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May 19, 2021 (TORONTO) — Canada Health Infoway (Infoway) and Intrahealth Canada Limited (Intrahealth) are pleased to where can i get flagyl without a prescription announce that prescribers in New Brunswick will now have access to e-prescribing through Intrahealth’s electronic medical record solution, Profile EMR flagyl for males. Profile EMR is now conformed with PrescribeIT®, Infoway’s national e-prescribing service that enables prescribers and pharmacists to electronically create, receive, renew and cancel prescriptions, while improving overall where can i get flagyl without a prescription patient care through secure clinician messaging. Intrahealth is now beginning deployments to all interested prescribers in New Brunswick.Intrahealth, which is based in Vancouver, serves primary care markets in New Brunswick and British Columbia, as well as community health clinics in Ontario.

In New Brunswick, 232 clinics and 420 prescribers use Intrahealth’s Profile EMR.“We are very excited to begin this rollout of PrescribeIT® to users of our Profile EMR in New Brunswick,” said Silvio Labriola, General Manager, where can i get flagyl without a prescription Intrahealth. €œInitial deployments in the province have been very successful, including the first French language clinic, Clinique Medicale Centre-Ville in Bathurst, and we look forward to making it widely available in June.”“I encourage prescribers who use the Profile EMR to take advantage of this opportunity to enable the PrescribeIT® service,” said Dr. Daniel Fletcher, family physician in Harvey Station, where can i get flagyl without a prescription NB.

€œIt’s easy where can i get flagyl without a prescription to use, has improved the efficiency of my workflows and has reduced the amount of paper generated with faxed prescriptions. It’s also a great fit for prescribers who are offering virtual care to their patients.”“PrescribeIT® integrated seamlessly into our pharmacy management system, and it has improved medication safety and includes enhanced communication with prescribers through its secure messaging feature,” said Alison Smith, pharmacy manager at Sobeys Pharmacy in Bathurst, NB.“It’s great news that Intrahealth is beginning the rollout of PrescribeIT® to its Profile EMR users across New Brunswick,” said Jamie Bruce, Executive Vice President, Infoway. €œWe congratulate Intrahealth where can i get flagyl without a prescription on this terrific progress and we look forward to a long and rewarding partnership that will benefit so many Canadians, prescribers and pharmacists.”In addition to New Brunswick, PrescribeIT® is also available in Alberta, Ontario, Saskatchewan and Newfoundland and Labrador, and Infoway has signed agreements with all other provinces and territories.

As of March 31, 2021, more than 6,000 prescribers and close to 5,000 pharmacies had enrolled in the service, and 17 EMR and eight PMS vendors had signed on to offer PrescribeIT®, giving millions of Canadians access to e-prescribing.About Intrahealth Canada LimitedIncorporated in 2005, Intrahealth Canada provides medical software solutions to general practitioner clinics and public health authorities. Privately owned and founded by two New Zealand medical doctors, the company offers robust, secure and scalable solutions via innovative where can i get flagyl without a prescription technology that keeps pace with today’s mobile lifestyles. The platform functions across multiple community-based practice types where can i get flagyl without a prescription — primary care, specialist physician, community care, home care, residential care, and more.

Our solutions meet the needs of front-line professionals by delivering core information to coordinating hubs, implementing programs more rapidly, and reducing the compliance burden on physicians and other clinicians. We help our customers capture structured data that holds context, meaning, and can be where can i get flagyl without a prescription analyzed and processed automatically. Intrahealth is a wholly owned subsidiary where can i get flagyl without a prescription of WELL Health Technologies Corp.

(TSX. WELL). Visit http://www.intrahealth.comAbout Canada Health InfowayInfoway helps to improve the health of Canadians by working with partners to accelerate the development, adoption and effective use of digital health across Canada.

Through our investments, we help deliver better quality and access to care and more efficient delivery of health services for patients and clinicians. Infoway is an independent, not-for-profit organization funded by the federal government. Visit www.infoway-inforoute.ca.About PrescribeIT®Canada Health Infoway is working with Health Canada, the provinces and territories, and industry stakeholders to develop, operate and maintain the national e-prescribing service known as PrescribeIT®.

PrescribeIT® will serve all Canadians, pharmacies and prescribers and provide safer and more effective medication management by enabling prescribers to transmit a prescription electronically between a prescriber’s electronic medical record (EMR) and the pharmacy management system (PMS) of a patient’s pharmacy of choice. PrescribeIT® will protect Canadians’ personal health information from being sold or used for commercial activities. Visit www.PrescribeIT.ca.-30-Media InquiriesInquiries about PrescribeIT® Tania EnsorSenior Director, Marketing, Stakeholder Relations and Reputation Management, PrescribeIT®Canada Health Infoway416.707.6285Email UsFollow @PrescribeIT_CAInquiries about IntrahealthSilvio LabriolaGeneral Manager, Intrahealth Canada Limited604.980.5577 ext.

112This email address is being protected from spambots. You need JavaScript enabled to view it.April 8, 2021 (TORONTO, ON and VICTORIA, BC) — The British Columbia Ministry of Health (the BC Ministry of Health) and Canada Health Infoway (Infoway) are pleased to announce that they have entered into an agreement to work together to explore a solution that could allow Electronic Medical Records (EMRs) and Pharmacy Management Systems the option of supporting Provincial Prescription Management (e-Prescribing) in the province by connecting to PharmaNet through PrescribeIT®. Under this Agreement, the BC Ministry of Health and Infoway will work to identify a possible solution that meets BC Ministry of Health conformance requirements and aligns with the provincial enterprise architecture, health sector standards, legislation and information management requirements.

