A core outcome set for trials in miscarriage management and prevention: An international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage.

Sporadic miscarriage: evidence to provide effective care.

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units.

Recurrent miscarriage: evidence to accelerate action.

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.

Genotyping Sri Lankan women with polycystic ovary syndrome (PCOS): towards a novel screening tool.

Introduction: Polycystic ovary syndrome (PCOS) is the multigenic, endocrine disorder of young women. Inheritance of PCOS is likely to be oligogenic and genetic basis remains largely unknown. Screening the candidate genes of PCOS and their SNPs individually is time consuming. Hence, developing a tool that would help in screening multiple candidate genes simultaneously is essential to determine the exact genetic basis of PCOS. Objectives: This study aimed to develop a simple and cost-effective genetic screening tool to simultaneously genotype 16 single nucleotide polymorphisms (SNPs) of PCOS. Methods: The genetic screening tool was developed using allele specific real time quantitative PCR (AS-qPCR) in 96 well PCR plate. Eight SNPs identified in our previous study as well as 8 SNPs identified from other reported studies that had a strong association in the etiology of PCOS were used to develop the tool. Samples from our previous study were reanalyzed using the developed genetic screening tool. Genetic screening tool results were validated with Sanger sequencing. Results: Totally 10 AS-qPCR runs (160 reactions = 16SNPs*10runs) were performed using the developed tool and all except 3 genotype results agreed with Sanger sequencing. The tool showed 100% specificity and 96% sensitivity. Conclusion: The developed genetic screening tool has excellent potential in determining the genotype of multiple SNPs of PCOS simultaneously. This tool is highly suitable for developing countries as a cost effective and accurate early genetic screening test for PCOS. Thus, provides a reliable, fast and user-friendly genotyping method facilitating a wider implication in clinical practice.

In depth analysis of the association of FTO SNP (rs9939609) with the expression of classical phenotype of PCOS: a Sri Lankan study.

BACKGROUND: PCOS is a common disorder of women due to genetic, endocrine and environmental effects that manifests from puberty. The rs9939609 variant of fat mass and obesity associated (FTO) gene is linked to metabolic derangement in PCOS. We previously identified FTO (rs9939609) as a susceptibility locus for PCOS among Sri Lankan women and also explored the role of kisspeptin. Associated factors of the FTO candidate gene among South Asians with PCOS are unknown. METHODS: This study aimed to determine the association between FTO (rs9939609) polymorphism with clinical (BMI, acanthosis nigricans, hirsutism) and biochemical (serum kisspeptin and testosterone levels) characteristics of PCOS in a cohort of Sri Lankan women. Genetic and clinical data including serum kisspeptin and testosterone concentrations of our previously reported cases (n = 55) and controls (n = 110) were re-analyzed, specifically for an association with rs9939609 variant of FTO gene. RESULTS: Logistic regression analysis (AA - OR = 5.7, 95% CI = 2.41-13.63, p < 0.05) and genetic inheritance analysis (AA - OR = 5.49, 95%CI = 2.34-12.88, p < 0.05) showed that FTO (rs9939609) polymorphism is significantly associated with PCOS and its metabolic manifestations. Serum testosterone was significantly higher in affected women with mutant genotypes (AA+AT) than with the normal allele (TT) (p < 0.05). Although serum kisspeptin was higher in subjects with PCOS and mutant alleles than controls, this difference was not significant (p > 0.05). CONCLUSION: FTO gene variant rs9939609 is associated with hyperandrogenemia and metabolic manifestations of PCOS among women of Sri Lankan descent with the well-characterized phenotype. Serum kisspeptin and the FTO genotypes lack a significant association when adjusted for confounders.

