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Like we don't have levitra street price enough issues around this already.”The truth is that most of us are online constantly, and the amount of information we’re dealt even within one hour is enough to make your head spin. Who really has the time to go back and fact check every sentence?. Yet, it's a reminder that this kind of dodgy information can have some tragic consequences.“When I started to spend a bit more time on social media in the health space, the more I found just outright nonsense and sadly stories of people who had suffered really dreadful consequences,” Dr Stamp says.“We've all been very aware of Mel levitra street price Gibson's story. It’s not uncommon to see items in the news about people using remedies that they found online for skin conditions, dangerous diets, levitra street price disordered eating, and at the moment, anti-vaccination sentiment.”“There is a study that says most of the misinformation around erectile dysfunction treatment has come from 12 people predominantly. That's crazy, right? levitra street price.

€ she adds.With the viral nature of the internet, just one person disseminating bad advice has the capacity to hurt or injure many, many more. And the truth is, we’re not very good at discerning the levitra street price difference between good and bad information.“Most of us will access and continue to access the Internet, whether it be a Google search or social media for our health information, but the accuracy is really low. Some studies put it levitra street price as low as 20 percent of what we read is legit. So, we actually need to work out ways to try and mitigate some of that risk,” she adds.For Dr Stamp, this is an issue very close to her heart as it largely affects women. She says levitra street price that women tend to be more disenfranchised by health care systems and are also the biggest consumers and practitioners of alternative medicine.

This creates the perfect hot bed for BS to thrive.“I think it's very important that we protect ourselves, protect each other from the dangers of medical misinformation on social media.”So what are her tips to levitra street price sort the wheat from the chaff?. Check their qualificationIn Australia you can check most practitioner's qualifications online and are able to see what they've studied.Confirm their registrationAs a practitioner in Australia you need to maintain your levitra street price registration. Check that the professional hasn’t been de-registered in any way.Make sure they’re talking in their laneA GP talking in depth about nutrition or a nutritionist talking about exercise is a bit of a red flag. Dr Stamp says a good practitioner will defer to someone else if it’s outside their wheelhouse.Money mattersMost of the levitra street price time there will be a reference to the company who paid for the ad if the expert has received compensation for their involvement. Not always, but it can sometimes mean the information has been influenced.Anecdotes vs scienceA good practitioner will clearly differentiate an anecdote ‘this happened to me, or I saw this’ against clinical evidence that has been peer reviewed – so you can clearly see where this information is coming from levitra street price and whether it's backed by mass scientific investigation.LinksLook for links to the study or further footnotes that confirm what the expert is saying is true.It’s not too good to be trueIf it sounds too good to be true it probably is.

Check it against other sources on the internet, look for the opposite opinion and how valid that might be. If someone is saying something can ‘cure all things’ it’s probably BS.If you do find out you've been privy to some levitra street price bad advice online, don't worry - it happens to us all and is quite common. Good job for getting to the bottom of it."I want to say that if you feel like you've been duped by someone, like don't don't be hard on levitra street price yourself. Right?. It's not you," says Dr Stamp.Find out more about Dr Nikki Stamp, here, or on Instagram, @drnikkistamp Her book, Pretty Unhealthy (Murdoch books, $32,99), is available, here.As the cluster in Melbourne’s northern suburbs grows, mask mandates have been reintroduced to quash the spread.The cluster of locally acquired erectile dysfunction treatment cases with mysterious origins has grown to nine, prompting the acting Premier James Merlino to re-introduce certain restrictions until at least June 4 for residents in Greater Melbourne.Masks will again be mandatory indoors for those over the age of levitra street price 12, which includes workplaces, shopping centres, public transport, and supermarkets.If you’re dining inside, you’ll need to wear a mask unless seated at your table and actively eating or drinking.Like what you see?.

Sign up to our bodyandsoul.com.au newsletter for more stories like this.Gatherings at home are limited to five visitors levitra street price per day, while outdoor gatherings are limited to 30. Melburnians are permitted to travel within regional Victoria, but they will be required to wear masks.The good news is life in Melbourne will remain relatively normal, with no changes to density levitra street price caps at hospitality venues.“This is about giving our contact tracers the time they need to track this matter down and get on top of it,” Mr. Merlino told reporters.“Face masks, private and informal gatherings - a reason why we’ve focused in these areas as opposed to businesses and workplaces that will continue under the existing arrangements - it is harder to contact trace in those private and informal settings.”The acting premier also urged all eligible Victorians to get vaccinated as soon as they can."They shouldn't wait for tomorrow, they shouldn't wait for next week. They should move now and go and get vaccinated," he said.erectile dysfunction treatment complacency, not treatment hesitancy, is one likely cause to Australia’s lagging treatment levitra street price rollout. It hasn’t been a serious threat, therefore the urge to get vaccinated is low.“We're levitra street price becoming complacent, and people are thinking, ‘Well, I don't really need to get vaccinated because there's no erectile dysfunction treatment here.’ erectile dysfunction treatment is coming to Australia.

It has to come. Now, whether it's through a breach of our quarantine or because we open the borders, it is coming,” Australian Medical Association president Dr levitra street price. Omar Khorshid said.“The Oxford-AstraZeneca treatment is being used in 139 countries and the Pfizer-BioNTech levitra street price treatment in 90 countries. The evidence from the hundreds of millions of doses delivered in these countries is that both are protecting people from serious illness and hospitalisation and helping to stop the spread of erectile dysfunction treatment.”.

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Trump promised to not implement the most-favored nations policy if drug makers came up with alternative levitra uk buy policies. But the Sunday release is a resoundingly clear sign that those negotiations have fallen apart.The drug industry has also hinted they will sue to block the policy from being implemented — and that was before the industry saw the new, expanded version.advertisement By issuing the new executive order, Trump is directing his health secretary to implement a policy whereby Medicare would not pay more than the lowest price for a drug that is offered in countries with comparable gross domestic product. It’s unclear, however, if the policy levitra uk buy will be permanent. The executive orders direct the HHS secretary to test the ideas before making them permanent.

It’s still unclear when the Trump administration will formally implement the new executive order levitra uk buy. Drug industry lobbyists expect Trump to try and skip over most of the formal regulatory steps by issuing a so-called interim final rule, a rare regulatory maneuver that lets president’s skip most of the formal regulatory steps in certain emergencies. However, the drug industry has hinted they will sue if Trump tries to use that maneuver.Pfizer and BioNTech are moving to enlarge the Phase 3 trial of their erectile dysfunction treatment by 50%, which could allow the companies to collect more safety and efficacy data and to increase the diversity of the levitra uk buy study’s participants.The companies said in a press release that they would increase the size of the study to 44,000 participants, up from an initial recruitment goal of 30,000 individuals.The U.S. Food and Drug Administration will have to approve the change before it goes into effect.advertisement “The companies continue to expect that a conclusive readout on efficacy is likely by the end of October,” the press release said.

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The companies said the study will now include adolescents as young as 16, people with stable HIV, and those with hepatitis C or hepatitis B.advertisement The companies said that the trial is expected to reach its initial target of 30,000 patients next week. Moderna, which levitra uk buy started its trial on the same day as Pfizer, said on Sept. 4 that it is working to increase the diversity of trial participants in its study, “even if those efforts impact the speed of enrollment.” The Pfizer/BioNTech study could finish sooner than Moderna’s, even though the two began on the same day, for other reasons, as well. Both treatments require a second shot levitra uk buy.

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News that the trial is resuming comes four days after the disclosure that levitra cheapest price it had been paused because of a suspected serious adverse reaction in a participant.A spokesperson for AstraZeneca told STAT that at this point, only the trial in the U.K. Has been levitra uk buy resumed. The company is also conducting Phase 2/3 or Phase 3 trials in the U.S., Brazil, and South Africa.“The Company will continue to work with health authorities across the world and be guided as to when other clinical trials can resume to provide the treatment broadly, equitably and at no profit during this levitra,” the spokesperson, Michele Meixell, wrote in an email.advertisement Saturday’s statement from AstraZeneca said the independent U.K. Investigation into the event has concluded and it advised the Medicines Health Regulatory Authority, levitra uk buy Britain’s equivalent of the Food and Drug Administration, that it was safe to resume the trial.

The MHRA concurred and gave the green light for the trial to restart. The illness that triggered the international pause, which occurred in a woman who was in the levitra uk buy treatment arm of the U.K. Trial, has not been officially disclosed, though AstraZeneca CEO Pascal Soriot told a group of investors on Wednesday that her symptoms were consistent with transverse myelitis, a serious condition involving inflammation of the spinal cord that can cause muscle weakness, paralysis, pain and bladder problems.advertisement The AstraZeneca statement said information about the illness the woman suffered cannot be disclosed. Oxford University, where the treatment was developed, said in a separate statement that the nature of the illness cannot be revealed “for reasons of participant confidentiality.”As part of the review process, independent boards overseeing trials of levitra uk buy a number of other erectile dysfunction treatments were analyzing their own data, looking for cases.

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What's levitra uk buy included?. Daily reporting and analysis The most comprehensive industry coverage from a powerhouse team of reporters Subscriber-only newsletters Daily newsletters to brief you on the most important industry news of the day STAT+ Conversations Weekly opportunities to engage with our reporters and leading industry experts in live video conversations Exclusive industry events Premium access to subscriber-only networking events around the country The best reporters in the industry The most trusted and well-connected newsroom in the health care industry And much more Exclusive interviews with industry leaders, profiles, and premium tools, like our CRISPR Trackr.Making a key ruling in a long-running battle over lucrative patent rights, a government patent board has knocked down the University of California’s initial claims that its scientists turned CRISPR into a genome editor in plant and animal cells in 2012, threatening its effort to secure patents on the groundbreaking technology.The decision from the Patent Trial and Appeal Board comes in an ongoing dispute over who first invented the use of CRISPR genome editing in eukaryotic cells (animal and plant cells, not bacteria or DNA floating in a test tube). It’s the latest turn in a years long and at times nasty battle between the Broad Institute of Cambridge, Mass., and UC and its partners, the University of Vienna and scientist Emmanuelle Charpentier (collectively levitra uk buy known in the case as CVC). Unlock this article by subscribing to STAT Plus and enjoy your first 30 days free!.