This model would provide BC prescribers and pharmacists with an alternative option to direct integration with the PharmaNet system for electronic prescribing.“We are extremely pleased to be working with BC on this initiative,” said Michael Green, President and CEO of Infoway. €œWe now have agreements in place with all 13 provinces and territories and we will continue to work closely with our provincial and territorial government partners to advance our shared priorities.”About Canada Health InfowayInfoway helps to improve the health of Canadians by working with partners to accelerate the development, adoption and effective use of digital health across Canada. Through our investments, we help deliver better quality and access to care and more efficient delivery of health services for patients and clinicians.

Infoway is an independent, not-for-profit organization funded by the federal government. Visit www.infoway-inforoute.ca/en/.About PrescribeIT®Canada Health Infoway is working with Health Canada, the provinces and territories, and industry stakeholders to develop, operate and maintain the national e-prescribing service known as PrescribeIT®. PrescribeIT® will serve all Canadians, pharmacies and prescribers and provide safer and more effective medication management by enabling prescribers to transmit a prescription electronically between a prescriber’s electronic medical record (EMR) and the pharmacy management system (PMS) of a patient’s pharmacy of choice.

PrescribeIT® will protect Canadians’ personal health information from being sold or used for commercial activities. Visit www.prescribeit.ca/.-30-Media InquiriesInquiries about PrescribeIT® Tania EnsorSenior Director, Marketing, Stakeholder Relations and Reputation Management, PrescribeIT®Canada Health Infoway416.707.6285Email UsFollow @PrescribeIT_CA.

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Authority to withhold services in case of non-payment As stated in the Food and Drug Act, Health Canada has the authority to withhold services, approvals, rights and/or flagyl antibiotico privileges, if the fee for an MDEL application is not paid. Non-payment of fees 30.64. The Minister may withdraw or withhold a service, the use of a facility, a regulatory process or approval or a product, right or privilege under this Act from any person who fails to pay the fee fixed for it under subsection 30.61(1). For more information, please flagyl antibiotico refer to.

Cancellation of existing MDELs We will cancel MDELs for existing MDEL holders with outstanding fees for. initial applications or annual licence review applications If your establishment licence is cancelled, you are no longer authorized to conduct licensable activities (such as manufacturing, distributing or importing medical devices). You must stop licensable activities as soon as you flagyl antibiotico receive your cancellation notice. Resuming activities after MDEL cancellation To resume licensable activities, you must re-apply for a new establishment licence and pay the MDEL fee.

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Through the workplace screening initiative, Canada is supplying RADTs to eligible workplaces across the country. The initiative will help companies detect early cases of flagyl antibiotico buy antibiotics, for people who are asymptomatic. This initiative is being administered in collaboration with the provinces and territories. Interim enforcement approach In the interest of public health, Health Canada is placing less priority on enforcing off-label distribution of RADTs under the following circumstances.

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MDEL Bulletin, June 24 2021, from the Medical Devices Compliance Program On this page Fees for Medical Device Establishment Licences (MDELs) We issue Medical Device Establishment where can i get flagyl without a prescription Licences (MDELs) to. class I manufacturers importers or distributors of all device classes for human use in Canada The MDEL fee is a flat fee, regardless of when we receive your initial application. The same fee where can i get flagyl without a prescription applies to applications for. a new MDEL the reinstatement of a suspended MDEL the annual licence review (ALR) of an MDEL If you submit any of these applications, you must pay the MDEL fee when you receive an invoice. See Part 3, Division 2 of the Fees in Respect of Drugs and Medical Devices Order.

Normally, we collect where can i get flagyl without a prescription the MDEL fee before we review an application. However, to help meet the demand for medical devices during the buy antibiotics flagyl, we have been reviewing and processing MDEL applications before collecting the fees. As a result, some MDEL holders still haven't paid the fees for their 2020 initial MDEL application, despite multiple reminders. Authority to withhold services in case of non-payment As stated in the Food and Drug where can i get flagyl without a prescription Act, Health Canada has the authority to withhold services, approvals, rights and/or privileges, if the fee for an MDEL application is not paid. Non-payment of fees 30.64.

The Minister may withdraw or withhold a service, the use of a facility, a regulatory process or approval or a product, right or privilege under this Act from any person who fails to pay the fee fixed for it under subsection 30.61(1). For more information, please refer where can i get flagyl without a prescription to. Cancellation of existing MDELs We will cancel MDELs for existing MDEL holders with outstanding fees for. initial applications or annual licence review applications If your establishment licence is cancelled, you are no longer authorized to conduct licensable activities (such as manufacturing, distributing or importing medical devices). You must stop licensable activities as where can i get flagyl without a prescription soon as you receive your cancellation notice.

Resuming activities after MDEL cancellation To resume licensable activities, you must re-apply for a new establishment licence and pay the MDEL fee. See section 45 of the Medical Device Regulations. To find out how to re-apply for a where can i get flagyl without a prescription MDEL, please refer to our Guidance on medical device establishment licensing (GUI-0016). In line with the Compliance and Enforcement Policy (POL-0001), Health Canada monitors activities for compliance. If your MDEL has been cancelled, you may be subject to compliance and enforcement actions if you conduct non-compliant activities.

