National Health And Medical Research Council Research Articles

Factors associated with HIV pre-exposure prophylaxis use among Asian men who have sex with men in Sydney and Melbourne, Australia: a cross-sectional study

Asian-born MSM are a priority population as Australia aims to end HIV transmission, but they reported additional barriers to access PrEP and other HIV prevention methods. This study investigates factors associated with PrEP use among Asian MSM in Sydney and Melbourne, Australia, to inform strategies to improve PrEP uptake in this population. This was a sub-analysis of a community-based cross-sectional survey conducted from March to June 2021. We recruited participants online in Sydney and Melbourne, Australia. Univariable and multivariable logistic regression analyses were performed to identify the factors associated with PrEP use in the last six months and lifetime. Latent class analyses were used to identify subgroups of Asian MSM sharing similar characteristics related to their risk practices for HIV. Overall, 870 Asian MSM were included: 288 Oceanian-born Asian MSM and 582 Asian-born MSM. Three latent classes were identified: 1) Asian-born MSM who recently arrived in Australia with limited English, were less likely to use PrEP and at higher risk of HIV infection (e.g., had condomless anal sex with a casual sex partner in the last six months) (4.6%); 2) Asian MSM who were at lower risk of HIV infection and less likely to use PrEP (69.3%) and; 3) Asian MSM who were at substantial risk of HIV infection and more likely to use PrEP (26.1%). Compared to Oceanian-born Asian MSM, those who were born in Southeast Asia (adjusted odds ratio (aOR)=0.5, 95% confidence interval (CI) 0.3-0.7) and South Asia (aOR=0.4, 95% CI 0.2-0.8) were less likely to ever use PrEP. Compared to Oceanian-born Asian MSM, those who were born in Southeast Asia (aOR=0.4, 95% CI 0.3-0.7), Northeast Asia (aOR=0.5, 95% CI 0.3-0.8) and South Asia (aOR=0.4, 95% CI 0.2-0.7) were less likely to use PrEP in the last six months. To end HIV transmission in Australia, it will be necessary to develop strategies to improve PrEP access for the significant minority of Asian-born MSM who are at substantial risk of HIV infection. EPFC and JJO are supported by an Australian National Health and Medical Research Council (NHMRC) Emerging Leadership Investigator Grant (EPFC: GNT1172873 and JJO: GNT1193955). CKF is supported by an Australian National Health and Medical Research Council (NHMRC) Leadership Investigator Grant (GNT1172900).

DEVELOPMENT OF THE NEXT ESSA RESEARCH STRATEGY

INTRODUCTION The generation and use of research is a function within ESSA and the first research strategy was developed for the period 2018 - 2021. Research program activities are diverse. ESSA has hosted the Research Committee and the Publications Committee for 5 years. ESSA has facilitated the development of member-driven Guidelines, Consensus and Position Statements for use by professionals in practice. ESSA has hosted an annual Research Grant Program and a biannual scientific conference. This paper outlines the research strategy development project. METHODS The previous strategy delivered research grants and ESSA publications. Investments were made into administration and research governance including release of the ESSA Research Publications Development Guideline. Consultation on the development of the next Research Strategy included presentations and surveys to engage members, key stakeholders and staff about: the program; the key strategy pillars; principles; and actions. Actions were assessed for feasibility and priority. RESULTS The outcomes of the consultation on the ESSA Research Strategy 2023-2026 identified four pillars of capacity building, engagement, translation and data, and research for policy and practice priorities. The use of research publications by ESSA accredited professionals and industry will be guided by a translation framework, aligning with the objectives of the National Health and Medical Research Council (NHMRC) Translation Strategy 2022-2025, the resources of the National Centre of Implementation Science and the ESSA Strategic Plan. This will support members to leverage research findings, to encourage researchers to develop translation collateral and to implement new research results. The strategy will have actions, references and tools to help accredited professionals to engage in research translation. CONCLUSIONS The Research Strategy and translation framework will be outlined. The paper will include examples relating to physical activity. ESSA’s next Research Strategy is to further support research generation and use by ESSA accredited professionals, staff and the industry.

How much is invested in obesity prevention in Australia? An analysis of major research and Federal Government funding, 2013–2022

How much is invested in obesity prevention in Australia? An analysis of major research and Federal Government funding, 2013–2022

Economic evaluations of assisted reproductive technologies in high-income countries: a systematic review.