Association between visceral adiposity index, hirsutism and cardiometabolic risk factors in women with polycystic ovarian syndrome: A cross-sectional study

Introduction: Visceral adiposity index (VAI) is a mathematical index derived from the body mass index (BMI), waist circumference (WC), serum fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). It reflects visceral adipocyte dysfunction (VAD) and is associated with cardiometabolic risk. Women with polycystic ovarian syndrome (PCOS) have adipocyte dysfunction, which is associated with metabolic disorders. Hirsutism in PCOS is considered to be due to high insulin levels which enhances androgen activity at the pilosebaceous unit. Objectives: To determine the association between VAI, hirsutism and cardiometabolic risk factors in patients with PCOS. Methods: A total of 99 patients aged 18-40 years with PCOS diagnosed by the Rotterdam consensus criteria-2003 and a hirsutism score of 8 or more according to the Ferriman-Gallway Score (FGS) were studied. BMI, WC, fasting lipid profile, serum leptin, insulin, sex hormone binding globulin (SHBG), free-androgen index (FAI), fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were determined. Homeostasis model assessment (HOMA)-beta, HOMA-insulin resistance (IR) and VAI were calculated. Diameter and rate of hair growth at sideburns and chin; density of hair at sideburns were measured. Data were analyzed by SPSS-22.0. Results: There was no significant association between parameters of hirsutism and VAI. There was a significant association between VAI and OGTT, FAI, systolic and diastolic blood pressure: but not between VAI and other metabolic parameters. Conclusion: Visceral adipocyte dysfunction is closely linked to glucose intolerance and blood pressure in women with PCOS. However, hirsutism is unlikely to be due to adipocyte dysfunction.

Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database.

BACKGROUND: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), which affects 10% of women and represents a lifelong metabolic disorder, with increased risk of type 2 diabetes, hypertension, and cardiovascular events. Previous studies have suggested an increased risk of nonalcoholic fatty liver disease (NAFLD) in individuals with PCOS and implicated androgen excess as a potential driver. METHODS AND FINDINGS: We carried out a retrospective longitudinal cohort study utilizing a large primary care database in the United Kingdom, evaluating NAFLD rates in 63,120 women with PCOS and 121,064 age-, body mass index (BMI)-, and location-matched control women registered from January 2000 to May 2016. In 2 independent cohorts, we also determined the rate of NAFLD in women with a measurement of serum testosterone (n = 71,061) and sex hormone-binding globulin (SHBG; n = 49,625). We used multivariate Cox models to estimate the hazard ratio (HR) for NAFLD and found that women with PCOS had an increased rate of NAFLD (HR = 2.23, 95% CI 1.86-2.66, p < 0.001), also after adjusting for BMI or dysglycemia. Serum testosterone >3.0 nmol/L was associated with an increase in NAFLD (HR = 2.30, 95% CI 1.16-4.53, p = 0.017 for 3-3.49 nmol/L and HR = 2.40, 95% CI 1.24-4.66, p = 0.009 for >3.5 nmol/L). Mirroring this finding, SHBG <30 nmol/L was associated with increased NAFLD hazard (HR = 4.75, 95% CI 2.44-9.25, p < 0.001 for 20-29.99 nmol/L and HR = 4.98, 95% CI 2.45-10.11, p < 0.001 for <20 nmol/L). Limitations of this study include its retrospective nature, absence of detailed information on criteria used to diagnosis PCOS and NAFLD, and absence of data on laboratory assays used to measure serum androgens. CONCLUSIONS: We found that women with PCOS have an increased rate of NAFLD. In addition to increased BMI and dysglycemia, androgen excess contributes to the development of NAFLD in women with PCOS. In women with PCOS-related androgen excess, systematic NAFLD screening should be considered.

Obstetric outcomes and effects on babies born to women treated for epilepsy during pregnancy in a resource limited setting: a comparative cohort study.