If you have questions about a MDEL or the application process, please contact the where can i get flagyl without a prescription Medical Device Establishment Licensing Unit at hc.mdel.questions.leim.sc@canada.ca. If you have questions about invoicing and fees for an MDEL application, please contact the Cost Recovery Invoicing Unit at hc.criu-ufrc.sc@canada.ca. Related linksMDEL Bulletin, June 15, 2021, from the Medical Devices Compliance Program On this page Rapid antigen tests and the workplace screening initiative There are currently various technologies to detect SARS CoV-2, the flagyl that causes buy antibiotics. Antigen-based testing where can i get flagyl without a prescription devices detect specific proteins on the surface of the flagyl and typically provide results in less than 1 hour. While some rapid antigen detection tests (RADTs) have been approved for people without symptoms, most RADTs are indicated for use on people with symptoms and are to be conducted by laboratory personnel, healthcare professionals or trained operators.

Health Canada has authorized several RADTs under two interim orders. The indications where can i get flagyl without a prescription and conditions of use of authorized products may change over time as manufacturers continue to collect data. Screening asymptomatic individuals for SARS CoV-2 is proving to be effective in high-risk settings where social distancing and other measures are not feasible. Through the workplace screening initiative, Canada is supplying RADTs to eligible workplaces across the country. The initiative will help companies detect early cases of buy antibiotics, where can i get flagyl without a prescription for people who are asymptomatic.

This initiative is being administered in collaboration with the provinces and territories. Interim enforcement approach In the interest of public health, Health Canada is placing less priority on enforcing off-label distribution of RADTs under the following circumstances. This enforcement discretion will be in where can i get flagyl without a prescription effect until December 31, 2021. The exception is if. post-market monitoring identifies new risks or there’s no longer a need to apply this discretion based on public health status Related links.

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The second function of the eye movement allows your gaze to be shifted. There are flagyl 400 dosage for diarrhea three types of gaze shifting. Smooth pursuit. Holds the flagyl 400 dosage for diarrhea image of a moving target on our eyesSaccades.

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Vestibular therapy and exercises can help with these conditions. Occupational Therapist Dawn Wylie, O.T.R.L., is a vestibular and balance specialist and part of MidMichigan Health’s Rehabilitation Services team. She sees patients in Alma.There are four key phases for a wound to heal successfully:[click image to enlarge] Specialized Wound Treatment Centers have better outcomes because they bring together many disciplines to not only treat wounds, but also to address the underlying barriers to healing.Hemostasis – clotting to control bleeding.Inflammation – swelling occurs as helpful materials are transported to the flagyl 400 dosage for diarrhea wound site and invasive microbes are pushed out.Proliferation – a protective layer of tissue is formed.Remodeling – rebuilding of tissue and revascularization and reorganization of the new tissue to function like the surrounding tissue.Any factors that interfere with one or more of these phases can prevent wounds from healing. Some of the most common factors include:Poor Circulation – Oxygen and materials needed for healing can’t get to the wound site.

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Call MidMichigan’s Wound Treatment Centers toll free at (877) 683-0800 or visit www.midmichigan.org/woundcenter.Source. Www.ncbi.nlm.nih.gov/pmc/articles/PMC2903966/.

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Have you been told you have a lazy eye?. Does it seem like your where can i get flagyl without a prescription glasses aren’t working well?. Has your eye doctor told you there’s nothing wrong with your current glasses prescription?.

If you’ve answered yes to any of these questions, you may have a problem with your visual or vestibular system, such as a condition of convergence insufficiency or unilateral or bilateral vestibular hypofunction. The visual sensory system consists of the receptors in our eyes that detect light and the colors of objects, and the ability to have where can i get flagyl without a prescription fine discrimination and visual acuity through the pupil. In other words, it helps us see things clearly.

The oculomotor system is a motor component of the where can i get flagyl without a prescription eye function. It helps bring targets onto the fovea, found in the pupil, and keeps the targets on the fovea. This system uses six where can i get flagyl without a prescription muscles that we have in each eye to move the eye in all positions.

The eye movements perform two functions. First, it holds the image on the retina, and second, it allows the gaze or focus to be shifted. One of the two functions of the eye movements is that it holds where can i get flagyl without a prescription the images in the retina.

There are three ways that oculomotor control works with eye movements to hold images onto the retina. Visual where can i get flagyl without a prescription Fixation. Where the retina holds the image of a stationary object on the fovea while your head is stationary, for example, reading a posted sign while standing to look at it.Vestibular Ocular Reflex.

Where images of the seen world are held steady on the retina during brief head rotations, for example, following a flying insect or animal.Optokinetic Reflex where can i get flagyl without a prescription. Where images of what we see in the world are held steady on the retina during sustained low frequency head rotation, such as driving and looking out the window at passing objects or reading. The second function of the eye movement allows your gaze to be shifted.

There are three types of gaze shifting where can i get flagyl without a prescription. Smooth pursuit. Holds the where can i get flagyl without a prescription image of a moving target on our eyesSaccades.

Where there is rapid movements of the eyes, for example, when we’re watching a tennis matchVergence. Moving the where can i get flagyl without a prescription eyes in opposite directions to provide depth perception such as when reading a book or looking at your computer or phone. Vestibular hypofunction occurs when the vestibular nerve is not responding to movement at an accurate rate.

The person experiencing this can feel “off,” dizzy, unbalanced and may where can i get flagyl without a prescription have trouble focusing. Vestibular therapy and exercises can help with these conditions. Occupational Therapist Dawn Wylie, O.T.R.L., is a vestibular and balance specialist and part of MidMichigan Health’s Rehabilitation Services team.