Which assited reproductive technology (ART) interventions in high-income countries are cost-effective and which are not? Among all ART interventions assessed in economic evaluations, most high-cost interventions, including preimplantation genetic testing for aneuploidy (PGT-A) for a general population and ICSI for unexplained infertility, are unlikely to be cost-effective owing to minimal or no increase in effectiveness. Approaches to reduce costs in order to increase access have been identified as a research priority for future infertility research. There has been an increasing number of ART interventions implemented in routine clinical practice globally, before robust assessments of evidence on economic evaluations. The extent of clinical effectiveness of some studied comparisons has been evaluated in high-quality research, allowing more informative decision making around cost-effectiveness. We performed a systematic review and searched seven databases (MEDLINE, PUBMED, EMBASE, COCHRANE, ECONLIT, SCOPUS, and CINAHL) for studies examining ART interventions for infertility together with an economic evaluation component (cost-effectiveness, cost-benefit, cost-utility, or cost-minimization assessment), in high-income countries, published since January 2011. The last search was 22 June 2022. Two independent reviewers assessed publications and included those fulfilling the eligibility criteria. Studies were examined to assess the cost-effectiveness of the studied intervention, as well as the reporting quality of the study. The chosen outcome measure and payer perspective were also noted. Completeness of reporting was assessed against the Consolidated Health Economic Evaluation Reporting Standard. Results are presented and summarized based on the intervention studied. The review included 40 studies which were conducted in 11 high-income countries. Most studies (n = 34) included a cost-effectiveness analysis. ART interventions included medication or strategies for controlled ovarian stimulation (n = 15), IVF (n = 9), PGT-A (n = 7), single embryo transfer (n = 5), ICSI (n = 3), and freeze-all embryo transfer (n = 1). Live birth was the mostly commonly reported primary outcome (n = 27), and quality-adjusted life years was reported in three studies. The health funder perspective was used in 85% (n = 34) of studies. None of the included studies measured patient preference for treatment. It remains uncertain whether PGT-A improves pregnancy rates compared to IVF cycles managed without PGT-A, and therefore cost-effectiveness could not be demonstrated for this intervention. Similarly, ICSI in non-male factor infertility appears not to be clinically effective compared to standard fertilization in an IVF cycle and is therefore not cost-effective. Interventions such as use of biosimilars or HMG for ovarian stimulation are cheaper but compromise clinical effectiveness. Lack of both preference-based and standardized outcomes limits the comparability of results across studies. The selection of efficacy evidence offered for some interventions for economic evaluations is not always based on high-quality randomized trials and systematic reviews. In addition, there is insufficient knowledge of the willingness to pay thresholds of individuals and state funders for treatment of infertility. There is variable quality of reporting scores, which might increase uncertainty around the cost-effectiveness results. Investment in strategies to help infertile people who utilize ART is justifiable at both personal and population levels. This systematic review may assist ART funders decide how to best invest to maximize the likelihood of delivery of a healthy child. There was no funding for this study. E.C. and R.W. receive salary support from the National Health and Medical Research Council (NHMRC) through their fellowship scheme (EC GNT1159536, RW 2021/GNT2009767). M.D.-T. reports consulting fees from King Fahad Medical School. All other authors have no competing interests to declare. Prospero CRD42021261537.

Improving the antibiotic duration of therapy with the implementation of antimicrobial lanyard cards and education in a regional hospital

AbstractBackgroundThere is increasing evidence to support reducing antibiotic duration of therapy (DoT). The Therapeutic Guidelines: Antibiotic (version 16 [TG]) have been updated accordingly. However, these recommendations are not consistently followed.AimThe project aimed to reduce antibiotic DoT for common infections using antimicrobial lanyard cards and education.MethodA retrospective pre‐ and post‐implementation audit was undertaken to examine whether antimicrobial stewardship education and lanyard cards defined DoT per infection and severity in accordance with the TG improved antibiotic DoT for common respiratory, urinary, abdominal, and skin infections. Cards were distributed to doctors and pharmacists, with education delivered by an antimicrobial stewardship (AMS) pharmacist. This project was exempt due to the local policy requirements that constitute research by the Darling Downs Hospital and Health Service Human Research Ethics Committee (Reference no: EX/2022/QTDD/86644). The justification for this ethics exemption was as follows: the study conformed with the National Health and Medical Research Council (NHMRC) Ethical considerations in quality assurance and evaluation activities; education was incorporated as part of routine, scheduled sessions ran at Toowoomba hospital and staff were provided with information on the project as part of the education; consent was not required from staff to attend the education nor for using the lanyard cards; the research did not include any assessment of the education program, use of lanyard cards, or involvement of staff.ResultsFor all patients an improvement was found in the percentage of antibiotics prescribed per the TG (55–72%, p = 0.0095). This included statistically significant differences for respiratory (42–89%, p = 0.0002), but not for urinary (87–91%, p = 0.99), skin (58–77%, p = 0.3039), or abdominal infections (48–44%, p = 0.6990). The mean total excess treatment days decreased across all infections from 1.86 to 0.95 days (p = 0.0036, 95% confidence interval = −1.52 to −0.30).ConclusionThe introduction of antibiotic DoT cards, with AMS education, can improve antimicrobial prescribing in line with the TG in a regional hospital.