BACKGROUND: Management of epilepsy during pregnancy in a resource-limited setting (RLS) is challenging. This study aimed to assess obstetric outcomes and effects on babies of women with epilepsy (WWE) exposed to Anti-epileptic drugs (AEDs) compared to non-exposed controls in a RLS. METHODS: Pregnant WWE were recruited from antenatal and neurology clinics of a tertiary care hospitals in Sri Lanka. Patients were reviewed in each trimester and post-partum. Medication adherence, adverse effects, seizure control and carbamazepine blood levels were monitored. Post-partum, measurements for anthropometric and dysmorphic features of the babies and congenital abnormalities were recorded. Age and sex matched babies not exposed to AED recruited as controls were also examined. RESULTS: Ninety-six pregnant WWE were recruited (mean period of gestation 22.9 weeks). Mean age was 28 years and 48(50%) were primigravidae. Fifty percent (48) were on monotherapy, while 23.8, 15.9 and 4.1% were on two, three and four AEDs respectively. AEDs in first trimester (TM1) were carbamazepine (71%), valproate (25.8%) clobazam (29.5%), lamotrigine (7%) topiramate (5%) and others (3.4%). Sodium valproate use reduced significantly from T1 to T2(p < 0.05). Sub-therapeutic carbamazepine levels correlated positively (r = 0.547) with poor medication adherence (p = 0.009) and negatively (r = 0.306) with adverse effects (p = 0.002). Seventy-six WWE completed follow-up reporting w 75 (98.6%) live births and one T1 miscarriage (1.3%). Three (4.3%) were preterm. Majority (73.33%) were normal vaginal deliveries. Cesarean sections were not increased in WWE. Fifty-nine (61.45%) babies were examined. For those examined during infancy, 53 age and sex matched controls were recruited and examined.. Congenital abnormalities occurred in 5 (9.43%) babies of WWE [atrio-ventricular septal defect (2), renal hypoplasia (1), cryptorchidism (1), microcephaly (1)] compared to 2 (3.77%) in controls (2 microcephaly; p = 0.24). Fetal exposure to AEDs increased a risk of low birth weight (RR 2.8; p = 0.049). Anthropometric parameters of AED exposed babies were lower at birth but not statistically significant between the two groups (weight p = 0.263, length p = 0.363, occipito-frontal circumference (OFC) p = 0.307). However, weight (p = 0.009), length (p = 0.016) and OFC (p = 0.002) were significantly lower compared to controls at an average of 3.52 months. CONCLUSION: Most pregnancies are unplanned in the RLS studied, and AEDs were altered during pregnancy. Congenital anomalies occurred at rates comparable to previous reports. Fetal exposure to AED had growth retardation in infancy compared to non-exposed babies.

Quality of life and its associated factors among home-dwelling older people residing in the District of Colombo, Sri Lanka: a community-based cross-sectional study.

INTRODUCTION: This community-based cross-sectional study explored the factors affecting overall and domain-specific (physical health, psychological health, social relationships and environmental) quality of life (QOL) of home-dwelling older residents of the District of Colombo, Sri Lanka. METHODS: A representative sample (n=723) of older adults aged >65 years was obtained by the multistage cluster sampling technique. QOL was assessed using the validated Sinhala version of WHOQOL BREF Questionnaire. Data analysis was done using SPSS V.20. RESULTS: The mean±SD age was 72.23±6.3 years with the overall QOL score being (mean±SD) 56.73±12.57/100. The mean±SD QOL score of physical health, psychological health, social relationships and environmental domains were 55.81±15.80, 59.25±14.68, 46.36±20.08 and 64.61±11.96, respectively. The overall QOL in the adjusted model showed a significant positive association with the educational status, living conditions (with spouse, with spouse and children), participation in religious activities, being visited by friends or relatives and financial independence. The overall QOL was negatively associated with limitations in activities of daily living and instrumental activities of daily living, chronic arthritis and heart disease in the adjusted model. Living with the spouse was positively associated with the psychological domain of QOL. Osteoporosis and chronic arthritis affected the physical health domain, while cancer and disabling stroke affected the psychological domain of QOL negatively. All statistical significances were considered at p<0.05. CONCLUSION: The overall QOL of home-dwelling elders of the Colombo District is moderate, with the lowest score being in social relationships and the highest in the environmental domain. Educational status, engaging in religious activities and financial independence are key factors associated with a better QOL. Limitations in physical activity and chronic diseases are associated with a reduced QOL. Living with the spouse is a key factor associated with the psychological health domain.

Phenotype and metabolic profile of South Asian women with polycystic ovary syndrome (PCOS): results of a large database from a specialist Endocrine Clinic.