She sees patients in Alma.There are four key phases for a wound to heal successfully:[click image to enlarge] Specialized Wound Treatment Centers have better outcomes because they bring together many disciplines to not only treat wounds, but also to address the underlying barriers to healing.Hemostasis – clotting to control bleeding.Inflammation – swelling occurs as helpful materials are transported to the wound site and invasive microbes are pushed out.Proliferation – a protective layer of tissue is where can i get flagyl without a prescription formed.Remodeling – rebuilding of tissue and revascularization and reorganization of the new tissue to function like the surrounding tissue.Any factors that interfere with one or more of these phases can prevent wounds from healing. Some of the most common factors include:Poor Circulation – Oxygen and materials needed for healing can’t get to the wound site. Dead cells and harmful materials can’t be carried away.Diabetes – Diabetes where can i get flagyl without a prescription interferes with healing in many ways, including lower oxygen levels, weaker immunity and decreased ability to form new skin cells and blood vessels.

Diabetic nerve damage can also make it harder to sense a wound and seek treatment. – Harmful bacteria can prolong inflammation and prevent newNutrition Deficits – Wounds need energy, protein and other vital nutrients to heal.Repeat Trauma – Wounds on feet, moving joints and any body parts that may easily get bumped, rubbed or pressured are more susceptible to reopening. Other factors that can interfere with healing include age, sex hormones, stress, obesity, some medications, alcoholism and smoking.Specialized Wound Treatment Addresses Root Causes Specialized Wound Treatment Centers have better outcomes because they bring together many disciplines to not only treat the wound, but to also address these underlying issues that may be barriers to healing. The Wound Treatment Centers at MidMichigan Health have a cross functional team with where can i get flagyl without a prescription specialists in these and other areas:infectious disease managementcardiologydiabetes educationnutrition managementphysical therapypain managementlab and imagingdebridementhyperbaric oxygen therapyMidMichigan’s specialized Wound Treatment Centers in Alma, Alpena, Clare, Midland and West Branch have a median time to heal of 28 days and 94 percent patient satisfaction.

These outcomes places us among the top 21 percent of nearly 800 Healogics centers nationwide. Healogics is the nation’s where can i get flagyl without a prescription leading wound care management company.Take Action. Seek Specialized Treatment.If you or someone you love is living with a non-healing wound, don’t wait – seek specialized treatment.

Even if you have tried other treatments, but your wound isn’t healing, a multi-disciplinary Wound Treatment Center can identify and address the underlying reasons that the wound did not heal. Call MidMichigan’s Wound Treatment Centers toll free at (877) 683-0800 or visit www.midmichigan.org/woundcenter.Source. Www.ncbi.nlm.nih.gov/pmc/articles/PMC2903966/.

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€‹The families of four children who were tragically killed by a drunk and drugged driver are launching an annual forgiveness day with the support of the NSW Government.Siblings Antony, Angelina and Sienna Abdallah and their cousin Veronique Sakr were killed in February this year when an out-of-control ute mounted the footpath.The two families have taken the extraordinary step of forgiving the man behind the wheel as an important step in their grieving process.The families want i4give Day to be held every year on the anniversary of the deaths in memory of the children.In launching this day, a cheap generic flagyl memorial service will be held on the eve of the anniversary, Sunday, 31 January how long to take flagyl 2021, which will be live streamed to the public.Daniel Abdallah said he wants i4give Day to become one when people can remember the four children but it may also help others who have suffered.“We still feel pain and sorrow everyday, but forgiveness has helped to get rid of the anger and bitterness. It’s helped us get through each day and how long to take flagyl make sure we are there for our other children,” said Mr Abdallah.Both families say this is about honouring their four little saints in heaven.“Our four children are now our four saints and this day is for them. Forgiveness is how long to take flagyl the greatest gift you can give yourself and others.

The more you practise the better you become at it and it allows you live peacefully and to heal.” Leila Abdallah said.“Christmas Eve is a very hard time for us as it is how long to take flagyl also Angelina’s birthday. Even though it is tough, we’ll be celebrating Christmas for the rest what do you need to buy flagyl of our kids.”Veronique’s how long to take flagyl mother Bridget Sakr, said “Christmas can be a difficult time for many families. I hope people can reflect on what so tragically happened to our beautiful children to mend bridges with estranged family members and how long to take flagyl move forward, to love each other in peace and harmony.

Life is too precious.”People across the state will be encouraged to reflect on events and relationships in their own lives how long to take flagyl and look to the example set by the Abdallah and Sakr families.Minister for Mental Health Bronnie Taylor said that while grieving is a normal part of life, when a tragedy such as this occurs the impact on the family is profound.“The grief experienced can take many forms and there is no set timeline. For some people a psychologist or grief and trauma therapist may be of assistance and the need for this may occur months or years after the event,” Mrs Taylor said.“For some people where the loss has occurred through trauma, forgiveness may play a healing role as part of the grieving process.“This day is about honouring Antony, Angelina, Sienna and how long to take flagyl Veronique. Their families have shown amazing strength through such a terrible tragedy.”A website i4give.com will also be launched where people will be directed to links dealing how long to take flagyl with grief and trauma counselling..

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IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development go (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 flagyl 400mg online 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 by an international group of professionals and patient representatives.18 These flagyl 400mg online 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 flagyl 400mg online (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare flagyl 400mg online 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 flagyl 400mg online 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 flagyl 400mg online the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary flagyl 400mg online multicentre group was formed with all members responsible for updating the literature for a specific part of the guideline.

Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, flagyl 400mg online gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using flagyl 400mg online 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 access or retrievable through flagyl 400mg online institutional access.

Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the flagyl 400mg online 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 flagyl 400mg online 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 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 flagyl 400mg online 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 flagyl 400mg online or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus.