Wrestling with evidence-based practice: An evidence mapping review of publication trends in the South African Journal of Occupational Therapy

Introduction: Occupational therapy research to support clinical decision-making must be responsive to local needs, illustrate our unique value to clients, communities and providers, and demonstrate efficacy for quality assurance and reimbursement. This article examines the publication trends in the South African Journal of Occupational Therapy (SAJOT) with the intention of contributing to dialogues about evidence-based practice. Methods: A mapping review was undertaken of articles published in the SAJOT from January 2009 to December 2021. All articles excepting commentaries, book reviews and editorials were included. Articles were categorised by year of publication, title, author, research approach, study design, practice area, research affiliation, and nature of authorship.Quantitative research articles were classified according to the Australian National Health and Medical Research Council (NHMRC) levels of evidence. Results: Of the 265 articles published in the 13-year period, slightly more took a quantitative approach (52.1%) comparedwith qualitative approaches (42.4%). Most quantitative studies were Level 111-2 studies (31.3%). Children and Youth was the practice area with the highest number of articles (34.8%) and the strongest evidence base. Conclusion: As occupational therapy continues to wrestle with EBP, further dialogue about a national occupational therapy research strategy to identify and harness enablers and explore and mitigate the barriers identified in this review, is recommended. Implications for practice • This research serves as a bridge between theoretical findings and practical applications, by providing data from research that can be put into action through the development of research agendas by institutions. • By understanding what research has been done, professionals can make informed decisions that are backed by evidence-based findings. This not only enhances the quality of their work but also improves overall efficiency and effectiveness. • The study helps practitioners identify areas where improvements or interventions are needed. They shed light on potential challenges and offer possible solutions that can be implemented to address specific issues or concerns within their respective fields. • This data provides a platform for collaboration between researchers and practitioners across institutions in terms of common research agendas.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Skłodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. N/A.

International Guidelines and Significant Advances in Diagnosis

Objective: To develop and translate rigorous, comprehensive evidence-based guidelines for diagnosis, assessment, and treatment, to improve the lives of those with polycystic ovary syndrome (PCOS) worldwide. Here we will focus on diagnosis. Participants: Extensive health professional and consumer or patient engagement informed the guideline priority areas. International society-nominated panels included consumers, and experts in paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, psychology, dietetics, exercise physiology, sleep, bariatric/metabolic surgery, public health, other co-opted experts, project management, evidence synthesis and translation. Evidence: Best practice, evidence-based guideline development involved extensive evidence synthesis and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework covered evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Process: Governance included an international advisory board, project board and five guideline development groups with 52 members, consumer, and translation committees. The Centre for Research Excellence in Women’s Health in Reproductive Life, funded by the Australian National Health and Medical Research Council (NHMRC), and led by Monash University, partnered with the American Society for Reproductive Medicine, the Endocrine Society, the European Society of Endocrinology and the European Society of Human Reproduction and Embryology. Thirty-six organisations collaborated with international meetings over nine months. Fifty-five prioritised clinical questions involved 52 systematic and three narrative reviews, generating evidence-based and consensus recommendations with accompanying practice points. Committee members nominated by collaborating organisations provided international peer review, and evidence expert-reviewed methods and outputs were submitted to NHMRC for independent review. Recommendations: PCOS should be diagnosed using the revised consensus Rotterdam criteria, which are now updated to evidence-based criteria in the International Guideline. In adults this requires the presence of two of i) clinical/biochemical hyperandrogenism ii) ovulatory dysfunction and iii) polycystic ovaries on ultrasound or elevated anti-mullerian hormone (AMH) levels, after other causes of these features are excluded. Where irregular menstrual cycles and hyperandrogenism are present, ultrasound or AMH are not required for diagnosis. In adolescents, both hyperandrogenism and ovulatory dysfunction are required, with ultrasound and AMH not recommended, due to poor specificity. Conclusion: Overall, evidence in PCOS is low to moderate quality. Based on high prevalence and significant health impact, greater priority, funding, and research is recommended. Guideline translation will be extensive including multilingual education outputs and evidence-based resources for consumers (the ASKPCOS app), healthcare professionals and policy makers.

National Health and Medical Research Council statement on electronic cigarettes: 2022 update.