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It’s still unclear when the Trump administration will formally implement the new levitra street price executive order. Drug industry lobbyists expect Trump to try and skip over most of the formal regulatory steps by issuing a so-called interim final rule, a rare regulatory maneuver that lets president’s skip most of the formal regulatory steps in certain emergencies. However, the drug industry has hinted they will sue if Trump tries levitra street price to use that maneuver.Pfizer and BioNTech are moving to enlarge the Phase 3 trial of their erectile dysfunction treatment by 50%, which could allow the companies to collect more safety and efficacy data and to increase the diversity of the study’s participants.The companies said in a press release that they would increase the size of the study to 44,000 participants, up from an initial recruitment goal of 30,000 individuals.The U.S.

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Expanding the trial will likely make it easier for the company to demonstrate whether the treatment is effective against erectile dysfunction, the levitra that causes erectile dysfunction treatment. The companies also said levitra street price that the change will allow the study to include a more diverse population. The companies said the study will now include adolescents as young as 16, people with stable HIV, and those with hepatitis C or hepatitis B.advertisement The companies said that the trial is expected to reach its initial target of 30,000 patients next week.

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Pfizer’s is given after three weeks, while Moderna’s is given after four. The Pfizer trial also starts to count cases of erectile dysfunction treatment sooner after participants receive their levitra street price shots than the Moderna study.But the Pfizer/BioNTech treatment could also prove to be one of the most difficult of the experimental treatments to distribute, should they prove effective. The treatment must be kept at a temperature of -70 degrees Celsius.There has been political pressure to move a treatment quickly, with President Trump saying that one could be available before election day.

Last week, several drugmakers, including Pfizer, issued a pledge not to move a treatment forward sooner than was justified by the results of their clinical trials.A large, United Kingdom-based Phase 2/3 study testing levitra street price a erectile dysfunction treatment being developed by AstraZeneca has been restarted, according to a statement from the company. News that the trial is resuming comes four days can you buy over the counter levitra after the disclosure that it had been paused because of a suspected serious adverse reaction in a participant.A spokesperson for AstraZeneca told STAT that at this point, only the trial in the U.K. Has been levitra street price resumed.

The company is also conducting Phase 2/3 or Phase 3 trials in the U.S., Brazil, and South Africa.“The Company will continue to work with health authorities across the world and be guided as to when other clinical trials can resume to provide the treatment broadly, equitably and at no profit during this levitra,” the spokesperson, Michele Meixell, wrote in an email.advertisement Saturday’s statement from AstraZeneca said the independent U.K. Investigation into the event has concluded and it advised the Medicines Health Regulatory Authority, levitra street price Britain’s equivalent of the Food and Drug Administration, that it was safe to resume the trial. The MHRA concurred and gave the green light for the trial to restart.

The illness that triggered the international pause, which occurred in a woman who was in the treatment arm of levitra street price the U.K. Trial, has not been officially disclosed, though AstraZeneca CEO Pascal Soriot told a group of investors on Wednesday that her symptoms were consistent with transverse myelitis, a serious condition involving inflammation of the spinal cord that can cause muscle weakness, paralysis, pain and bladder problems.advertisement The AstraZeneca statement said information about the illness the woman suffered cannot be disclosed. Oxford University, where the treatment was developed, said in a separate statement that the nature of the illness cannot be revealed “for reasons of participant confidentiality.”As part of the review levitra street price process, independent boards overseeing trials of a number of other erectile dysfunction treatments were analyzing their own data, looking for cases.

There are at least 35 treatments in clinical trials around the world, nine of which are in Phase 3, the final stage of testing. It’s not uncommon for clinical trials to be paused. This is the second known hold of studies of the levitra street price AstraZeneca treatment.

A woman in the U.K. Trial was diagnosed with multiple sclerosis in July, but that event, which triggered the first pause, was deemed not to be related to the treatment.An AstraZeneca spokesperson previously described the decision as a levitra street price “routine action which has to happen whenever there is a potentially unexplained illness” in a trial. Still, the pause drew extraordinary attention because of the urgent need for progress on erectile dysfunction treatments in the midst of the levitra.In the latest gambit by a state lawmaker to lower prescription drug costs, a Pennsylvania legislator has introduced a bill that would tie prices paid by residents to what Canadians are charged for medicines.Specifically, the legislation would require the state to create a list of the 250 costliest drugs every year.

From there, the Pennsylvania Insurance Department would set a maximum rate levitra street price paid by health insurers for each medicine on the list based on pricing in Canada’s four largest provinces. And health insurers would have to pass along lower premiums resulting from any reduced medication costs, or pay a fine. Unlock this article by subscribing to STAT Plus and enjoy your first 30 days levitra street price free!.

GET STARTED Log In | Learn More What is it?. STAT Plus is STAT's premium subscription service for in-depth biotech, pharma, levitra street price policy, and life science coverage and analysis. Our award-winning team covers news on Wall Street, policy developments in Washington, early science breakthroughs and clinical trial results, and health care disruption in Silicon Valley and beyond.

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Unlock this article by subscribing to STAT Plus and enjoy your first 30 days free!. GET STARTED Log In | Learn More What is it?. STAT Plus is STAT's premium subscription service for in-depth biotech, pharma, policy, and life science coverage and analysis.

Our award-winning team covers news on Wall Street, policy developments in Washington, early science breakthroughs and clinical trial results, and health care disruption in Silicon Valley and beyond. What's included?. Daily reporting and analysis The most comprehensive industry coverage from a powerhouse team of reporters Subscriber-only newsletters Daily newsletters to brief you on the most important industry news of the day STAT+ Conversations Weekly opportunities to engage with our reporters and leading industry experts in live video conversations Exclusive industry events Premium access to subscriber-only networking events around the country The best reporters in the industry The most trusted and well-connected newsroom in the health care industry And much more Exclusive interviews with industry leaders, profiles, and premium tools, like our CRISPR Trackr..

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The disclosed information will be made publicly available for non-commercial purposes low price levitra after Health Canada completes its regulatory review process, while adhering to Canada’s Privacy Act.Providing levitra over the counter walgreens public access to this information supports Canada’s objective for transparent decision-making. Public access also provides valuable information that may help with the use or development of erectile dysfunction treatment19 drugs and medical devices.This guidance document outlines the process for publicly disclosing information in a market authorization application under the 2 interim orders. The process includes. procedures when releasing information types of information that levitra over the counter walgreens fall under the guidelines for CBI and that may be eligible for redaction protection of personal informationScope and application This document applies to information relied upon to issue a market authorization under the. Interim order respecting the importation, sale and advertising of drugs for use in relation to erectile dysfunction treatment (September 16, 2020) and interim order respecting the importation and sale of medical devices for use in relation to erectile dysfunction treatment(March 18, 2020)The public release of safety and efficacy/effectiveness information reviewed under the 2 interim orders is governed by common law.

Information requested for release is assessed case by case to determine what is CBI. Personal information is removed before the safety and efficacy/effectiveness information is released to the public.Following Health Canada’s review of an levitra over the counter walgreens application, safety and efficacy information will be released as follows. Automatically disclosed in applications submitted under the interim order for importing, selling and advertising drugs (proactive release) disclosed on request in applications submitted under the interim order for importing and selling medical devices (released upon request)Information in applications that have been authorized, including those authorized and then revoked, is in scope for public release. This includes. Original application documents documents filed after market authorization is levitra over the counter walgreens issued (filed at Health Canada’s request or to meet a condition of approval)Information in applications that are refused and were never authorized is out of scope for public release.

This document does not apply to clinical information submitted to support the market authorization of a medical device under the Medical Device Regulations or of a new drug submission under the Food and Drug Regulations (FDR). The exception are new drug submissions for erectile dysfunction treatment indications submitted under the FDR. For more information on the public release of this information, see the Public Release levitra over the counter walgreens of Clinical Information. Guidance document.Also not applicable under this document is the CBI disclosure authority under section 21.1(3)(c) of the Food and Drugs Act. This section permits the Minister of Health to disclose CBI to certain persons for the purpose of protection or promotion of human health or the safety of the public.

For information on this authority, see the guidance document Disclosure of Confidential Business levitra over the counter walgreens Information under Paragraph 21.1(3)(c) of the Food and Drugs Act.Proactive release of drug application informationWe will proactively publish safety and efficacy information used to support interim order drug applications upon authorization. This includes clinical information in applications submitted under sections 3, 6 and 14 of the interim order.How to request clinical information in medical device applicationsWe will publish safety and effectiveness information used to support interim order medical device applications when we receive a request from the public and within the limits of our administrative capacity. Requests made for multiple applications will be processed in sequence and subject to prioritization. Further prioritization may be given to products that have levitra over the counter walgreens a greater impact on the health system, such as. Products that are used a lot products that have a higher public interestRequests received for information in applications under the interim order will be prioritized over requests for clinical information in non-erectile dysfunction treatment19-related drugs submissions and device applications.To request clinical information on medical device applications, use our special portal to submit an electronic request form.

Be sure to identify the product name listed on the following sites. Publication process Publication of safety and efficacy information used to support drug interim order applications The publication of information follows the process described in section 4 and Appendix C of the Public Release of Clinical Information guidance document.In accordance with PRCI timelines, we aim to publish a final redacted and anonymized package on levitra over the counter walgreens our clinical information portal within 120 calendar days from starting the process. The process starts automatically on the day an authorization is issued.Step 1. Notice to the company and request for proposed CBI redactions and anonymizationFollowing the authorization of a drug under the interim order, Health Canada will give the manufacturer an opportunity to take part in a process initiation meeting. The first 60 days of the 120-day publication process is allocated levitra over the counter walgreens for the company to review the clinical information.

The company uses the Proposed Redaction Control Sheet (Appendix E, Public Release of Clinical Information (PRCI) guidance document) to propose any redaction of CBI. Proposed CBI redactions should pertain to information that meets the definition of confidential business information. This is levitra over the counter walgreens defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the definition. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitorsFollowing an assessment of the proposals, text within an in-scope document found to meet the above definition will be protected. Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business information.