However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always flagyl 400mg online 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 flagyl 400mg online 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 flagyl 400mg online ultrasound findings and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

And the type of information genetic testing flagyl 400mg online can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to flagyl 400mg online 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 flagyl 400mg online instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not flagyl 400mg online knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely.

Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, flagyl 400mg online 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 flagyl 400mg online proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS flagyl 400mg online.

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 flagyl 400mg online sex development (DSD) in the prenatal setting. A diagnostic algorithm.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a like this 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 to resolve this variability where can i get flagyl without a prescription in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ where can i get flagyl without a prescription 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 where can i get flagyl without a prescription part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, 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 where can i get flagyl without a prescription 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 where can i get flagyl without a prescription 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for 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 where can i get flagyl without a prescription communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part of where can i get flagyl without a prescription 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 where can i get flagyl without a prescription Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care) where can i get flagyl without a prescription. Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open where can i get flagyl without a prescription access or retrievable through institutional access.

Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after where can i get flagyl without a prescription 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 where can i get flagyl without a prescription 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 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, where can i get flagyl without a prescription reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is where can i get flagyl without a prescription 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 where can i get flagyl without a prescription ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any where can i get flagyl without a prescription 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 where can i get flagyl without a prescription the ultrasound findings and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

And the type of information where can i get flagyl without a prescription genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the where can i get flagyl without a prescription pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs where can i get flagyl without a prescription as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will where can i get flagyl without a prescription 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 prenatal counselling, a where can i get flagyl without a prescription 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 where can i get flagyl without a prescription clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider where can i get flagyl without a prescription 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 where can i get flagyl without a prescription limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused https://for.dontkinhooot.tw/loc.php?id=mt11134-22-4366/events/ 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..

Flagyl

STATUTORYHelms Amendment (1973)Prohibits the use of foreign assistance to pay for the performance flagyl of abortion as a method of family planning or to motivate or coerce any http://www.em-tilleuls-souffelweyersheim.ac-strasbourg.fr/?slideshow=rentree2016 person to practice abortion. Note. Meaning of “motivate” clarified by Leahy Amendment (1994). See below.AbortionAll foreign assistance authorized under the Foreign Assistance Act of 1961(FAA).

All funds under State-Foreign Operations Appropriations (State-Foreign Ops.)Yes, in effect.Permanent law, amendment to the FAA. Also included in annual State-Foreign Ops.Involuntary Sterilization Amendment (1978)Prohibits the use of funds to pay for involuntary sterilizations as a method of family planning or to coerce or provide a financial incentive to anyone to undergo sterilization.Voluntarism/Informed Choice &. Consent. Incentives.

Involuntary SterilizationAll foreign assistance authorized by the FAA of 1961. All foreign assistance funds under State-Foreign Ops.Yes, in effect.Permanent law, amendment to the FAA. Also included in annual State-Foreign Ops.Peace Corps Provision (1978)Prohibits Peace Corps funding from paying for an abortion for a Peace Corps volunteer or trainee. Beginning in FY 2015, allows for payment in cases where the life of the woman is endangered by pregnancy or in cases of rape or incest.AbortionAll Peace Corps fundingYes, in effect.Included under the “Peace Corps” heading of the State-Foreign Ops.Biden Amendment (1981)States that funds may not be used for biomedical research related to methods of or the performance of abortion or involuntary sterilization as a means of family planning.Abortion.

Involuntary SterilizationAll foreign assistance authorized by the FAA of 1961. All foreign assistance funds under State-Foreign Ops.Yes, in effect.Permanent law, amendment to the FAA. Also included in annual State-Foreign Ops.Siljander Amendment (1981)Prohibits the use of funds to lobby for or against abortion. When initially introduced, the amendment prohibited only lobbying for abortion, but in subsequent years Congress modified the language to include lobbying against abortion as well.AbortionAll funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.DeConcini Amendment (1985)Requires that U.S.

Funds be provided to organizations that offer, either directly or through referral to, information about access to a broad range of family planning methods and services. See Livingston-Obey Amendment (1986) below.Voluntarism/Informed ChoiceAll FP funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.Kemp-Kasten Amendment (1985)Prohibits funding any organization or program, as determined by the President, that supports or participates in the management of a program of coercive abortion or involuntary sterilization.UNFPA Funding. Abortion. Voluntarism/Informed Choice &.

Consent. Involuntary SterilizationAll funds under State-Foreign Ops. As well as unobligated balances from prior appropriations actsYes, in effect.Included in annual State-Foreign Ops. Each year.

Presidents determined that it applied to UNFPA in FY85-FY92, FY02-FY08, FY17-FY20.Involuntary Sterilization and Abortion Provision (1985)Specifies that U.S. Foreign assistance funding could be withheld from a country or organization if the president certifies that the use of such funds would violate key provisions of the FAA of 1961 related to abortion or involuntary sterilization (namely the Helms, Biden, and Involuntary Sterilization Amendments).Voluntarism/Informed Choice &. Consent. Incentives.

Abortion. Involuntary SterilizationAll foreign assistance funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.Livingston-Obey Amendment (1986)Prohibits discrimination by the U.S. Government against organizations that offer only “natural family planning” for religious or conscientious reasons when the U.S. Government is awarding related grants.