Electronic cigarette (e-cigarette) use in Australia has rapidly increased since the 2017 National Health and Medical Research Council (NHMRC) Chief Executive Officer (CEO) statement on e-cigarettes. The type of products available and the demographic characteristics of people using these products have changed. New evidence has been published and there is growing concern among public health professionals about the increased use, particularly among young people who do not currently smoke combustible cigarettes. The combination of these issues led NHMRC to review the current evidence and provide an updated statement on e-cigarettes. In this article, we describe the comprehensive process used to review the evidence and develop the 2022 NHMRC CEO statement on electronic cigarettes. E-cigarettes can be harmful; all e-cigarette users are exposed to chemicals and toxins that have the potential to cause adverse health effects. There are no health benefits of using e-cigarettes if you do not currently smoke tobacco cigarettes. Adolescents are more likely to try e-cigarettes if they are exposed to e-cigarettes on social media. Short term e-cigarette use may help some smokers to quit who have been previously unsuccessful with other smoking cessation aids. There are other proven safe and effective options available to help smokers to quit. The evidence base for the harms of e-cigarette use has strengthened since the previous NHMRC statement. Significant gaps in the evidence base remain, especially about the longer term health harms of using e-cigarettes and the toxicity of many chemicals in e-cigarettes inhaled as an aerosol.

Familial aggregation of esophageal cancer.

Esophageal cancer has a substantial health burden in China, especially in the northern regions. Although family history has been established to be associated with esophageal cancer risk, some quantitative aspects of the association remain unclear or imprecise, including the age-specific magnitude of familial aggregation, the risks associated with the number and type of affected relatives, and how the familial risk combines with other known risk factors. A study conducted by Zhou et al[1] on the familial association of esophageal cancer answered some of the questions above. The study has several strengths including its large sample size of 33,008 participants with a high proportion of family history (15.2% having an affected first-degree relative), collection of data on known risk factors and detailed family history, and pathologically confirmed esophageal cancer diagnoses. Major findings of the study. The study had two major findings. First, the esophageal cancer familial risk ratio associated with an affected first-degree relative was 1.65, with considerable precision (95% confidence intervals: 1.47–1.84). Second, the familial risk ratio increased to 4.05 (albeit with wide confidence intervals) if the first-degree relative was diagnosed <35 years, and decreased with the increasing of diagnosed age of the relative. These findings suggest that esophageal cancer has a substantial familial aggregation, which appears to decrease with age. If this familial aggregation was due entirely to polygenic risk factors, then on average those individuals in the upper quartile of risk would be at >10 times the risk of those in the lower quartile. The strength of this risk gradient is much greater at a younger age, such as a >60-fold interquartile risk ratio for having esophageal cancer diagnosed <35 years.[2] Limitations of the study. The study only investigated family history in relatives defined by familial relatedness, but not by the specific type of relatives, and in particular parents and siblings. A difference in familial risk between parents and siblings would suggest different inheritance modes of the susceptibility genes. The absence of a difference would suggest that the genes are likely to act dominantly or additively, while the existence of a difference would suggest that the genes are likely to act recessively, given that recessively inherited genes result in higher risks in siblings than in parents and offspring. For several common cancers like breast cancer (especially if diagnosed at a young age), there is a higher familial risk for having an affected sibling.[3] However, there are some caveats related to this; see below. Another limitation is that the study only investigated age-specific familial aggregation in terms of the diagnosis age of the relatives, but not that of the cases. For breast cancer, the decreasing trend is more obvious with the diagnosis age of the cases.[4] The resource of Zhou et al[1] would be useful for investigating if esophageal cancer familial aggregation also depends on the diagnosis age of the cases. On the other hand, the study did not analyze the familial risk ratio associated with having relatives diagnosed >50 years. Nevertheless, based on their results, the familial risk ratio with having a first-degree relative diagnosed >50 years must be <1.65, which further supports the evidence that esophageal cancer familial aggregation decreases with age. The familial aggregation of several common cancers, like breast cancer, also decreases with age.