Exceptions to the PRCI regulations described in C.08.009.2(2)(a) and (b) of levitra over the counter walgreens the Food and Drug Regulations or section 43.12(2)(a) and (b) of the Medical Device Regulations will be considered when applying redactions to confidential business information. Further information on the application of these exceptions can be found in the Health Canada PRCI guidance document.All personal information should be anonymized in accordance with section 6 of the Public Release of Clinical Information guidance document. The proposal package from the manufacturer should include. The proposed redaction control sheet the draft anonymization report annotated documentsManufacturers submit for Health Canada assessment using either CanadaPost ePost Connect or a suitable secure file transfer site of the manufacturer’s choosing.Step levitra over the counter walgreens 2. Health Canada assessment of company representationsWithin 30 days of receiving the proposal package, Health Canada will complete and return our assessment of the proposed CBI redactions and anonymization methodology.

Proposed redactions that meet the definition of confidential business information will be protected. We will review the levitra over the counter walgreens anonymization methodology to ensure all personal information is protected while maximizing the disclosure of useful clinical information. Step 3. Revision of proposed CBI redactions and anonymizationIf proposed CBI redactions are rejected or revision is required to the anonymization methodology, in accordance with the Public Release of Clinical Information. Guidance document, the manufacturer will be given 15 days to make the revisions levitra over the counter walgreens and resubmit.

We will send our final assessment to the manufacturer within 5 days of receiving the revised package. Step 4. Finalization and publicationWithin levitra over the counter walgreens 5 days of receiving our final assessment, the manufacturer must format and submit the final redacted and anonymization clinical documents within 5 days of receiving our final assessment. The final documents must comply with the Guidance Document. Preparation of Regulatory Activities using the Electronic Common Technical Document (eCTD) Format.

These documents are to be submitted using the Common levitra over the counter walgreens Electronic Submission Gateway. We will publish the final redacted documents within 5 days of receiving the final sequence.Publication of safety and effectiveness information used to support medical device interim order applicationsThe publication of information within an interim order application will proceed through the abbreviated process described below. Our goal is to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from initiation of the process.Step 1. Health Canada screening of requestsAfter we receive a request for information, we will retrieve the interim order application from docubridge (or other location) levitra over the counter walgreens. Information related to safety and effectiveness will be considered in-scope of publication.

Other information will not be released publicly. Only information available at the time the request is made will be considered levitra over the counter walgreens for disclosure. Information submitted after the original request for disclosure will be considered for public release upon receipt of a subsequent request.Examples of in scope information include. Clinical testing information validation testing that supports the effectiveness of the product, including testing performed in vitro or in silico summaries or overviews on safety or efficacy pre- or post-market, including literature reviewsExamples of out of scope information include. Manufacturing details not related to safety or efficacy engineering and design details general documents, such as user manuals, package inserts and instructions for use individual patient information, such as patient listings and case report forms, that require extensive anonymization interim clinical study data (see levitra over the counter walgreens the PRCI guidance)Step 2a.

Health Canada assessment of confidential business information To reduce administrative burden on the manufacturer, we will review in-scope records for confidential business information, as defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the definition will be protected. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitorsText in an in-scope document found to meet this definition will be redacted using a PDF redaction tool. Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business levitra over the counter walgreens information. Exceptions to the PRCI regulations are outlined section 43.12(2)(a) and (b) of the Medical Device Regulations. These exceptions will be considered when applying redactions to confidential business information.

Further information on the application of these exceptions can be levitra over the counter walgreens found in the PRCI guidance document.Step 2b. Assessing personal informationIn general, in-scope records do not contain a large volume of personal identification information. Any personal information, as defined in the Privacy Act and in accordance with PRCI guidance, information that could help to identify an individual will be protected. For example, this can include the names of authors and investigators as well as subject identification numbers.A large volume of levitra over the counter walgreens indirectly identifying information is not expected in the medical device records that are in-scope of publication. Consequently, limited protection of personal information is anticipated.Personal information will be redacted using a PDF redaction tool.

Step 3. Notice to the company and request for redaction levitra over the counter walgreens proposalFollowing the review and redaction of in scope documents, we will send the manufacturer a written notice indicating our intent to publish the identified documents. A copy of the release package will be sent for the manufacturer’s review. Any further proposed redactions by the manufacturer must be received within 14 calendar days.Manufacturer are asked to use the Proposed Redaction Control Sheet (see Appendix E of the PRCI guidance document) to suggest further redactions.Step 4. Health Canada assessment of company representationsAny further redactions proposed by the manufacturer will be assessed levitra over the counter walgreens in accordance with the process outlined in step 2, above.

Those that meet the definition of personal or confidential business information will be accepted.Step 5. PublicationIn-scope documents will be published within 120 days following receipt of the request. The redacted information will levitra over the counter walgreens be uploaded to the Clinical Information Portal, indexed by application number. Published documents will carry a watermark and be subject to terms of use, as described in the PRCI guidance.Mailing addressInformation Science and Openness DivisionResource Management and Operations DirectorateHealth Products and Food BranchHealth Canada Graham Spry Building 250 Lanark Ave Ottawa ON K1A 0K9 Telephone. 613-960-4687Email.

Hc.clinicaldata-donneescliniques.sc@canada.ca Terminology and definitions levitra over the counter walgreens Anonymization. Means the process through which personal information is modified by. removing direct identifiers and any related code that would enable linkage with identifying information and ensuring that the remaining indirect identifiers no longer present a serious possibility of re-identifying an individual CBI. Confidential business information, as meant in common law levitra over the counter walgreens and as defined in Section 2 of the Food and Drugs Act. in respect of a person to whose business or affairs the information relates, means (subject to the regulations) business information that.

Is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitors Clinical information. Means information in respect of a clinical trial, clinical studies or investigational testing, levitra over the counter walgreens such as. clinical overviews, clinical summaries and clinical study reports for drugs summaries and detailed information of all clinical studies and investigational testing that provided evidence of safety and effectiveness for medical devices Clinical study report. Means an "integrated" full report of an individual study of any therapeutic, prophylactic or diagnostic agent (drug or treatment) conducted in patients, in which. the clinical and statistical description, presentations and analyses are integrated into a single report incorporating tables and figures into the main text of the report or at the end of the text appendices contain the protocol, sample case report forms, investigator-related information, information related to the test drugs/investigational products, including active control/comparators, technical statistical documentation, related publications, levitra over the counter walgreens patient data listings and technical statistical details such as derivations, computations, analyses and computer output FDA.

Food and Drugs Act FDR. Food and Drug Regulations IMDRF ToC. International Medical Device Regulators Forum Table of Contents Medical levitra over the counter walgreens device. Has the same meaning as insee the Medical Devices Regulations. For information on the classification of medical devices, please see the guidance documents on the.

risk-based classification system for in vitro diagnostic devices (IVDDs) risk-based classification system for non-in vitro diagnostic devices (non-IVDDs) Non-commercial levitra over the counter walgreens purpose. Means the information will not be used to support a marketing authorization application anywhere in the world or sold or traded to another person Personal information. Has the same meaning as in Section 3 of the Privacy Act Related linksOn this page About the guidance document This guidance document supports the Interim Order Respecting Drugs, Medical Devices and Foods for a Special Dietary Purpose in Relation to erectile dysfunction treatment. The Minister of Health approved the Interim Order on March 30, 2020, to address the unprecedented demand and urgent need for medical devices to treat, diagnose and protect Canadians levitra over the counter walgreens against erectile dysfunction treatment. The guidance covers sections 15 to 19 of the Interim Order.

It remains in effect as long as the Interim Order is in effect. Under the Interim levitra over the counter walgreens Order, manufacturers and importers must report medical device shortages related to erectile dysfunction treatment to Health Canada. The devices to which the shortages apply are on the List of Medical Devices — Notification of Shortages (specified medical devices). A specified medical device is a device that is either. set out in the list of medical devices or part of a category of levitra over the counter walgreens medical devices that is set out in that list The guidance is intended to help manufacturers and importers meet their regulatory obligations.

It outlines their responsibilities concerning the mandatory reporting of medical device shortages. About medical device shortages and reporting A medical device shortage occurs when a manufacturer is unable to meet Canadian market demand for the device or for its components, accessories, parts or consumable materials. This does not apply when a substitute device, component, accessory, part levitra over the counter walgreens or consumable material is available in Canada. There are 2 types of shortages. actual, when the current supply can’t meet current demand anticipated, when the future supply can’t meet projected demand Manufacturers and importers must.

report a medical device shortage provide a levitra over the counter walgreens shortage status update if there is a change in the shortage information submitted provide additional information related to a shortage when requested by Health Canada report an end of a medical device shortage This guidance document also provides some guidance on how to voluntarily report a medical device shortage that does not fall under the Interim Order. Everyone has a role to play Manufacturers and importers Manufacturers and importers have a key role to play in preventing and reducing the impact of medical device shortages. They can control the volume of medical devices in the supply chain and can take steps to resolve a medical device shortage when one occurs. They are also in the best position to communicate to levitra over the counter walgreens customers about the availability of their devices. When a manufacturer experiences a shortage of a critical medical device it sells, we expect that the manufacturer will take all necessary measures to resolve the shortage as quickly as possible.

Provincial/territorial governments and health care authorities Provincial and territorial governments and health care authorities also have an important role to play in preventing and mitigating critical medical device shortages. They can levitra over the counter walgreens. conserve and reallocate stock within regions or provinces to where it is most needed and collaborate to share supply identify and secure additional supplies of medical devices from other vendors or another provincial or territorial government identify and secure other compatible substitute medical devices Government of Canada The federal government administers the Food and Drugs Act, Radiation Emitting Devices Act and Medical Devices Regulations. We do not provide or control the supply of medical devices in Canada or have the authority to compel a manufacturer to supply a device. We work with stakeholders levitra over the counter walgreens across the medical device supply chain to help determine the details and status of a shortage.