BACKGROUND: Compared with other populations, South Asians have a greater propensity to insulin resistance and the metabolic syndrome (MetS). This is the first study to determine the distribution of phenotypes of polycystic ovary syndrome (PCOS) and their relationship to the MetS among indigenous South Asians. METHOD: An evaluation of the phenotype and metabolic characteristics of PCOS was conducted by recruiting consecutive women diagnosed by Rotterdam consensus criteria from an Endocrine clinic in Colombo, Sri Lanka. Prevalence of MetS was determined, in relation to the phenotypic subgroup of PCOS and compared with ethnically matched, BMI- and age-adjusted controls (n =231). RESULTS: Acanthosis nigricans (AN) occurred in 64.6% of women with PCOS (n= 469). MetS occurred in 30.6% of the PCOS group compared with 6.34% of controls (P = 0.0001). Those with PCOS and MetS had significantly higher median BMI, blood pressure (BP), fasting plasma glucose, insulin and triglycerides and lower high-density lipoprotein and sex hormone-binding globulin (SHBG), but similar testosterone concentrations compared with those with PCOS alone. Prevalence of MetS was similar in the four PCOS phenotypes, although oligomenorrhoeic women were more obese compared with the normal cycling hyperandrogenic group. Multivariate logistic regression confirmed age ≥35 years, BMI ≥25 kg/m(2) and AN as significant predictors of MetS in PCOS. Case-control comparisons showed that the presence of PCOS results in higher odds of having the MetS, a high waist circumference, elevated diastolic BP, abnormal fasting lipids and high fasting insulin and plasma testosterone concentrations. CONCLUSIONS: Young indigenous South Asians with PCOS have greater odds of being centrally obese, with a third having the MetS that bears no relationship to the androgenic phenotype. Significant predictors for MetS within the PCOS cohort are advancing age, obesity determined by the Asian cut off (BMI >25 kg/m(2)) and AN, while family history of diabetes, hyperandrogenism and elevated SHBG have no predictive value.

Acute acalculous cholecystitis due to dengue hemorrhagic fever during pregnancy.

A 29-year-old pregnant woman presented with fever, right hypochondrial pain and fatigability at 29 weeks of gestation. Dengue hemorrhagic fever was diagnosed based on clinical, hematological and serological features. However, ultrasound scanning was suggestive of acute acalculous cholecystitis. The patient was managed symptomatically and made a good recovery 8 days following onset of fever. This is the first case of acute acalculous cholecystitis coinciding with dengue hemorrhagic fever reported during pregnancy from an endemic country in Asia. The possible viral and host factors for the development of such a severe form of disease and preventive measures are discussed.

Assessment of Information Needs of Patients with Breast Cancer: A Hospital-Based Study in Sri Lanka.

OBJECTIVE: This study assessed the information needs of breast cancer (BC) patients who presented themselves to the outpatient clinics or wards of the National Cancer Institute, Maharagama, Sri Lanka. METHODS: Information needs were measured using the validated questionnaire in the vernacular (Sri Lankan Information Needs Assessment Questionnaire - BC). RESULTS: All affected women indicated a strong need for information related to the disease, treatment, and psychosocial service while the need for information on procedures for diagnosis and physical care was not strong. Younger women (age ≤37) (P < 0.0001) and women with higher education (P < 0.0001) had significantly higher information needs. CONCLUSIONS: The results indicated that information needs to be addressed in educational packages require that younger women and those with higher education have specific needs.

Sex Difference in Risk Factors, GRACE Scores, and Management among Post-Acute Coronary Syndrome Patients in Sri Lanka.

