and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can and glucovance price in canada 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 glucovance price in canada in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal glucovance price in canada 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, glucovance price in canada treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, glucovance price in canada 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 glucovance price in canada of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS glucovance price in canada.

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 glucovance price in canada is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference buy glucovance canada 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 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 to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of buy glucovance canada 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 buy glucovance canada DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues.

International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, buy glucovance canada 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 buy glucovance canada 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 buy glucovance canada the prenatal to the 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 international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all buy glucovance canada 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 buy glucovance canada Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, buy glucovance canada multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports buy glucovance canada were excluded, as were articles that 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 was discussed by the writing committee and, after having obtained agreement on buy glucovance canada 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 buy glucovance canada incorporating their input, the final version was presented to the paediatric 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 buy glucovance canada 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 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 buy glucovance canada 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 restrictions and/or ethical considerations, the X buy glucovance canada 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 buy glucovance canada weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

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

The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about buy glucovance canada 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 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 buy glucovance canada. 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 buy glucovance canada 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 buy glucovance canada 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 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 buy glucovance canada algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS buy glucovance canada.

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 buy glucovance canada well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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