We also coordinate and facilitate information sharing. When it comes to medical device shortages, Health Canada depends on early reporting of anticipated or actual shortages to help us. prevent or manage impacts related to medical device shortages work with industry to identify levitra over the counter walgreens mitigation strategies inform the procurement of medical devices for Canada Depending on the situation, our options include. prioritizing the review and approval of regulatory applications received from manufacturers (for example, an application to authorize or import an acceptable compatible device) expediting the process for issuing Medical Device Establishment Licences (MDELs) permitting the importation and sale of medical devices that do not fully meet Canadian regulatory requirements, but are manufactured to comparable standards to help address product shortages due to the erectile dysfunction treatment levitra working with international regulators to identify other manufacturers and to share needed safety and manufacturing information helping health care professionals and institutions get access to compatible substitute medical devices on an emergency basis (for example, the Special Access Programme can be used to provide access to unlicensed alternative medical devices) As part of the Government of Canada’s response to erectile dysfunction treatment, the Public Health Agency of Canada is working with other government departments to procure bulk shipments to facilitate access to much-needed medical devices. These include ventilators, testing swabs, reagents and test kits as well as personal protective equipment.

Related linksOctober 9, 2020Our file number levitra over the counter walgreens. 20-113699-873 As a standing regulatory member of the International Council for Harmonisation (ICH), Health Canada is committed to the adoption and implementation of all ICH guidance. By way of this Notice, Health Canada is advising of its intent to implement ICH Q12. Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management and levitra over the counter walgreens the ICH Q12 associated annexes. This guidance has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process.

The ICH Assembly has endorsed the final draft and recommended its implementation by membership of ICH. The target timeframe for Health Canada implementation of ICH Q12 has been set to the third levitra over the counter walgreens quarter of 2021 in order to allow sufficient time for the preparation of regulators and stakeholders. Health Canada will be launching a stakeholder consultation in early 2021 to gather feedback on the final elements of the implementation of the Q12 guidance in Canada.This new Guideline is proposed to provide a framework to facilitate the management of post-approval Chemistry, Manufacturing and Controls (CMC) changes in a more predictable and efficient manner across the product lifecycle. Implementation of this new ICH Guideline will promote innovation and continual improvement in the biopharmaceutical sector and strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustments. It will allow regulators (assessors and inspectors) to better understand the firms' Pharmaceutical Quality Systems (PQSs) for management of post-approval CMC changes.ICH Q12 should be read in conjunction with levitra over the counter walgreens this accompanying notice and with the relevant sections of other applicable Health Canada guidances.

This and other ICH Guidance documents are available on the ICH Website. Please note that the ICH website is only available in English. If you would like to request a copy of the French version of the document, please contact the HPFB ICH inbox.Contact InformationFor levitra over the counter walgreens any comments or inquiries related to this notice, please contact:Health Canada – ICH CoordinatorE-mail. Hc.ich.sc@canada.ca Please include "Implementation of ICH Q12" in the subject line.The Register of Innovative Drugs is maintained pursuant to C.08.004.1 of the Food and Drug Regulations. The register indicates the drugs that are eligible for data protection.

Under C.08.004.1 (3) a subsequent manufacturer that seeks a notice of levitra over the counter walgreens compliance on the basis of a direct or indirect comparison between the new drug and an innovative drug may not file a submission before the end of a period of six years after the day on which the first notice of compliance was issued for the innovative new drug. In addition, the notice of compliance cannot be issued before the end of a period of eight years after the day on which the first notice of compliance was issued to the innovator. The format of the Register of Innovative Drugs is an electronic table, which is updated weekly. The register lists, in alphabetical order, the medicinal ingredients in the innovative drugs which were not previously approved in a drug by the Minister and that are not levitra over the counter walgreens variations of a previously approved medicinal ingredient. Please note that there may be other medicinal ingredients included in the drugs.

The register was re-formatted in summer 2016 to increase the clarity of the information provided regarding the medicinal ingredient, brand name and manufacturer of each innovative drug. For information related to treatment options, choices of medications and their uses, illnesses, side effects or drug interactions, please contact your health care professional (for example, doctor, pharmacist, etc.). We do not provide medical advice regarding the use of the products identified in this database. For comments or questions, please contact by hc.opml-bmbl.sc@canada.ca or by telephone at 613-941-7281..

All personal buy generic levitra online canada and confidential business information (CBI) will be protected prior levitra street price to release. The disclosed information will be made publicly available for non-commercial purposes after Health Canada completes its regulatory review process, while adhering to Canada’s Privacy Act.Providing public access to this information supports Canada’s objective for transparent decision-making. Public access also provides valuable information that may help with the use or development of erectile dysfunction treatment19 drugs and medical devices.This guidance document outlines the process for publicly disclosing information in a market authorization application under the 2 interim orders.

The process includes levitra street price. procedures when releasing information types of information that fall under the guidelines for CBI and that may be eligible for redaction protection of personal informationScope and application This document applies to information relied upon to issue a market authorization under the. Interim order respecting the importation, sale and advertising of drugs for use in relation to erectile dysfunction treatment (September 16, 2020) and interim order respecting the importation and sale of medical devices for use in relation to erectile dysfunction treatment(March 18, 2020)The public release of safety and efficacy/effectiveness information reviewed under the 2 interim orders is governed by common law.

Information requested levitra street price for release is assessed case by case to determine what is CBI. Personal information is removed before the safety and efficacy/effectiveness information is released to the public.Following Health Canada’s review of an application, safety and efficacy information will be released as follows. Automatically disclosed in applications submitted under the interim order for importing, selling and advertising drugs (proactive release) disclosed on request in applications submitted under the interim order for importing and selling medical devices (released upon request)Information in applications that have been authorized, including those authorized and then revoked, is in scope for public release.

This includes levitra street price. Original application documents documents filed after market authorization is issued (filed at Health Canada’s request or to meet a condition of approval)Information in applications that are refused and were never authorized is out of scope for public release. This document does not apply to clinical information submitted to support the market authorization of a medical device under the Medical Device Regulations or of a new drug submission under the Food and Drug Regulations (FDR).

The exception are new drug submissions for erectile dysfunction treatment indications submitted under the FDR levitra street price. For more information on the public release of this information, see the Public Release of Clinical Information. Guidance document.Also not applicable under this document is the CBI disclosure authority under section 21.1(3)(c) of the Food and Drugs Act.

This section permits the Minister of Health to disclose CBI to certain persons for the purpose of protection or promotion of human health or the safety of levitra street price the public. For information on this authority, see the guidance document Disclosure of Confidential Business Information under Paragraph 21.1(3)(c) of the Food and Drugs Act.Proactive release of drug application informationWe will proactively publish safety and efficacy information used to support interim order drug applications upon authorization. This includes clinical information in applications submitted under sections 3, 6 and 14 of the interim order.How to request clinical information in medical device applicationsWe will publish safety and effectiveness information used to support interim order medical device applications when we receive a request from the public and within the limits of our administrative capacity.

Requests made for multiple applications will be processed in sequence and levitra street price subject to prioritization. Further prioritization may be given to products that have a greater impact on the health system, such as. Products that are used a lot products that have a higher public interestRequests received for information in applications under the interim order will be prioritized over requests for clinical information in non-erectile dysfunction treatment19-related drugs submissions and device applications.To request clinical information on medical device applications, use our special portal to submit an electronic request form.

Be sure to identify the product name levitra street price listed on the following sites. Publication process Publication of safety and efficacy information used to support drug interim order applications The publication of information follows the process described in section 4 and Appendix C of the Public Release of Clinical Information guidance document.In accordance with PRCI timelines, we aim to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from starting the process. The process starts automatically on the day an authorization is issued.Step 1.

Notice to the company and request for proposed CBI redactions and anonymizationFollowing the authorization of a drug under the interim order, Health Canada will give the manufacturer an opportunity to take part in levitra street price a process initiation meeting. The first 60 days of the 120-day publication process is allocated for the company to review the clinical information. The company uses the Proposed Redaction Control Sheet (Appendix E, Public Release of Clinical Information (PRCI) guidance document) to propose any redaction of CBI.

Proposed CBI redactions should pertain to information that meets the levitra street price definition of confidential business information. This is defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the definition. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitorsFollowing an assessment of the proposals, text within an in-scope document found to meet the above definition will be protected.

Similar to levitra street price Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business information. Exceptions to the PRCI regulations described in C.08.009.2(2)(a) and (b) of the Food and Drug Regulations or section 43.12(2)(a) and (b) of the Medical Device Regulations will be considered when applying redactions to confidential business information. Further information on the application of these exceptions can be found in the Health Canada PRCI guidance document.All personal information should be anonymized in accordance with section 6 of the Public Release of Clinical Information guidance document.

The proposal package from the manufacturer should levitra street price include. The proposed redaction control sheet the draft anonymization report annotated documentsManufacturers submit for Health Canada assessment using either CanadaPost ePost Connect or a suitable secure file transfer site of the manufacturer’s choosing.Step 2. Health Canada assessment of company representationsWithin 30 days of receiving the proposal package, Health Canada will complete and return our assessment of the proposed CBI redactions and anonymization methodology.

Proposed redactions that meet the levitra street price definition of confidential business information will be protected. We will review the anonymization methodology to ensure all personal information is protected while maximizing the disclosure of useful clinical information. Step 3.

Revision of proposed CBI redactions and anonymizationIf proposed CBI redactions are levitra street price rejected or revision is required to the anonymization methodology, in accordance with the Public Release of Clinical Information. Guidance document, the manufacturer will be given 15 days to make the revisions and resubmit. We will send our final assessment to the manufacturer within 5 days of receiving the revised package.

Step 4 levitra street price. Finalization and publicationWithin 5 days of receiving our final assessment, the manufacturer must format and submit the final redacted and anonymization clinical documents within 5 days of receiving our final assessment. The final documents must comply with the Guidance Document.

Preparation of Regulatory Activities using the Electronic Common levitra street price Technical Document (eCTD) Format. These documents are to be submitted using the Common Electronic Submission Gateway. We will publish the final redacted documents within 5 days of receiving the final sequence.Publication of safety and effectiveness information used to support medical device interim order applicationsThe publication of information within an interim order application will proceed through the abbreviated process described below.

Our goal is to publish a final redacted and anonymized package on levitra street price our clinical information portal within 120 calendar days from initiation of the process.Step 1. Health Canada screening of requestsAfter we receive a request for information, we will retrieve the interim order application from docubridge (or other location). Information related to safety and effectiveness will be considered in-scope of publication.

Other information will not be released publicly levitra street price. Only information available at the time the request is made will be considered for disclosure. Information submitted after the original request for disclosure will be considered for public release upon receipt of a subsequent request.Examples of in scope information include.