OBJECTIVE: To assess sex-based differences in the prevalence of risk factor, their management, and differences in the prognosis among acute coronary syndrome (ACS) in Sri Lanka. METHODS: Patients diagnosed with ACS were recruited from hospitals throughout the island. The Joint European Societies guidelines were used to assess recommended targets for coronary heart disease risk factors, and the GRACE score was used to assess the post-ACS prognosis. Age-adjusted regression was performed to calculate odds ratios for men versus women in risk factor control. RESULTS: A total of 2116 patients, of whom 1242 (58.7%) were men, were included. Significant proportion of women were nonsmokers; OR = 0.11 (95% CI 0.09 to 0.13). The prevalence of hypertension (p < 0.001), diabetes (p < 0.001), and dyslipidemia (p=0.004) was higher in women. The LDL-C target was achieved in a significantly higher percentage of women (12.6%); OR = 0.33 (95% CI 0.10 to 1.05). When stratified by age, no significant differences were observed in achieving the risk factor targets or management strategies used except for fasting blood sugar (p < 0.05) where more men achieved control target in both age categories. Majority of the ACS patients had either high or intermediate risk for one-year mortality as per the GRACE score. In-hospital and 1-year mean mortality risk was significantly higher among men of less than 65 years of age (p < 0.05). CONCLUSIONS: Smoking is significantly lower among Sri Lankan women diagnosed with ACS. However, hypertension, diabetes, and dyslipidemia were more prevalent among them. There was no difference in primary and secondary preventive strategies and management in both sexes but could be further improved in both groups.

Effectiveness of Low-dose Ethinylestradiol/Cyproterone Acetate and Ethinylestradiol/Desogestrel with and without Metformin on Hirsutism in Polycystic Ovary Syndrome: A Randomized, Double-blind, Triple-dummy Study.

BACKGROUND: The effectiveness of different combined oral contraceptive pills and metformin in reducing hirsutism in patients with polycystic ovary syndrome (PCOS) remains unclear. OBJECTIVE: We sought to determine the effects of ethinylestradiol (35µg)/cyproterone acetate (2mg) (EE/CPA) and ethinylestradiol (20µg)/desogestrel (0.15mg) (EE/DES), alone or with metformin, on hirsutism in PCOS. METHODS: A randomized, double-blind, triple-dummy study was conducted on women with PCOS and hirsutism (N=107) who received one of four drug combinations (Arm A: EE/CPA; Arm B: EE/DES; Arm C: EE/CPA plus metformin; or Arm D: EE/DES plus metformin). Hirsutism was assessed at baseline, six months, and 12 months by using five outcomes variables. RESULTS: No outcomes variable showed a significant difference between the four arms at 12 months. There was a significant reduction in both hair density and modified Ferriman-Gallwey score (mFGS) in Arm A, mFGS in Arm B, hair density in Arm C, and diameter of sideburn hair in Arm D, respectively. Separately, there was a significant increase noted in the hair growth rate of chin and an improvement in patients' perceptions of hirsutism in all four study arms. CONCLUSION: EE/CPA and EE/DES were equally effective in improving hirsutism in PCOS, with no added benefit from low-dose metformin. Sri Lanka Clinical Trials Registry (http://www.slctr.lk) registration no. SLCTR/2015/007.

Evidence summaries and recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome: Lifestyle management.

Lifestyle is fundamental in chronic disease prevention and management, and it has been recommended as a first-line treatment in the Australian polycystic ovary syndrome (PCOS) guideline 2011. The first international evidence-based guideline on PCOS was developed in 2018, which expanded the scope and evidence in the Australian guideline. This paper summarizes the lifestyle recommendations and evidence summaries from the guideline. International multidisciplinary guideline development groups delivered the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 2018. The process followed the Appraisal of Guidelines for Research and Evaluation II and The Grading of Recommendations, Assessment, Development and Evaluation framework. Extensive communication and meetings addressed six prioritized clinical questions through five reviews. Evidence-based recommendations were formulated before consensus voting within the panel. Evidence shows the benefits of multicomponent lifestyle intervention, efficacy of exercise and weight gain prevention with no specific diet recommended. Lifestyle management is the first-line management in the intervention hierarchy in PCOS. Multicomponent lifestyle intervention including diet, exercise and behavioural strategies is central to PCOS management with a focus on weight and healthy lifestyle behaviours. The translation programme optimizes reach and dissemination for health professionals and consumers.

Association of Kiss1 and GPR54 Gene Polymorphisms with Polycystic Ovary Syndrome among Sri Lankan Women.