[3,4] This pattern suggests that familial factors are more important at younger ages (e.g., the breast cancer familial variance explained by BRCA1 and BRCA2 pathogenic variants is greater for young women[3]), and studying young cases could be more fruitful for identifying novel familial risk factors, especially susceptibility genes or variants. The study collected data on several known risk factors including sex, smoking, and alcohol consumption and adjusted for them in the analysis. What can be further investigated includes the change in familial risk before and after adjusting for the risk factors, and whether the magnitude of the familial risk differs across levels of known risk factors. The former has etiological implications of whether known risk factors help explain the familial aggregation, and the latter has implications for risk prediction and prevention — whether family history and known risk factors combine multiplicatively in increasing risk. If yes, the absolute risk attributed to known risk factors will be greater for people with a family history, and relevant interventions would be more fruitful for these people. Implications of the study findings. For etiology: Segregation analyses of esophageal cancer in Chinese populations have suggested that high-penetrant recessively inherited major genes explain esophageal cancer familial aggregation.[5] However, genetic studies have yet to find any major genes for esophageal cancer. There might be two reasons for the inconsistency. First, the findings of recessive genes from the segregation analyses might be explained by birth cohort effects that siblings have a higher background cancer incidence than parents, siblings are more likely to be diagnosed due to increased screening, and/or siblings share some non-genetic and lifestyle risk factors. Segregation analyses have also suggested recessive genes for cancers like breast cancer, which might be due to these effects too.[3] Second, the esophageal cancer segregation analyses only considered a single major gene model. The increase in familial risk ratio with the number of affected first-degree relatives observed by Zhou et al[1] suggests that there are many genetic risk groups, consistent with a polygenic susceptibility model and the evidence from genome-wide association studies (GWAS) of esophageal cancer. Segregation analyses have found that a model including major genes and polygenes is the optimal genetic susceptibility model for cancers like breast cancer.[3] On the other hand, the familial risk ratio associated with having one affected first-degree relative was 1.6 times the ratio associated with having one affected second-degree relative (on the log scale), <2, suggesting that part of the familial factors is likely to be non-genetic. This is plausible, especially given that the participants were from high-risk areas where environmental factors have been established to be related to esophageal cancer risk. For risk prediction and prevention: Under the polygenic susceptibility model,[6] the familial risk of 1.65 implies that 31% of individuals in the population have an increased risk (familial risk ratio >1.0), and these individuals account for 69% of all individuals affected; half of the esophageal cancer cases come from the 16% with the highest risk in the population. These have obvious public health implications—targeting high-risk individuals can significantly reduce the esophageal cancer burden at the population level. A related question is: how to identify the individuals who are at high risk? Obviously, individuals having just one affected first-degree relative do not have a substantially increased risk unless the relative is diagnosed at a young age (e.g., <35 years). High-risk individuals are those with a strong family history. Segregation analyses can be used to develop cancer risk models for identifying high-risk individuals based on multigenerational family history, genotypes, and other factors, and a successful example is the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm for estimating a woman's future risk of developing breast cancer. The same could be applied to esophageal cancer. Polygenic risk score (PRS) has been proposed to be able to identify high-risk individuals. For esophageal cancer, PRSs developed from the population of European ancestry almost have no discrimination accuracy, with an area under receiver operating characteristic curve (AUC) of ∼0.55.[7] Such AUC is equivalent to a familial variance of 0.03; therefore, these PRSs only explain ∼3% of the esophageal cancer familial variance of 1.0 under the assumption that European populations have the same familial risk ratio of 1.65. This suggests that more esophageal cancer genetic variants are yet to be found. The performance of esophageal cancer PRS in Chinese populations is unknown, as, to the best of our knowledge, there is no valid PRS specific to Chinese populations published. Breast and colorectal cancers have some of the largest cancer GWAS in the world, but PRSs developed from these studies only explain ∼20% on average of the familial variance in these cancers.[8,9] Assuming the same proportions apply to esophageal cancer, esophageal cancer PRS would have an AUC of 0.62. However, combining PRS with family history is expected to improve disease discrimination accuracy, as observed for breast cancer.[10] Note that, there is a maximum AUC that can be achieved by knowing all esophageal cancer genetic risk factors, which is 0.76 under the assumption that all familial factors are genetic. Another issue of PRS is its age dependency. For common cancers including breast and colorectal cancers which have an age-deceasing familial aggregation, the risk gradient of their PRSs also decreases with age, except the current best PRS for breast cancer.[8,9] The absence of clear age dependence in the risk associated with breast cancer PRS implies that this PRS explains a small proportion of familial aggregation at a young age, and it is unlikely to predict death due to breast cancer, that is, women with a higher PRS are not “eliminated.”[3,8,9] It would be interesting to know the age dependence when more esophageal cancer PRSs are developed in the future. Funding S.L. is a National Health and Medical Research Council (NHMRC) Emerging Leadership Fellow (GNT2017373). This work was conducted when S.L. was a Victorian Cancer Agency Early Career Research Fellow (ECRF19020). J.L.H. is an NHMRC Senior Principal Research Fellow. Conflicts of interest None.