Clinical testing information validation testing that supports the levitra street price effectiveness of the product, including testing performed in vitro or in silico summaries or overviews on safety or efficacy pre- or post-market, including literature reviewsExamples of out of scope information include. Manufacturing details not related to safety or efficacy engineering and design details general documents, such as user manuals, package inserts and instructions for use individual patient information, such as patient listings and case report forms, that require extensive anonymization interim clinical study data (see the PRCI guidance)Step 2a. Health Canada assessment of confidential business information To reduce administrative burden on the manufacturer, we will review in-scope records for confidential business information, as defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the definition will be protected.

That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to levitra street price their competitorsText in an in-scope document found to meet this definition will be redacted using a PDF redaction tool. Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business information. Exceptions to the PRCI regulations are outlined section 43.12(2)(a) and (b) of the Medical Device Regulations.

These exceptions will levitra street price be considered when applying redactions to confidential business information. Further information on the application of these exceptions can be found in the PRCI guidance document.Step 2b. Assessing personal informationIn general, in-scope records do not contain a large volume of personal identification information.

Any personal levitra street price information, as defined in the Privacy Act and in accordance with PRCI guidance, information that could help to identify an individual will be protected. For example, this can include the names of authors and investigators as well as subject identification numbers.A large volume of indirectly identifying information is not expected in the medical device records that are in-scope of publication. Consequently, limited protection of personal information is anticipated.Personal information will be redacted using a PDF redaction tool.

Step 3 levitra street price. Notice to the company and request for redaction proposalFollowing the review and redaction of in scope documents, we will send the manufacturer a written notice indicating our intent to publish the identified documents. A copy of the release package will be sent for the manufacturer’s review.

Any further proposed redactions by the manufacturer must be received within 14 calendar days.Manufacturer are asked to use the Proposed Redaction Control Sheet (see Appendix E of the PRCI guidance document) to levitra street price suggest further redactions.Step 4. Health Canada assessment of company representationsAny further redactions proposed by the manufacturer will be assessed in accordance with the process outlined in step 2, above. Those that meet the definition of personal or confidential business information will be accepted.Step 5.

PublicationIn-scope documents will be published within 120 days following receipt levitra street price of the request. The redacted information will be uploaded to the Clinical Information Portal, indexed by application number. Published documents will carry a watermark and be subject to terms of use, as described in the PRCI guidance.Mailing addressInformation Science and Openness DivisionResource Management and Operations DirectorateHealth Products and Food BranchHealth Canada Graham Spry Building 250 Lanark Ave Ottawa ON K1A 0K9 Telephone.

613-960-4687Email. Hc.clinicaldata-donneescliniques.sc@canada.ca Terminology and definitions Anonymization. Means the process through which personal information is modified by.

removing direct identifiers and any related code that would enable linkage with identifying information and ensuring that the remaining indirect identifiers no longer present a serious possibility of re-identifying an individual CBI. Confidential business information, as meant in common law and as defined in Section 2 of the Food and Drugs Act. in respect of a person to whose business or affairs the information relates, means (subject to the regulations) business information that.

Is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitors Clinical information. Means information in respect of a clinical trial, clinical studies or investigational testing, such as. clinical overviews, clinical summaries and clinical study reports for drugs summaries and detailed information of all clinical studies and investigational testing that provided evidence of safety and effectiveness for medical devices Clinical study report.

Means an "integrated" full report of an individual study of any therapeutic, prophylactic or diagnostic agent (drug or treatment) conducted in patients, in which. the clinical and statistical description, presentations and analyses are integrated into a single report incorporating tables and figures into the main text of the report or at the end of the text appendices contain the protocol, sample case report forms, investigator-related information, information related to the test drugs/investigational products, including active control/comparators, technical statistical documentation, related publications, patient data listings and technical statistical details such as derivations, computations, analyses and computer output FDA. Food and Drugs Act FDR.

Food and Drug Regulations IMDRF ToC. International Medical Device Regulators Forum Table of Contents Medical device. Has the same meaning as insee the Medical Devices Regulations.

For information on the classification of medical devices, please see the guidance documents on the. risk-based classification system for in vitro diagnostic devices (IVDDs) risk-based classification system for non-in vitro diagnostic devices (non-IVDDs) Non-commercial purpose. Means the information will not be used to support a marketing authorization application anywhere in the world or sold or traded to another person Personal information.

Has the same meaning as in Section 3 of the Privacy Act Related linksOn this page About the guidance document This guidance document supports the Interim Order Respecting Drugs, Medical Devices and Foods for a Special Dietary Purpose in Relation to erectile dysfunction treatment. The Minister of Health approved the Interim Order on March 30, 2020, to address the unprecedented demand and urgent need for medical devices to treat, diagnose and protect Canadians against erectile dysfunction treatment. The guidance covers sections 15 to 19 of the Interim Order.

It remains in effect as long as the Interim Order is in effect. Under the Interim Order, manufacturers and importers must report medical device shortages related to erectile dysfunction treatment to Health Canada. The devices to which the shortages apply are on the List of Medical Devices — Notification of Shortages (specified medical devices).

A specified medical device is a device that is either. set out in the list of medical devices or part of a category of medical devices that is set out in that list The guidance is intended to help manufacturers and importers meet their regulatory obligations. It outlines their responsibilities concerning the mandatory reporting of medical device shortages.

About medical device shortages and reporting A medical device shortage occurs when a manufacturer is unable to meet Canadian market demand for the device or for its components, accessories, parts or consumable materials. This does not apply when a substitute device, component, accessory, part or consumable material is available in Canada. There are 2 types of shortages.

actual, when the current supply can’t meet current demand anticipated, when the future supply can’t meet projected demand Manufacturers and importers must. report a medical device shortage provide a shortage status update if there is a change in the shortage information submitted provide additional information related to a shortage when requested by Health Canada report an end of a medical device shortage This guidance document also provides some guidance on how to voluntarily report a medical device shortage that does not fall under the Interim Order. Everyone has a role to play Manufacturers and importers Manufacturers and importers have a key role to play in preventing and reducing the impact of medical device shortages.

They can control the volume of medical devices in the supply chain and can take steps to resolve a medical device shortage when one occurs. They are also in the best position to communicate to customers about the availability of their devices. When a manufacturer experiences a shortage of a critical medical device it sells, we expect that the manufacturer will take all necessary measures to resolve the shortage as quickly as possible.

Provincial/territorial governments and health care authorities Provincial and territorial governments and health care authorities also have an important role to play in preventing and mitigating critical medical device shortages. They can. conserve and reallocate stock within regions or provinces to where it is most needed and collaborate to share supply identify and secure additional supplies of medical devices from other vendors or another provincial or territorial government identify and secure other compatible substitute medical devices Government of Canada The federal government administers the Food and Drugs Act, Radiation Emitting Devices Act and Medical Devices Regulations.

We do not provide or control the supply of medical devices in Canada or have the authority to compel a manufacturer to supply a device. We work with stakeholders across the medical device supply chain to help determine the details and status of a shortage. We also coordinate and facilitate information sharing.

When it comes to medical device shortages, Health Canada depends on early reporting of anticipated or actual shortages to help us. prevent or manage impacts related to medical device shortages work with industry to identify mitigation strategies inform the procurement of medical devices for Canada Depending on the situation, our options include. prioritizing the review and approval of regulatory applications received from manufacturers (for example, an application to authorize or import an acceptable compatible device) expediting the process for issuing Medical Device Establishment Licences (MDELs) permitting the importation and sale of medical devices that do not fully meet Canadian regulatory requirements, but are manufactured to comparable standards to help address product shortages due to the erectile dysfunction treatment levitra working with international regulators to identify other manufacturers and to share needed safety and manufacturing information helping health care professionals and institutions get access to compatible substitute medical devices on an emergency basis (for example, the Special Access Programme can be used to provide access to unlicensed alternative medical devices) As part of the Government of Canada’s response to erectile dysfunction treatment, the Public Health Agency of Canada is working with other government departments to procure bulk shipments to facilitate access to much-needed medical devices.

These include ventilators, testing swabs, reagents and test kits as well as personal protective equipment. Related linksOctober 9, 2020Our file number. 20-113699-873 As a standing regulatory member of the International Council for Harmonisation (ICH), Health Canada is committed to the adoption and implementation of all ICH guidance.

By way of this Notice, Health Canada is advising of its intent to implement ICH Q12. Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management and the ICH Q12 associated annexes. This guidance has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process.

The ICH Assembly has endorsed the final draft and recommended its implementation by membership of ICH. The target timeframe for Health Canada implementation of ICH Q12 has been set to the third quarter of 2021 in order to allow sufficient time for the preparation of regulators and stakeholders. Health Canada will be launching a stakeholder consultation in early 2021 to gather feedback on the final elements of the implementation of the Q12 guidance in Canada.This new Guideline is proposed to provide a framework to facilitate the management of post-approval Chemistry, Manufacturing and Controls (CMC) changes in a more predictable and efficient manner across the product lifecycle.

Implementation of this new ICH Guideline will promote innovation and continual improvement in the biopharmaceutical sector and strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustments. It will allow regulators (assessors and inspectors) to better understand the firms' Pharmaceutical Quality Systems (PQSs) for management of post-approval CMC changes.ICH Q12 should be read in conjunction with this accompanying notice and with the relevant sections of other applicable Health Canada guidances. This and other ICH Guidance documents are available on the ICH Website.

Please note that the ICH website is only available in English. If you would like to request a copy of the French version of the document, please contact the HPFB ICH inbox.Contact InformationFor any comments or inquiries related to this notice, please contact:Health Canada – ICH CoordinatorE-mail. Hc.ich.sc@canada.ca Please include "Implementation of ICH Q12" in the subject line.The Register of Innovative Drugs is maintained pursuant to C.08.004.1 of the Food and Drug Regulations.

The register indicates the drugs that are eligible for data protection. Under C.08.004.1 (3) a subsequent manufacturer that seeks a notice of compliance on the basis of a direct or indirect comparison between the new drug and an innovative drug may not file a submission before the end of a period of six years after the day on which the first notice of compliance was issued for the innovative new drug. In addition, the notice of compliance cannot be issued before the end of a period of eight years after the day on which the first notice of compliance was issued to the innovator.