All such applicants must comply with the requirements of the DeConcini Amendment (1985).Voluntarism/Informed ChoiceAll FP funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.Leahy Amendment (1994)Clarifies Helms Amendment (1973) language that uses the term “motivate” by stating that “motivate” shall not be construed to prohibit, where legal, the provision of information or counseling about all pregnancy options.Abortion. Voluntarism/Informed ChoiceAll authorizing and appropriating legislation related to the State Dept., foreign operations, and related programsYes, in effect.Included in annual State-Foreign Ops.Timing of Release of UNFPA Contribution Funds (1994)Not more than half of funding designated for the U.S. Contribution to UNFPA is to be released before a particular date (varies by fiscal year).UNFPA FundingFunds made available to UNFPANo, not in effect.Sometimes included in annual State-Foreign Ops.Conditions on Availability of UNFPA Funds (UNFPA Segregated U.S. Contribution Account.

UNFPA Does Not Fund Abortions. Prohibition on the Use of U.S. Funds in China by UNFPA) (1994)States that funds may not be made available to UNFPA unless:· UNFPA keeps the U.S. Contribution to the agency in a separate account, not to be commingled with other funds, and· UNFPA does not fund abortions (note.

Language used beginning in FY00).It also prohibits UNFPA from using any funds from the U.S. Contribution in their programming in China.UNFPA Funding. AbortionFunds made available to UNFPAYes, in effect.Included in annual State-Foreign Ops.UNFPA Dollar-for-Dollar Withholding of Amount UNFPA Plans to Spend in China During Fiscal Year (1994)Reduces the U.S. Contribution to UNFPA by one dollar for every dollar that UNFPA spends on its programming in China.UNFPA FundingFunds made available to UNFPAYes, in effect.Typically included in annual State-Foreign Ops.Tiahrt Amendment (1998)Prohibits the use of targets/quotas and financial incentives in family planning projects and requires projects to provide comprehensible information on family planning methods.

Protects people who choose not to use family planning from being denied rights or benefits and requires experimental family planning methods be provided only in the context of a scientific study. Intended to “promote voluntarism and prevent coercion in family planning programs,” it specifically prohibits three types of targets. Total number of births, number of family planning acceptors, and acceptors of a particular method of family planning.Voluntarism/Informed Choice &. Consent.

Incentives and DisincentivesAll FP funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.Reallocation of Funds Not Made Available to UNFPA (2004)Provides for funds not made available to UNFPA to be reallocated to USAID’s family planning, maternal, and reproductive health activities/services (and, in some years, assistance to vulnerable children and victims of trafficking in persons).UNFPA FundingFunds appropriated for UNFPAYes, in effect.Typically included in annual State-Foreign Ops.Medically Accurate Information on Condoms (2005)Ensures that information provided by U.S.-supported programs about the use of condoms is medically accurate information and includes the public health benefits and failure rates of such use.CondomsAll funds under State-Foreign Ops.Yes, in effect.Typically included in annual State-Foreign Ops.POLICYUSAID Policy Paper on Population Assistance (1982)Outlines the longstanding USAID guidelines surrounding its fundamental programmatic principles of voluntarism and informed choice and consent.Voluntarism/Informed Choice &. ConsentAll FP/RH assistance provided by USAIDYes, in effect.Policy Determination 3 (PD-3) and Addendum. USAID Policy Guidelines on Voluntary Sterilization (1982)Describes guidelines for informed consent and voluntarism specifically for voluntary sterilization services, including provisions to ensure ready access to other contraceptive methods and prohibiting incentive payments that might induce a person to select voluntary sterilization over another method.Voluntarism/Informed Choice &. Consent.

Voluntary SterilizationAll FP/RH assistance provided by USAIDYes, in effect.Mexico City Policy (“Global Gag Rule”, 1984) As a condition for receiving U.S. Family planning assistance and, now, also other global health assistance (see “Applies to”), requires foreign NGOs to certify that they will not perform or promote abortion as a method of family planning using funds from any source. Under the Trump administration, it was called “Protecting Life in Global Health Assistance” policy.Abortion1984- 2003. When in effect, was applied to FP assistance at USAID only.

In 2003, expanded to include all FP assistance at USAID and the State Dept., exempting multilateral organizations and HIV/AIDS funding under PEPFAR. 2009-17. Not in effect. 2017-21.

Applied to all global health assistance. 2021-present. Not in effect.No, not in effect.Not currently in force.USAID Post-Abortion Care Policy (2001)Clarifies that post-abortion care – the treatment of injuries or illnesses caused by legal or illegal abortion – is permitted under the Helms Amendment and that any restrictions under the Mexico City Policy, when in force, do not limit organizations from treating injuries or illnesses caused by legal or illegal abortions (i.e., providing post-abortion care). Notes USAID does not finance manual vacuum aspiration equipment purchase/distribution for any purpose.Post-Abortion CareAll FP/RH assistance provided by USAIDYes, in effect.Guidance on the Definition and Use of the Global Health Programs Account.

Section on Allowable Uses of Funds for Family Planning/Reproductive Health (2014)Outlines allowable uses of funds for FP/RH by providing a description of activities allowed and examples of activities not allowed, addressing not only FP/RH activities but also family planning activities’ integration with other global health and multisectoral activities.FP/RH Activities. FP/RH System Strengthening Activities. Integrated FP ActivitiesAll FP/RH assistance provided by USAIDYes, in effect.Updated periodically.PEPFAR FY 2021 Country and Regional Operational Plan GuidanceOutlines certain FP/RH activities that may be reported under specific PEPFAR budget categories, such as youth-friendly sexual and RH services that are part of prevention for adolescent girls and young women.HIV/AIDS Program Linkages with FP/RH Activities. Abortion“Wraparound” PEPFAR activities related to FP/RHYes, in effect.Updated annually.NOTES.

PEPFAR= U.S. President’s Emergency Plan for AIDS Relief. UNFPA= United Nations Population Fund. USAID= U.S.