Coverage gaps in empiric antibiotic regimens used to treat serious bacterial infections in neonates and children in Southeast Asia and the Pacific

High levels of antimicrobial resistance (AMR) are propagating deaths due to neonatal and paediatric infections globally. This is of particular concern in Southeast Asia and the Pacific, where healthcare resources are constrained and access to newer agents to treat multidrug-resistant pathogens is limited. To assess the coverage provided by commonly prescribed empiric antibiotic regimens for children in low- and middle-income countries in Southeast Asia and the Pacific, we built a weighted incidence syndromic combination antibiogram (WISCA), parameterised using data obtained from a systematic review of published literature incorporating WHO-defined SEARO and WPRO regions in Ovid MEDLINE, EMBASE, Global Health and PubMed. Susceptibility data for bacterial pathogens were extracted to provide coverage estimates for pre-specified antibiotics (aminopenicillins, gentamicin, third-generation cephalosporins and carbapenems), reported at the regional level. 6648 bacterial isolates from 11 countries across 86 papers were included in the Bayesian WISCA model, which weighted bacterial incidence and antimicrobial susceptibility of relevant isolates. Coverage provided by aminopenicillins in neonatal sepsis/meningitis was 26% (80% credible interval: 16-49) whilst gentamicin coverage was 45% (29-62). Third-generation cephalosporin coverage was only 29% (16-49) in neonatal sepsis/meningitis, 51% (38-64) in paediatric sepsis and 65% (51-77) in paediatric meningitis. Carbapenems were estimated to provide the highest coverage: 81% (65-90) in neonatal sepsis/meningitis, 83% (72-90) in paediatric sepsis and 79% (62-91) in paediatric meningitis. These findings reveal alarmingly high rates of resistance to commonly prescribed empirical therapies for neonatal and paediatric sepsis and meningitis in the Asia-Pacific region. This research was funded in whole, or in part, by the Wellcome Trust [220211]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. PCMW is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant. NHMRC had no involvement in the design or conduct of the research.

Inter-observer agreement on levels of evidence in radiology articles

Levels of evidence (LE) are established through a hierarchical classification of studies according to their design. At present, there are many heterogeneous LE classifications, and this hampers their applicability. Our study aims to identify which LE classification has the best interobserver concordance for radiology articles. For this purpose, an interobserver agreement analysis were performed on 105 original articles applying two NE scales (Oxford Center of Evidence Based Medicine (OCEBM) y National Health and Medical Research Council (NHMRC)). The inter-rater agreement of the LE assigned after reading the abstracts was good when using the OCEBM scale (K = 0.679), and somewhat lower with the NHMRC (K = 0.577 -moderate-). All differences were statistically significant (P < .000). So, in conclusion, of the two scales analysed (OCEBM and NHMRC), the OCEBM led to the strongest level of inter-rater agreement.

The Study of Ketamine for Youth Depression (SKY-D): study protocol for a randomised controlled trial of low-dose ketamine for young people with major depressive disorder

BackgroundExisting treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD).MethodsSKY-D is a double-masked, randomised controlled trial funded by the Australian Government’s National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes.DiscussionResults from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people.Trial registrationAustralian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513.

Cost and cost-effectiveness analysis of mass drug administration compared to school-based targeted preventive chemotherapy for hookworm control in Dak Lak province, Vietnam

School-based targeted preventive chemotherapy (PC), the main strategy for soil-transmitted helminths (STH) control, excludes other at-risk populations including adults and preschool children. Mass drug administration (MDA), covering all age groups, would bring additional health benefits but also requires greater investment. This cost survey and cost-effectiveness analysis compared MDA with school-based targeted PC for STH control in Dak Lak, Vietnam, where STH are endemic. A cost survey was conducted in 2020 to estimate the total and per person economic and financial cost of each strategy. Monte Carlo simulation accounted for uncertainty in cost estimates. The primary effectiveness measure was hookworm-related disability-adjusted life years (DALYs) averted, and secondary measures were hookworm infection-years averted and moderate-to-heavy intensity hookworm infection-years averted. A Markov model was used to determine the incremental cost-effectiveness ratio (ICER) of MDA compared to school-based targeted PC using a government payer perspective and a ten-year time horizon. One-way and probabilistic sensitivity analyses (PSA) were performed. Costs are reported in 2020 USD ($). The economic cost per person was $0.27 for MDA and $0.43 for school-based targeted PC. MDA in Dak Lak will cost $472,000 per year, while school-based targeted PC will cost $117,000. Over 10 years, MDA is estimated to avert an additional 121,465 DALYs; 4,019,262 hookworm infection-years, and 765,844 moderate-to-heavy intensity hookworm infection-years compared to school-based targeted PC. The ICER was $28.55 per DALY averted; $0.87 per hookworm infection-years averted, and $4.54 per moderate-to-heavy intensity hookworm infection-years averted. MDA was cost-effective in all PSA iterations. In areas where hookworm predominates and adults suffer a significant burden of infection, MDA is cost effective compared to school based targeted PC and is the best strategy to achieve global targets. The project was funded by the National Health and Medical Research Council (NHMRC) of Australia (Project Grant APP1139561) and JPCDT was supported by a UNSW Scientia PhD Scholarship.

Concordancia interobservador de los niveles de evidencia en artículos radiológicos

Levels of evidence (LE) are established through a hierarchical classification of studies according to their design. At present, there are many heterogeneous LE classifications, and this hampers their applicability. Our study aims to identify which LE classification has the best interobserver concordance for radiology articles. For this purpose, an interobserver agreement analysis were performed on 105 original articles applying two NE scales (Oxford Center of Evidence Based Medicine (OCEBM) y National Health and Medical Research Council (NHMRC)). The inter-rater agreement of the LE assigned after reading the abstracts was good when using the OCEBM scale (K=0.679), and somewhat lower with the NHMRC (K=0.577 -moderate-). All differences were statistically significant (p<0.000). So, in conclusion, of the two scales analysed (OCEBM and NHMRC), the OCEBM led to the strongest level of inter-rater agreement.