The format of the Register of Innovative Drugs is an electronic table, which is updated weekly. The register lists, in alphabetical order, the medicinal ingredients in the innovative drugs which were not previously approved in a drug by the Minister and that are not variations of a previously approved medicinal ingredient. Please note that there may be other medicinal ingredients included in the drugs.

The register was re-formatted in summer 2016 to increase the clarity of the information provided regarding the medicinal ingredient, brand name and manufacturer of each innovative drug. For information related to treatment options, choices of medications and their uses, illnesses, side effects or drug interactions, please contact your health care professional (for example, doctor, pharmacist, etc.). We do not provide medical advice regarding the use of the products identified in this database.

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Describing the “joy” felt by children and aid workers as classrooms reopened on Monday after more than 14 months of erectile dysfunction treatment restrictions, Mads Oyen, UNICEF’s chief of field operations, explained that going back to school was about more than just learning.Bells are ringing🔔in #southsudan to mark the reopening cialis levitra o viagra cual es mejor of schools. "We share in cialis levitra o viagra cual es mejor the excitement of the children, their teachers &. The parents that finally the doors of our schools can reopen for children to learn, play and enjoy their right to safe education." @HamidaLasseko pic.twitter.com/owyBrZxKVd— UNICEF South Sudan (@unicefssudan) May 3, 2021 “Especially in a country like South Sudan, where we’re also faced with humanitarian emergencies in many parts of the country”, he cialis levitra o viagra cual es mejor explained. €œSchools are places for children to be safe and to be protected and also to access basic services, school feeding and so on.”Despite the welcome development, the UNICEF official noted that many children had not been able to return to class, their future development held up by a chronic humanitarian emergency, fuelled by ongoing violence and climate shocks.Malaria one threat among manyThe warning comes ahead of the upcoming rainy season, which brings with it a higher risk of cholera, malaria and respiratory s.There has already been a near-doubling of outpatient admissions in the last weeks, likely from malaria s or res, Mr Oyens said.“(It’s) about controlling malaria, it’s about controlling any measles outbreaks, it’s about providing clean water to kids”, he explained, before highlighting the “multiple risks” that children face.These include “violence, exploitation and abuse (and) recruitment by armed groups, still going on, psychosocial distress and cialis levitra o viagra cual es mejor family separation”.Fewer that one in 10 children has access to child protection services, the veteran UNICEF worker said, noting that between January and March this year, the agency scaled up treatment to more than 50,000 children who were suffering from severe acute malnutrition.The recovery rate was more than 95 per cent “in some of the most difficult-to-operate areas of the world”, he added.Health threat to 800,000In a related development, the International Organization for Migration (IOM) warned on Tuesday that life-saving healthcare for more than 800,000 South Sudanese, may have to be cut if funding is not found urgently. €œInternally displaced persons, returnees and conflict-affected populations already living in dire conditions may soon face even greater danger to their lives and health due to the erectile dysfunction treatment levitra and the onset of the rainy season and floods”, the UN agency said.Come June, primary healthcare services may no longer be available for women and children, the elderly and those living with disabilities.These services range from maternal and child health, including the cialis levitra o viagra cual es mejor screening of under-fives to detect malnutrition, sexual and reproductive health services and testing and treatment for HIV/AIDS and tuberculosis.‘A right and necessity’“Health is not a luxury, it’s a right and a necessity.

We must mobilize to ensure no one is left behind,” cialis levitra o viagra cual es mejor said Jacqueline Weekers, Director of Migration Health for IOM. €œIn the past year, we have learned the hard way that when some people don’t have access to health services, everyone can be at risk.”Before erectile dysfunction treatment, cialis levitra o viagra cual es mejor South Sudan’s health system was already heavily dependent on humanitarian actors who now face worrying funding shortfalls, IOM said, in an appeal for $744,175 per month to continue providing life-saving care. Essential health services are provided in former UN Protection of Civilian sites, host communities as well as remote and hard-to-reach locations serviced by the IOM’s mobile rapid response teams.

Describing the “joy” felt by children and aid workers as classrooms reopened on Monday after more than levitra street price 14 months of erectile dysfunction treatment restrictions, Mads Oyen, UNICEF’s chief of field operations, explained that going back to school was about more than just learning.Bells are ringing🔔in #southsudan to mark the reopening of schools. "We share levitra street price in the excitement of the children, their teachers &. The parents that finally the doors of our schools can reopen for children to learn, play and enjoy their right to safe education." @HamidaLasseko pic.twitter.com/owyBrZxKVd— UNICEF South Sudan (@unicefssudan) May 3, 2021 “Especially in a levitra street price country like South Sudan, where we’re also faced with humanitarian emergencies in many parts of the country”, he explained.

€œSchools are places for children to be safe and to be protected and also to access basic services, school feeding and so on.”Despite the welcome development, the UNICEF official noted that many children had not been able to return to class, their future development held up by a chronic humanitarian emergency, fuelled by ongoing violence and climate shocks.Malaria one threat among manyThe warning comes ahead of the upcoming rainy season, which brings with it a higher risk of cholera, malaria and respiratory s.There has already been a near-doubling of outpatient admissions in the last weeks, likely from malaria s or res, Mr Oyens said.“(It’s) about controlling malaria, it’s about controlling any measles outbreaks, it’s about providing clean water to kids”, he explained, before highlighting the “multiple risks” that children face.These include “violence, exploitation and abuse (and) recruitment by armed groups, still going on, psychosocial distress and family separation”.Fewer that one in 10 children has access to child protection services, the veteran UNICEF worker said, noting that between January and March this year, the agency scaled up treatment to more than 50,000 children who were suffering from severe acute malnutrition.The recovery rate was more than 95 per cent “in some of the most difficult-to-operate areas of the world”, he added.Health threat to 800,000In a levitra street price related development, the International Organization for Migration (IOM) warned on Tuesday that life-saving healthcare for more than 800,000 South Sudanese, may have to be cut if funding is not found urgently. €œInternally displaced persons, returnees and conflict-affected populations already living in dire conditions may soon face even greater danger to their lives and health due to levitra street price the erectile dysfunction treatment levitra and the onset of the rainy season and floods”, the UN agency said.Come June, primary healthcare services may no longer be available for women and children, the elderly and those living with disabilities.These services range from maternal and child health, including the screening of under-fives to detect malnutrition, sexual and reproductive health services and testing and treatment for HIV/AIDS and tuberculosis.‘A right and necessity’“Health is not a luxury, it’s a right and a necessity. We must mobilize levitra street price to ensure no one is left behind,” said Jacqueline Weekers, Director of Migration Health for IOM.

€œIn the past levitra street price year, we have learned the hard way that when some people don’t have access to health services, everyone can be at risk.”Before erectile dysfunction treatment, South Sudan’s health system was already heavily dependent on humanitarian actors who now face worrying funding shortfalls, IOM said, in an appeal for $744,175 per month to continue providing life-saving care. Essential health services are provided in former UN Protection of Civilian sites, host communities as well as remote and hard-to-reach locations serviced by the IOM’s mobile rapid response teams.

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erectile dysfunction, the levitra that causes the respiratory illness erectile dysfunction treatment, has killed approximately 2.2% of those worldwide who levitra walmart are known to have contracted it. But the situation could be a lot worse without modern medicine and science.The last such global scourge was the influenza levitra of 1918, which is estimated to have killed 50 million people at a time when there was no internet or easy access to long-distance telephones to disseminate information. Science was levitra walmart limited, which made it difficult to identify the cause and initiate treatment development.

The world is 100% more prepared for the current levitra than it was 100 years ago. However, it has still affected our lives profoundly.I am a levitra walmart physician scientist who specializes in the study of levitraes and runs a microbiology laboratory that tests for erectile dysfunction s. I’ve seen firsthand patients with severe erectile dysfunction treatment illness and have dedicated myself to developing diagnostics for this disease.

It’s a remarkable testament to science that a novel disease-causing levitra levitra walmart has been discovered, the genetic material completely decoded, new therapies created to fight it and multiple safe and effective treatments developed all within the span of a year – an accomplishment that the journal Science has pegged the breakthrough of 2020.Most treatments take 10-15 years to develop. Until now the fastest treatment developed was against the mumps levitra, which took four years. Now, in the midst of the erectile dysfunction levitra, levitra walmart one treatment is already authorized for use in the U.S., with a second close behind.

Other treatments have already been rolled out in countries across the globe.Science Fast-TrackedThis levitra put science front and center. One of the levitra walmart most significant scientific advances in the past 15 years has been the ability to read the genetic instructions – or genome – that encode levitraes. The process of sequencing the genome of a levitra is called next generation sequencing, and it has revolutionized science by allowing researchers to rapidly decode the genome of a levitra or bacterium, quickly and cost-effectively.

This strategy was used to determine levitra walmart the sequence of erectile dysfunction early in January 2020 before epidemiologists even recognized that it had already spread around the world. Obtaining the sequence allowed for the rapid development of diagnostics for erectile dysfunction and to figure out who was infected and how the levitra might spread.SARS-CoV erectile dysfunction was responsible for an outbreak that spanned 2002-2004, but was not particularly contagious and was limited mostly to Southeast Asia.erectile dysfunction has evolved two separate qualities that allow it to spread more easily. First, it has an enormous potential for triggering asymptomatic s, in which the levitra infects carriers who don’t experience symptoms and may never know they are infected and transmitting the levitra walmart levitra to others.Second, it can spread via aerosolized particles.

Most of these levitraes spread via large respiratory droplets, which are visible and fall out of the air within three to six feet. But erectile dysfunction can also spread through airborne transmission via much smaller particles that remain in the air for several hours.While in 1918 people went on blind faith that masking reduced transmission, this time around, science provided us with concrete answers. There have been several studies demonstrating the efficacy levitra walmart of masking.

These types of studies inform the public that mask-wearing, social distancing, hand-washing and limiting crowd sizes decrease circulating levitra and thus reduce hospitalizations and death. While they don’t get much fanfare, these studies are among the most important discoveries in response to this levitra.Science Aids DiagnosticsMany tests for the levitra levitra walmart are performed using PCR, which is short for polymerase chain reaction. This method uses specialized proteins and levitra-matching DNA sequences called primers to create more copies of the levitra.