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women of reproductive age. Its aetiology, though yet unclear, is presumed to have an oligogenic basis interacting with environmental factors. Kisspeptins are peptide products of Kiss1 gene that control the hypothalamic pituitary (HPG) axis by acting via G protein-coupled receptor known as GPR54. There is paucity of data on the role of Kiss1 and GPR54 gene in PCOS. We aimed to identify the polymorphisms in Kiss1 and GPR54 genes and explore their association with serum kisspeptin levels among Sri Lankan women with well-characterized PCOS. Consecutive women with PCOS manifesting from adolescence (n=55) and adult controls (n=110) were recruited. Serum kisspeptin and testosterone levels were determined by ELISA method. Whole gene sequencing was performed to identify the polymorphisms in Kiss1 and GPR54 genes. Serum kisspeptin and testosterone concentrations were significantly higher in women with PCOS than controls: kisspeptin 4.873nmol/L versus 4.127nmol/L; testosterone 4.713nmol/L versus 3.415 nmol/L, p<0.05. Sequencing the GPR54 gene revealed 5 single nucleotide polymorphisms (SNPs), rs10407968, rs1250729403, rs350131, chr19:918686, and chr19:918735, with two novel SNPs (chr19:918686 and chr19:918735), while sequencing the Kiss1 gene revealed 2 SNPs, rs5780218 and rs4889. All identified SNPs showed no significant difference in frequency between patients and controls. GPR54 gene rs350131 polymorphism (G/T) was detected more frequently in our study population. The heterozygous allele (AG) of GPR54 gene novel polymorphism chr19:918686 showed a marginal association with serum kisspeptin levels (p=0.053). Genetic variations in GPR54 and Kiss1 genes are unlikely to be associated with PCOS among Sri Lankan women manifesting from adolescence. Meanwhile the heterozygous allele of chr19:918686 is probably associated with serum kisspeptin concentrations, which suggests a potential role in the aetiology of PCOS.

Increased risk of obstructive sleep apnoea in women with polycystic ovary syndrome: a population-based cohort study.

OBJECTIVE: Obesity is very common in patients with obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS). Longitudinal studies assessing OSA risk in PCOS and examining the role of obesity are lacking. Our objective was to assess the risk of OSA in women with vs without PCOS and to examine the role of obesity in the observed findings. DESIGN: Population-based retrospective cohort study utilizing The Health Improvement Network (THIN), UK. METHODS: 76 978 women with PCOS and 143 077 age-, BMI- and location-matched women without PCOS between January 2000 and May 2017 were identified. Hazard ratio (HR) for OSA among women with and without PCOS were calculated after controlling for confounding variables using multivariate Cox models. RESULTS: Median patient age was 30 (IQR: 25-35) years; median follow-up was 3.5 (IQR: 1.4-7.1) years. We found 298 OSA cases in PCOS women vs 222 in controls, with incidence rates for OSA of 8.1 and 3.3 per 10 000 person years, respectively. Women with PCOS were at increased risk of developing OSA (adjusted HR = 2.26, 95% CI: 1.89-2.69, P < 0.001), with similar HRs for normal weight, overweight and obese PCOS women. CONCLUSIONS: Women with PCOS are at increased risk of developing OSA compared to control women irrespective of obesity. Considering the significant metabolic morbidity associated with OSA, clinicians should have a low threshold to test for OSA in women with PCOS. Whether OSA treatment has an impact on PCOS symptoms and outcomes needs to be examined.

Exercise Recommendations for Women with Polycystic Ovary Syndrome: Is the Evidence Enough?