Infection prevention and control in computed tomography: creating a national survey

BackgroundInfection prevention and control (IPC) is essential for quality healthcare, with healthcare associated infections (HAI) a known risk to patients requiring medical imaging (MI). To date, few papers have adopted a national approach to understanding or benchmarking the knowledge of, attitudes toward, and practice (KAP) of IPC in the context of MI and no validated surveys or scales are identified in the literature. The Computed Tomography (CT) suite is a unique MI environment where radiographers deliver prescription medicines to patients via intravenous (IV) means through an injector system. This paper describes the development of a survey that informs the use of IPC processes in the CT suite. MethodsStandard Precautions via current national guidelines formed the benchmark of the survey, with a KAP survey used as the framework to explore IPC. The questions and associated responses are developed based on the National Health and Medical Research Council (NHMRC) guidelines, industry/professional protocols and adapted to the equipment and practices commonly used in the CT suite of MI departments by radiographers and nurses. ResultsKey survey development steps are described to include the justification of the benchmarking source, the survey framework and design. Detailed information is given to show the evolution of truth statements and sources, KAP question variations, and rationales for the methodology of question responses. National guidelines are mapped to survey questions and responses and pilot testing reflections are included. ConclusionThis paper reports on the construction of a standardised KAP survey for IPC specific to the CT suite in the Australian healthcare setting. The survey is ready for dissemination amongst MI departments. Documented use will aid validation and reliability as a survey tool to measure and map IPC specifically in relation to IV contrast administration.

Long-term healthcare utilization and costs of babies born after assisted reproductive technologies (ART): a record linkage study with 10-years' follow-up in England.

Is the long-term health care utilization of children born after ARTmore costly to the healthcare system in England than children born to mothers with no fertility problems? Children born after ART had significantly more general practitioner (GP) consultations and higher primary care costs up to 10 years after birth, and significantly higher hospital admission costs in the first year after birth, compared to children born to mothers with no fertility problems. There is evidence that children born after ART are at an increased risk of adverse birth outcomes and a small increased risk of rare adverse outcomes in childhood. We conducted a longitudinal study of 368088 mother and baby pairs in England using a bespoke linked dataset. Singleton babies born 1997-2018, and their mothers, who were registered at GP practices in England contributing data to the Clinical Practice Research Datalink (CPRD), were identified through the CPRD GOLD mother-baby dataset; this data was augmented with further linkage to the mothers' Human Fertilisation and Embryology Authority (HFEA) Register data. Four groups of babies were identified through the mothers' records: a 'fertile' comparison group, an 'untreated sub-fertile' group, an 'ovulation induction' group, and an ART group. Babies were followed-up from birth to 28 February 2021, unless censored due to loss to follow-up (e.g. leaving GP practice, emigration) or death. The CPRD collects anonymized coded patient electronic health records from a network of GPs in the UK. We estimated primary care costs and hospital admission costs for babies in the four fertility groups using the CPRD GOLD data and the linked Hospital Episode Statistics (HES) Admitted Patient Care (APC) data. Linear regression was used to compare the care costs in the different groups. Inverse probability weights were generated and applied to adjust for potential bias caused by attrition due to loss to follow-up. Children born to mothers with no fertility problems had significantly fewer consultations and lower primary care costs compared to the other groups throughout the 10-years' follow up. Regarding hospital costs, children born after ART had significantly higher hospital admission costs in the first year after birth compared to those born to mothers with no fertility problems (difference = £307 (95% CI: 153, 477)). The same pattern was observed in children born after untreated subfertility and ovulation induction. HFEA linkage uses non-donor data cycles only, and the introduction of consent for data use reduced the availability of HFEA records after 2009. The fertility groups were derived by augmenting HFEA data with evidence from primary care records; however, there remains some potential misclassification of exposure groups. The cost of neonatal critical care is not captured in the HES APC data, which may cause underestimation of the cost differences between the comparison group and the infertility groups. The findings can help anticipate the financial impact on the healthcare system associated with subfertility and ART, particularly as the demand for these treatments grows. C.C. and this work were funded by a UK Medical Research Council Career Development Award [MR/L019671/1] and a UK MRC Transition Support Award [MR/W029286/1]. X.H. is an Australia National Health and Medical Research Council (NHMRC) Emerging Leadership Fellow [grant number 2009253]. The authors declare no competing interest. N/A.

High prevalence of medical conditions and unhealthy lifestyle behaviours in women with PCOS during preconception: findings from the Australian LongitudinalStudy on Women's Health.