Agency for International Development.About This TrackerThis tracker provides the number of confirmed cases and deaths from novel antibiotics by country, the trend in confirmed case and death counts by country, and a global map showing which countries have confirmed cases and deaths. The data are drawn from the Johns Hopkins University (JHU) antibiotics Resource Center’s buy antibiotics Map and the World Health Organization’s (WHO) antibiotics Disease (buy antibiotics-2019) situation reports.This tracker will be updated regularly, as new data are released.Related Content. About buy antibiotics antibioticsIn late 2019, a new antibiotics emerged in central China to cause disease in humans. Cases of this disease, known as buy antibiotics, have since been reported across around the globe.

On January 30, 2020, the World Health Organization (WHO) declared the flagyl represents a public health emergency of international concern, and on January 31, 2020, the U.S. Department of Health and Human Services declared it to be a health emergency for the United States..

STATUTORYHelms Amendment (1973)Prohibits the use of foreign assistance to pay for the performance of abortion as a method of family planning or to motivate or coerce any person to practice where can i get flagyl without a prescription abortion. Note. Meaning of “motivate” clarified by Leahy Amendment (1994). See below.AbortionAll foreign assistance authorized under the Foreign Assistance Act of 1961(FAA).

All funds under State-Foreign Operations Appropriations (State-Foreign Ops.)Yes, in effect.Permanent law, amendment to the FAA. Also included in annual State-Foreign Ops.Involuntary Sterilization Amendment (1978)Prohibits the use of funds to pay for involuntary sterilizations as a method of family planning or to coerce or provide a financial incentive to anyone to undergo sterilization.Voluntarism/Informed Choice &. Consent. Incentives.

Involuntary SterilizationAll foreign assistance authorized by the FAA of 1961. All foreign assistance funds under State-Foreign Ops.Yes, in effect.Permanent law, amendment to the FAA. Also included in annual State-Foreign Ops.Peace Corps Provision (1978)Prohibits Peace Corps funding from paying for an abortion for a Peace Corps volunteer or trainee. Beginning in FY 2015, allows for payment in cases where the life of the woman is endangered by pregnancy or in cases of rape or incest.AbortionAll Peace Corps fundingYes, in effect.Included under the “Peace Corps” heading of the State-Foreign Ops.Biden Amendment (1981)States that funds may not be used for biomedical research related to methods of or the performance of abortion or involuntary sterilization as a means of family planning.Abortion.

Involuntary SterilizationAll foreign assistance authorized by the FAA of 1961. All foreign assistance funds under State-Foreign Ops.Yes, in effect.Permanent law, amendment to the FAA. Also included in annual State-Foreign Ops.Siljander Amendment (1981)Prohibits the use of funds to lobby for or against abortion. When initially introduced, the amendment prohibited only lobbying for abortion, but in subsequent years Congress modified the language to include lobbying against abortion as well.AbortionAll funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.DeConcini Amendment (1985)Requires that U.S.

Funds be provided to organizations that offer, either directly or through referral to, information about access to a broad range of family planning methods and services. See Livingston-Obey Amendment (1986) below.Voluntarism/Informed ChoiceAll FP funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.Kemp-Kasten Amendment (1985)Prohibits funding any organization or program, as determined by the President, that supports or participates in the management of a program of coercive abortion or involuntary sterilization.UNFPA Funding. Abortion. Voluntarism/Informed Choice &.

Consent. Involuntary SterilizationAll funds under State-Foreign Ops. As well as unobligated balances from prior appropriations actsYes, in effect.Included in annual State-Foreign Ops. Each year.

Presidents determined that it applied to UNFPA in FY85-FY92, FY02-FY08, FY17-FY20.Involuntary Sterilization and Abortion Provision (1985)Specifies that U.S. Foreign assistance funding could be withheld from a country or organization if the president certifies that the use of such funds would violate key provisions of the FAA of 1961 related to abortion or involuntary sterilization (namely the Helms, Biden, and Involuntary Sterilization Amendments).Voluntarism/Informed Choice &. Consent. Incentives.

Abortion. Involuntary SterilizationAll foreign assistance funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.Livingston-Obey Amendment (1986)Prohibits discrimination by the U.S. Government against organizations that offer only “natural family planning” for religious or conscientious reasons when the U.S. Government is awarding related grants.

All such applicants must comply with the requirements of the DeConcini Amendment (1985).Voluntarism/Informed ChoiceAll FP funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.Leahy Amendment (1994)Clarifies Helms Amendment (1973) language that uses the term “motivate” by stating that “motivate” shall not be construed to prohibit, where legal, the provision of information or counseling about all pregnancy options.Abortion. Voluntarism/Informed ChoiceAll authorizing and appropriating legislation related to the State Dept., foreign operations, and related programsYes, in effect.Included in annual State-Foreign Ops.Timing of Release of UNFPA Contribution Funds (1994)Not more than half of funding designated for the U.S. Contribution to UNFPA is to be released before a particular date (varies by fiscal year).UNFPA FundingFunds made available to UNFPANo, not in effect.Sometimes included in annual State-Foreign Ops.Conditions on Availability of UNFPA Funds (UNFPA Segregated U.S. Contribution Account.

UNFPA Does Not Fund Abortions. Prohibition on the Use of U.S. Funds in China by UNFPA) (1994)States that funds may not be made available to UNFPA unless:· UNFPA keeps the U.S. Contribution to the agency in a separate account, not to be commingled with other funds, and· UNFPA does not fund abortions (note.