These additional copies allow PCR machines levitra walmart to detect the presence of the levitra. Doctors can then tell you if you are infected. Because of the availability of the levitra’s genome sequence, any researcher can design primers that match the levitra to develop a diagnostic test.Early on, the World Health Organization developed a PCR test to detect the levitra and disseminated instructions on how to use it to researchers and physicians around the globe.This was a levitra walmart remarkable achievement that allowed countries across the world to rapidly develop diagnostic tests using this template.

This distribution changed the course of the levitra in many countries.Treatments Have Lowered Mortality RatesTreatments for infectious diseases often evolve over time. There is no treatment yet for hepatitis C, but over recent years treatments have evolved from those that make you very ill to those that are highly efficacious levitra walmart with few side effects.We are now seeing similar things in the erectile dysfunction levitra, just on an accelerated timeline. With the aid of clinical studies, we now have treatments such as steroids, antiviral medications like Remdesivir and infusions of antibodies.

Physicians also know how to alter a patient’s position in ways that increase levitra walmart the chance of survival.treatment Development Could End levitraThis levitra could end if the levitra swept through the population killing millions but leaving the survivors with natural immunity. More likely the levitra will snuff itself out when most of the population has been vaccinated with a erectile dysfunction treatment. That is especially true in parts of the world where frequent testing and public health strategies are difficult to implement.It took many years to develop an influenza treatment, with the first available in levitra walmart 1942.

Other successes with smallpox and polio, and more recent ones like HPV and Haemophilus influenzae Type b, have provided blueprints for treatment development.Governments across the world have partnered with private companies to expedite the development of erectile dysfunction treatments. This has led to multiple different companies developing their own different versions of treatments. Normally, these take years to develop levitra walmart.

However, by leveraging recent successes and accumulated knowledge, the timeline was accelerated significantly. Normally, new treatments go through levitra walmart phase 1 (safety), phase 2 (efficacy) and phase 3 (comparison) trials, but as demonstrated in the current trials, phases 2 and 3 can be combined for expediency. And large-scale manufacturing can begin when the treatment is still in trials, potentially cutting years off the timeline.Technology is at the forefront of the development of these treatments.

Some of the erectile dysfunction treatments take advantage of mRNA technology, which levitra walmart essentially programs our cells to develop immune responses against erectile dysfunction.Others use levitraes as delivery mechanisms for erectile dysfunction proteins to which your body develops an immune response. Both types have thus far been shown to be effective, but long-term safety will remain controversial when treatments are developed on such an expedited timeline.Lessons LearnedThis disease, which began in Wuhan, Hubei Province, China, and was first diagnosed in either November or December of 2019, is the perfect illustration of just how rapidly levitraes spread in a connected world. We got levitra walmart previews of what could happen from the recent outbreaks of Ebola and Zika levitra, but the spread of erectile dysfunction has been on a different level.

It has underscored that when we receive warnings about contagious levitraes, rapid and decisive action must be taken in all parts of the world to reduce its spread.Where there is more strict compliance with public health policies, there have been profound reductions in levitra transmission.While the research that has made all this possible might fly under the radar right now, history will record this time as one of the greatest periods for scientific advancements.David Pride is an Associate Director of Microbiology, University of California San Diego. This article is republished from The Conversation under levitra walmart a Creative Commons license. Read the original article.Humans go to extremes to collect salt.

We dig it up from levitra walmart underground deposits or wait patiently for pools of seawater to evaporate and leave it behind, just so we can stir, sprinkle and scoop the mineral into our food.Our desire likely stems somewhat from biological need. €œWe have this hardwired, hedonic response to these concentrations of sodium that are physiologically relevant to us from an evolutionary perspective,” says Russell Keast, a food scientist at Deakin University in Australia. Sodium, which constitutes half of each table levitra walmart salt molecule, keeps our nerves and muscle fibers functioning properly.

Early humans came across the compound relatively rarely, which could explain why we like the taste so much, Keast says. Enjoying the biting taste would have ensured our early levitra walmart ancestors ate enough of the stuff when they found it. But the salt content in most diets has crossed into new territory.

Instead of consuming what we need for our bodies to function, most of us ingest too much salt because commercial food producers rely on the ingredient to make dishes appetizing and keep production running smoothly. Weaning diners off of our high-salt diets is harder than it might seem, in levitra walmart part because it's in our nature to crave more of the mineral, Keast says. €œIt’s an evolutionary relic we’re stuck with."Running Salty InterferenceBesides being necessary for our bodies to operate, salt improves the way foods taste.

When mixed into a dish, salt dampens the levitra walmart bitterness and enhances the sweetness in the other ingredients. Effectively this means salt can directly impact three of the five tastes our mouths detect. Sweet, bitter, levitra walmart salty, sour and umami.

Exactly how salt remixes the taste of a food still isn’t clear, Keast says. Presumably, the shift happens at a neurological levitra walmart level, after taste buds detect all the compounds in each bite and relay perception signals to our brains. Even more impressively, salt can achieve these food alterations without revealing itself as a detectable flavor.

In research where study participants sample a range of broths, for example, levitra walmart plain veggie water lacks appeal. When the broth is salted, recipients perceive and enjoy the changed flavor but can’t identify what it is that tastes different. Only once the amount of salt reaches what scientists call a “recognition threshold” levitra walmart do people taste so-called saltiness.

At that point, the appeal of the broth starts to drop, Keast says. A dish at it’s Goldylocks level of salt — not levitra walmart too much and not too little — is when the overall taste is at its best. Salt ChemistryThe threshold at which salt levels become obvious (and unappealing) is different for each food, which explains why sodium content gets shockingly high in some products.

Grain-based foods, for example, easily incorporate high salt levels without ruining food taste. And in levitra walmart the U.S. And U.K., breads, cereals, cookies and cakes account for about 30 to 50 percent of all the sodium a person consumes each day.

For these foods, high salt levels have less to do with flavor levitra walmart and more to do with product consistency, says Michael Nickerson, a food scientist at the University of Saskatchewan. Breads — which are essentially flour, water, yeast and salt — reach an even and consistent rise thanks to that last ingredient.As yeast churns out carbon dioxide in dough, salt regulates how much of the gas each microbe produces, making sure the resulting air pockets in the final product aren’t too big. For the bread to rise in the first place, gluten proteins levitra walmart in the grain need to organize into a network that stretches in response to the gas the yeast creates.

Here, too, salt pitches in. The mineral masks some of the positive and negative levitra walmart charges on each gluten protein, helping the strands aggregate and build stronger networks.Simultaneously, the added salt helps the gluten bridges hold onto water and makes dough less sticky, saving commercial bakeries from nightmare scenarios. €œThis has a big implication in the big processing factories, in which they don't have to shut down the whole equipment, clean it all off, and start over again,” Nickerson says.Home bakers generally aren’t worried about their machinery gumming up with too-wet dough.

If kitchen levitra walmart experiments with bread suffer from insufficient salt, Nickerson says, it would likely involve collapsed portions that fell when the gluten networks were weak and the yeast went uncontrolled. In commercial bakeries, consistency from loaf to loaf (or cracker to cracker) is key, so salt volumes get cranked much higher.Sodium OverloadHow to bring those salt levels back down drives some of Keast’s and Nickerson’s work. Because as helpful or tasty as salt may be, too much sodium in the diet can raise blood pressure, which in turn levitra walmart raises risks of heart disease and stroke.

Simply cutting the ingredient from commercially-produced foods doesn’t go unnoticed. Customers think “reduced sodium” soups, for example, taste worse, and brands don’t levitra walmart want one box of crackers to differ from the next. While fixes are in the works, the science of salt (and its substitutes) has a lot of room to grow, Keast says.

€œWhile we’ve got our theories and do our research, there’s still a lot left to be known.”.

erectile dysfunction, the levitra that causes the respiratory illness erectile dysfunction treatment, has killed approximately 2.2% of those worldwide who are known to have contracted levitra street price it. But the situation could be a lot worse without modern medicine and science.The last such global scourge was the influenza levitra of 1918, which is estimated to have killed 50 million people at a time when there was no internet or easy access to long-distance telephones to disseminate information. Science was levitra street price limited, which made it difficult to identify the cause and initiate treatment development. The world is 100% more prepared for the current levitra than it was 100 years ago.

However, it has still affected our lives profoundly.I am a physician scientist who specializes in the levitra street price study of levitraes and runs a microbiology laboratory that tests for erectile dysfunction s. I’ve seen firsthand patients with severe erectile dysfunction treatment illness and have dedicated myself to developing diagnostics for this disease. It’s a remarkable testament to science that a novel disease-causing levitra has been discovered, the genetic material completely decoded, new therapies created levitra street price to fight it and multiple safe and effective treatments developed all within the span of a year – an accomplishment that the journal Science has pegged the breakthrough of 2020.Most treatments take 10-15 years to develop. Until now the fastest treatment developed was against the mumps levitra, which took four years.

Now, in the midst of the erectile dysfunction levitra, levitra street price one treatment is already authorized for use in the U.S., with a second close behind. Other treatments have already been rolled out in countries across the globe.Science Fast-TrackedThis levitra put science front and center. One of the most significant scientific advances in the past 15 years has been the ability to read the genetic instructions levitra street price – or genome – that encode levitraes. The process of sequencing the genome of a levitra is called next generation sequencing, and it has revolutionized science by allowing researchers to rapidly decode the genome of a levitra or bacterium, quickly and cost-effectively.

This strategy was used to determine the sequence of erectile dysfunction early in January 2020 before epidemiologists even levitra street price recognized that it had already spread around the world. Obtaining the sequence allowed for the rapid development of diagnostics for erectile dysfunction and to figure out who was infected and how the levitra might spread.SARS-CoV erectile dysfunction was responsible for an outbreak that spanned 2002-2004, but was not particularly contagious and was limited mostly to Southeast Asia.erectile dysfunction has evolved two separate qualities that allow it to spread more easily. First, it levitra street price has an enormous potential for triggering asymptomatic s, in which the levitra infects carriers who don’t experience symptoms and may never know they are infected and transmitting the levitra to others.Second, it can spread via aerosolized particles. Most of these levitraes spread via large respiratory droplets, which are visible and fall out of the air within three to six feet.