What are the pre-existing medical conditions and lifestyle behaviours of women with and without PCOS during the preconception period? During the preconception period, medical conditions of obesity, depression, anxiety, and a history of infertility were more highly prevalent in women with than without PCOS, and more women with than without PCOS were engaged in unhealthylifestyle behaviours. Women with PCOS are predisposed to infertility and pregnancy complications. Optimizing preconception medical health and lifestyle behaviours can improve maternal and pregnancy outcomes but, to the best of our knowledge, no study has examined the preconception medical conditions and lifestyle behaviours of women with PCOS. This is a cross-sectional study on 942 women with PCOS and 7024 women without PCOS, aged 24-30 years from the Australian Longitudinal Study of Women's Health, an ongoing, national survey-based prospective cohort study. The current study analysed self-reported data from Survey 6 collected in 2019 of the cohort of women born between 1989 and 1995. Explored outcomes included BMI, pre-existing medical conditions, and modifiable lifestyle behaviours, including smoking, recreational drug use, alcohol intake, and physical activity level, during the preconception period. Differences between subgroups were tested using Student's t-test, χ2 test, or Fisher's exact test as appropriate. The associations of pregnancy intention with medical conditions and lifestyle behaviours were examined using logistic regression. Obesity, depression, anxiety, and infertility were highly prevalent in women actively planning for pregnancy. Among women with PCOS, the prevalence of obesity was 47.02%, followed by depression at 32.70%, anxiety at 39.62%, and infertility at 47.17%. Conversely among women without PCOS, the corresponding prevalence was lower, at 22.33% for obesity, 18.98% for depression, 23.93% for anxiety, and 16.42% for infertility. In women actively planning for pregnancy, only those without PCOS demonstrated a lower prevalence of unhealthy lifestyle behaviours compared to non-planning women. The prevalence of unhealthy lifestyle behaviours was similar in women with PCOS regardless of their pregnancy intentions. Multivariable logistic regressionrevealed that only moderate/high stress with motherhood/children (adjusted odds ratio (OR) 3.31, 95% CI 1.60-6.85) and history of infertility (adjusted OR 9.67, 95% CI 5.02-18.64) were significantly associated with active pregnancy planning in women with PCOS. The findings were based on self-reported data. The cohort of women surveyed may have a higher level of education than women in the community, therefore our findings may underestimate the true prevalence of pre-existing medical conditions and lifestyle challenges faced by the broader population. A higher proportion of women with than without PCOS had pre-existing medical conditions and engaged in potentially modifiable unhealthy lifestyle behaviours during preconception despite their risk for subfertility and pregnancy complications. Healthcare professionals play a pivotal role in guiding this high-risk group of women during this period, offering counselling, education, and support for the adoption of healthy lifestyles to improve fertility, pregnancy outcomes, and intergenerational health. C.T.T. holds a seed grant from the National Health and Medical Research Council (NHMRC) through the Centre of Research Excellence in Women's Health in Reproductive Life (CRE WHiRL) and Royal Australasian College of Physician Foundation Roger Bartop Research Establishment Fellowship. H.T. holds an NHMRC Medical Research Fellowship. C.L.H. holds an NHMRC CRE Health in Preconconception and Pregnancy Senior Postdoctoral Fellowship. A.E.J. holds a CRE WhiRL Early to Mid-career Fellowship. The authors have no conflicts of interest to declare. N/A.

PROSPECTS FOR THE USE OF UMBILICAL CORD BLOOD IN THE TREATMENT OF DISEASES OF THE CARDIOVASCULAR SYSTEM

Cardiovascular diseases are currently the most common cause of death worldwide. In this regard, experimental and clinical studies of the effectiveness of therapy of ischemic and non-ischemic heart diseases using stem cells are relevant. The purpose of this review was to evaluate the prospects of using cord blood stem cells in the treatment of cardiovascular diseases. Methods. The following databases were searched: «BIGG International database of GRADE guidelines», “Database of GRADE EtD's and Guidelines”, “Dynamed”, “ebmafrica.net”, “ECRI”, “MAGIC authoring and publication platform (MAGICapp)”, “National Health and Medical Research Council (NHMRC) portal”, “NICE Evidence”, “Pubmed”, “TRIP database”, “U.S. Preventive Services Task Force”. Results. An analysis of research related to this problem, which was conducted in recent years, was made, and considerations regarding the prospects of using umbilical cord blood in the treatment of diseases of the cardiovascular system were outlined. Conclusions. Despite some successes, realizing the full potential of cord blood stem cells in the treatment of cardiovascular diseases still requires further serious, targeted and well-funded research and expanded clinical trials.

Evidence-based guideline: unexplained infertility†.

What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature? The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI. UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation. The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated. Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee. This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations-of which 29 were formulated as strong recommendations and 11 as weak-10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided. Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised. The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI. The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose. This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).