Language used beginning in FY00).It also prohibits UNFPA from using any funds from the U.S. Contribution in their programming in China.UNFPA Funding. AbortionFunds made available to UNFPAYes, in effect.Included in annual State-Foreign Ops.UNFPA Dollar-for-Dollar Withholding of Amount UNFPA Plans to Spend in China During Fiscal Year (1994)Reduces the U.S. Contribution to UNFPA by one dollar for every dollar that UNFPA spends on its programming in China.UNFPA FundingFunds made available to UNFPAYes, in effect.Typically included in annual State-Foreign Ops.Tiahrt Amendment (1998)Prohibits the use of targets/quotas and financial incentives in family planning projects and requires projects to provide comprehensible information on family planning methods.

Protects people who choose not to use family planning from being denied rights or benefits and requires experimental family planning methods be provided only in the context of a scientific study. Intended to “promote voluntarism and prevent coercion in family planning programs,” it specifically prohibits three types of targets. Total number of births, number of family planning acceptors, and acceptors of a particular method of family planning.Voluntarism/Informed Choice &. Consent.

Incentives and DisincentivesAll FP funds under State-Foreign Ops.Yes, in effect.Included in annual State-Foreign Ops.Reallocation of Funds Not Made Available to UNFPA (2004)Provides for funds not made available to UNFPA to be reallocated to USAID’s family planning, maternal, and reproductive health activities/services (and, in some years, assistance to vulnerable children and victims of trafficking in persons).UNFPA FundingFunds appropriated for UNFPAYes, in effect.Typically included in annual State-Foreign Ops.Medically Accurate Information on Condoms (2005)Ensures that information provided by U.S.-supported programs about the use of condoms is medically accurate information and includes the public health benefits and failure rates of such use.CondomsAll funds under State-Foreign Ops.Yes, in effect.Typically included in annual State-Foreign Ops.POLICYUSAID Policy Paper on Population Assistance (1982)Outlines the longstanding USAID guidelines surrounding its fundamental programmatic principles of voluntarism and informed choice and consent.Voluntarism/Informed Choice &. ConsentAll FP/RH assistance provided by USAIDYes, in effect.Policy Determination 3 (PD-3) and Addendum. USAID Policy Guidelines on Voluntary Sterilization (1982)Describes guidelines for informed consent and voluntarism specifically for voluntary sterilization services, including provisions to ensure ready access to other contraceptive methods and prohibiting incentive payments that might induce a person to select voluntary sterilization over another method.Voluntarism/Informed Choice &. Consent.

Voluntary SterilizationAll FP/RH assistance provided by USAIDYes, in effect.Mexico City Policy (“Global Gag Rule”, 1984) As a condition for receiving U.S. Family planning assistance and, now, also other global health assistance (see “Applies to”), requires foreign NGOs to certify that they will not perform or promote abortion as a method of family planning using funds from any source. Under the Trump administration, it was called “Protecting Life in Global Health Assistance” policy.Abortion1984- 2003. When in effect, was applied to FP assistance at USAID only.

In 2003, expanded to include all FP assistance at USAID and the State Dept., exempting multilateral organizations and HIV/AIDS funding under PEPFAR. 2009-17. Not in effect. 2017-21.

Applied to all global health assistance. 2021-present. Not in effect.No, not in effect.Not currently in force.USAID Post-Abortion Care Policy (2001)Clarifies that post-abortion care – the treatment of injuries or illnesses caused by legal or illegal abortion – is permitted under the Helms Amendment and that any restrictions under the Mexico City Policy, when in force, do not limit organizations from treating injuries or illnesses caused by legal or illegal abortions (i.e., providing post-abortion care). Notes USAID does not finance manual vacuum aspiration equipment purchase/distribution for any purpose.Post-Abortion CareAll FP/RH assistance provided by USAIDYes, in effect.Guidance on the Definition and Use of the Global Health Programs Account.

Section on Allowable Uses of Funds for Family Planning/Reproductive Health (2014)Outlines allowable uses of funds for FP/RH by providing a description of activities allowed and examples of activities not allowed, addressing not only FP/RH activities but also family planning activities’ integration with other global health and multisectoral activities.FP/RH Activities. FP/RH System Strengthening Activities. Integrated FP ActivitiesAll FP/RH assistance provided by USAIDYes, in effect.Updated periodically.PEPFAR FY 2021 Country and Regional Operational Plan GuidanceOutlines certain FP/RH activities that may be reported under specific PEPFAR budget categories, such as youth-friendly sexual and RH services that are part of prevention for adolescent girls and young women.HIV/AIDS Program Linkages with FP/RH Activities. Abortion“Wraparound” PEPFAR activities related to FP/RHYes, in effect.Updated annually.NOTES.

PEPFAR= U.S. President’s Emergency Plan for AIDS Relief. UNFPA= United Nations Population Fund. USAID= U.S.

Agency for International Development.About This TrackerThis tracker provides the number of confirmed cases and deaths from novel antibiotics by country, the trend in confirmed case and death counts by country, and a global map showing which countries have confirmed cases and deaths. The data are drawn from the Johns Hopkins University (JHU) antibiotics Resource Center’s buy antibiotics Map and the World Health Organization’s (WHO) antibiotics Disease (buy antibiotics-2019) situation reports.This tracker will be updated regularly, as new data are released.Related Content. About buy antibiotics antibioticsIn late 2019, a new antibiotics emerged in central China to cause disease in humans. Cases of this disease, known as buy antibiotics, have since been reported across around the globe.

On January 30, 2020, the World Health Organization (WHO) declared the flagyl represents a public health emergency of international concern, and on January 31, 2020, the U.S. Department of Health and Human Services declared it to be a health emergency for the United States..

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