But erectile dysfunction can also spread through airborne transmission via much smaller particles that remain in the air for several hours.While in 1918 people went on blind faith that masking reduced transmission, this time around, science provided us with concrete answers. There have been several studies demonstrating levitra street price the efficacy of masking. These types of studies inform the public that mask-wearing, social distancing, hand-washing and limiting crowd sizes decrease circulating levitra and thus reduce hospitalizations and death. While they don’t get much fanfare, these studies are levitra street price among the most important discoveries in response to this levitra.Science Aids DiagnosticsMany tests for the levitra are performed using PCR, which is short for polymerase chain reaction.

This method uses specialized proteins and levitra-matching DNA sequences called primers to create more copies of the levitra. These additional levitra street price copies allow PCR machines to detect the presence of the levitra. Doctors can then tell you if you are infected. Because of the availability of the levitra’s genome sequence, any researcher can design primers that match the levitra to develop a diagnostic test.Early on, the World Health Organization developed a PCR test to detect the levitra and disseminated instructions levitra street price on how to use it to researchers and physicians around the globe.This was a remarkable achievement that allowed countries across the world to rapidly develop diagnostic tests using this template.

This distribution changed the course of the levitra in many countries.Treatments Have Lowered Mortality RatesTreatments for infectious diseases often evolve over time. There is no treatment yet for hepatitis C, but over recent years treatments have evolved from those that levitra street price make you very ill to those that are highly efficacious with few side effects.We are now seeing similar things in the erectile dysfunction levitra, just on an accelerated timeline. With the aid of clinical studies, we now have treatments such as steroids, antiviral medications like Remdesivir and infusions of antibodies. Physicians also know how to alter a patient’s position in ways that increase the chance of survival.treatment Development Could End levitraThis levitra could end if the levitra swept through the population killing millions but leaving the survivors with natural immunity levitra street price.

More likely the levitra will snuff itself out when most of the population has been vaccinated with a erectile dysfunction treatment. That is especially true in parts of the world where frequent testing and public health strategies are difficult to implement.It took many years to develop an influenza treatment, levitra street price with the first available in 1942. Other successes with smallpox and polio, and more recent ones like HPV and Haemophilus influenzae Type b, have provided blueprints for treatment development.Governments across the world have partnered with private companies to expedite the development of erectile dysfunction treatments. This has led to multiple different companies developing their own different versions of treatments.

Normally, these levitra street price take years to develop. However, by leveraging recent successes and accumulated knowledge, the timeline was accelerated significantly. Normally, new treatments go through phase 1 (safety), phase 2 (efficacy) and phase 3 (comparison) trials, but as levitra street price demonstrated in the current trials, phases 2 and 3 can be combined for expediency. And large-scale manufacturing can begin when the treatment is still in trials, potentially cutting years off the timeline.Technology is at the forefront of the development of these treatments.

Some of the erectile dysfunction treatments take advantage of mRNA technology, which essentially programs our cells to levitra street price develop immune responses against erectile dysfunction.Others use levitraes as delivery mechanisms for erectile dysfunction proteins to which your body develops an immune response. Both types have thus far been shown to be effective, but long-term safety will remain controversial when treatments are developed on such an expedited timeline.Lessons LearnedThis disease, which began in Wuhan, Hubei Province, China, and was first diagnosed in either November or December of 2019, is the perfect illustration of just how rapidly levitraes spread in a connected world. We got previews of what could happen from the recent outbreaks of Ebola levitra street price and Zika levitra, but the spread of erectile dysfunction has been on a different level. It has underscored that when we receive warnings about contagious levitraes, rapid and decisive action must be taken in all parts of the world to reduce its spread.Where there is more strict compliance with public health policies, there have been profound reductions in levitra transmission.While the research that has made all this possible might fly under the radar right now, history will record this time as one of the greatest periods for scientific advancements.David Pride is an Associate Director of Microbiology, University of California San Diego.

This article is republished from The levitra street price Conversation under a Creative Commons license. Read the original article.Humans go to extremes to collect salt. We dig it up from underground deposits or wait patiently for pools of seawater to evaporate levitra street price and leave it behind, just so we can stir, sprinkle and scoop the mineral into our food.Our desire likely stems somewhat from biological need. €œWe have this hardwired, hedonic response to these concentrations of sodium that are physiologically relevant to us from an evolutionary perspective,” says Russell Keast, a food scientist at Deakin University in Australia.

Sodium, which constitutes half of each table salt molecule, keeps our nerves and muscle fibers functioning levitra street price properly. Early humans came across the compound relatively rarely, which could explain why we like the taste so much, Keast says. Enjoying the biting taste would have ensured our early ancestors levitra street price ate enough of the stuff when they found it. But the salt content in most diets has crossed into new territory.

Instead of consuming what we need for our bodies to function, most of us ingest too much salt because commercial food producers rely on the ingredient to make dishes appetizing and keep production running smoothly. Weaning diners off levitra street price of our high-salt diets is harder than it might seem, in part because it's in our nature to crave more of the mineral, Keast says. €œIt’s an evolutionary relic we’re stuck with."Running Salty InterferenceBesides being necessary for our bodies to operate, salt improves the way foods taste. When mixed into a dish, salt dampens the bitterness and enhances the sweetness in the other levitra street price ingredients.

Effectively this means salt can directly impact three of the five tastes our mouths detect. Sweet, bitter, levitra street price salty, sour and umami. Exactly how salt remixes the taste of a food still isn’t clear, Keast says. Presumably, the shift happens at a neurological level, levitra street price after taste buds detect all the compounds in each bite and relay perception signals to our brains.

Even more impressively, salt can achieve these food alterations without revealing itself as a detectable flavor. In research where study levitra street price participants sample a range of broths, for example, plain veggie water lacks appeal. When the broth is salted, recipients perceive and enjoy the changed flavor but can’t identify what it is that tastes different. Only once the amount of salt reaches what levitra street price scientists call a “recognition threshold” do people taste so-called saltiness.

At that point, the appeal of the broth starts to drop, Keast says. A dish at it’s Goldylocks level of salt — not too much and not too little levitra street price — is when the overall taste is at its best. Salt ChemistryThe threshold at which salt levels become obvious (and unappealing) is different for each food, which explains why sodium content gets shockingly high in some products. Grain-based foods, for example, easily incorporate high salt levels without ruining food taste.

And in the levitra street price U.S. And U.K., breads, cereals, cookies and cakes account for about 30 to 50 percent of all the sodium a person consumes each day. For these foods, high salt levels have less to levitra street price do with flavor and more to do with product consistency, says Michael Nickerson, a food scientist at the University of Saskatchewan. Breads — which are essentially flour, water, yeast and salt — reach an even and consistent rise thanks to that last ingredient.As yeast churns out carbon dioxide in dough, salt regulates how much of the gas each microbe produces, making sure the resulting air pockets in the final product aren’t too big.

For the bread to rise in the first place, gluten levitra street price proteins in the grain need to organize into a network that stretches in response to the gas the yeast creates. Here, too, salt pitches in. The mineral masks some of the positive and negative charges on each gluten protein, helping levitra street price the strands aggregate and build stronger networks.Simultaneously, the added salt helps the gluten bridges hold onto water and makes dough less sticky, saving commercial bakeries from nightmare scenarios. €œThis has a big implication in the big processing factories, in which they don't have to shut down the whole equipment, clean it all off, and start over again,” Nickerson says.Home bakers generally aren’t worried about their machinery gumming up with too-wet dough.

If kitchen experiments with bread suffer from insufficient salt, Nickerson says, it would likely levitra street price involve collapsed portions that fell when the gluten networks were weak and the yeast went uncontrolled. In commercial bakeries, consistency from loaf to loaf (or cracker to cracker) is key, so salt volumes get cranked much higher.Sodium OverloadHow to bring those salt levels back down drives some of Keast’s and Nickerson’s work. Because as helpful or tasty as salt may be, too much sodium in the diet can raise blood levitra street price pressure, which in turn raises risks of heart disease and stroke. Simply cutting the ingredient from commercially-produced foods doesn’t go unnoticed.

Customers think “reduced sodium” soups, for example, taste levitra street price worse, and brands don’t want one box of crackers to differ from the next. While fixes are in the works, the science of salt (and its substitutes) has a lot of room to grow, Keast says. €œWhile we’ve got our theories and do our research, there’s still a lot left to be known.”.

Best way to use levitra

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 best way to use levitra studies, it has become look at here now 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 the 2006 DSD consensus document best way to use levitra by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured best way to use levitra 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 best way to use levitra such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish best way to use levitra guideline was written for these healthcare providers.

Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between best way to use levitra 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 best way to use levitra multicentre group was formed with all members responsible for updating the literature for a specific part of the guideline.

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

Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles best way to use levitra 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 best way to use levitra the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, the final version was presented to the best way to use levitra 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 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 best way to use levitra structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed best way to use levitra 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 best way to use levitra 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 best way to use levitra time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team. After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the best way to use levitra 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 cannot provide best way to use levitra. 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 best way to use levitra 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 best way to use levitra apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will look like and uncertainty best way to use levitra about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, best way to use levitra a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in best way to use levitra 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, best way to use levitra 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. NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose completing the analysis well best way to use levitra 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 http://infonet.sonnenwelt.at/?page_id=350 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 what do you need to buy levitra have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked levitra street price 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 the 2006 DSD levitra street price consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach levitra street price 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 across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus levitra street price far because they reflect evolving technologies or less visible stakeholders.

For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a levitra street price 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 levitra street price 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 levitra street price interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part of the guideline.

Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory levitra street price 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 levitra street price were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open levitra street price 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 levitra street price by the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft. This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline.

After receiving and incorporating their input, the final version levitra street price 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 occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur levitra street price 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 levitra street price 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 levitra street price considerations, the X and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed levitra street price (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

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

And the type levitra street price of information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need levitra street price 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, levitra street price which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing levitra street price exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely.

Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert levitra street price 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 levitra street price used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD 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 levitra street price 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.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) levitra street price 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 http://blog.lumitone.com/?p=297.

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..