In this opinion piece, we summarize, discuss implications of implementation, and critically evaluate our 2018 evidence-based guideline recommendations for exercise and physical activity in women with polycystic ovary syndrome (PCOS). We developed recommendations as part of a larger international guideline development project. The overall guideline scope and priorities were informed by extensive health professional and consumer engagement. The lifestyle guideline development group responsible for the exercise recommendations included experts in endocrinology, exercise physiology, gynecology, dietetics, and obstetrics, alongside consumers. Extensive online communications and two face-to-face meetings addressed five prioritized clinical questions related to lifestyle, including the role of exercise as therapy for women with PCOS. The guideline recommendations were formulated based on one narrative and two evidence-based reviews, before consensus voting within the guideline panel. The development process was in accordance with the Appraisal of Guidelines for Research and Evaluation (AGREE) II, and used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework to assess evidence quality, desirable and undesirable consequences, feasibility, acceptability, cost, implementation, and recommendation strength. Given the evidence for exercise as therapy in PCOS being of low quality, a consensus recommendation was made based on current exercise guidelines for the general population. Women with PCOS and clinicians are forced to adopt generic approaches when recommending exercise therapy that perpetuates clinical management with pharmacological solutions. The current status of evidence highlights the need for greater international co-operation between researchers and funding agencies to address key clinical knowledge gaps around exercise therapy in PCOS to generate evidence for appropriate, scalable, and sustainable best practice approaches.

Identification of selected genetic polymorphisms in polycystic ovary syndrome in Sri Lankan women using low cost genotyping techniques.

BACKGROUND: Polycystic ovary syndrome (PCOS), the commonest endocrine disorder affecting young women, appears to be a multigenic trait with contributing genes being unclear. Hence, analysis of polymorphisms in multiple candidate genes is required. Currently available genotyping methods are expensive, time-consuming with limited analytical sensitivity. AIM: (i) Develop and validate high resolution melting (HRM) assay and allele-specific real-time quantitative PCR (AS-qPCR) for genotyping selected SNPs associated with PCOS. (ii) Identify selected SNPs and their association with a Sri Lankan cohort of well-characterized PCOS. METHODS: DNA was extracted from women with well-characterized PCOS from adolescence (n = 55) and ethnically matched controls (n = 110). FTO (Fat mass and obesity associated gene; rs9939609), FSHB (Follicle stimulating hormone beta subunit; rs6169), FSHR (Follicle stimulating hormone receptor; rs6165/rs6166), and INSR (Insulin receptor; rs1799817) genes were genotyped using HRM assay. GnRH1 (Gonadotropin releasing hormone; rs6185), LHB (Luteinizing hormone beta subunit; rs1800447/rs34349826) and LHCGR (Luteinizing hormone/choriogonadotropin receptor; rs2293275) genes were genotyped using AS-qPCR method. Genotyping results were validated using Sanger sequencing. RESULTS: A significant association was observed within FTO gene polymorphism (rs9939609) and PCOS. Genotype frequency of FTO gene (rs9939609)-cases versus controls were TT-36.4% vs.65.4% (p<0.05), AT-23.6% vs.20.9%, AA-40% vs.13.6% (p<0.05). Genotype frequencies of the SNPs GnRH1 (rs6185), FSHB (rs6169), FSHR (rs6165 & rs6166), LHB (rs1800447 & rs34349826), LHCGR (rs2293275) and INSR (rs1799817) were not significantly different between cases and controls (p>0.05). Only the mutant alleles were observed for LHB rs1800447 and rs34349826 SNPs in both groups. The HRM and AS-qPCR assay results had 100% concordance with sequencing results. CONCLUSIONS: FTO gene rs9939609 polymorphism is significantly more prevalent among Sri Lankan PCOS subjects while the other selected SNPs of HPG axis genes and INSR gene showed no association. HRM and AS-qPCR assays provide a reliable, fast and user-friendly genotyping method facilitating wider implication in clinical practice.

Management, characteristics and outcomes of patients with acute coronary syndrome in Sri Lanka.

BACKGROUND: Ischaemic heart disease is the leading cause of in-hospital mortality in Sri Lanka. Acute Coronary Syndrome Sri Lanka Audit Project (ACSSLAP) is the first national clinical-audit project that evaluated patient characteristics, clinical outcomes and care provided by state-sector hospitals. METHODS: ACSSLAP prospectively evaluated acute care, in-hospital care and discharge plans provided by all state-sector hospitals managing patients with ACS. Data were collected from 30 consecutive patients from each hospital during 2-4 weeks window. Local and international recommendations were used as audit standards. RESULTS: Data from 87/98 (88.7%) hospitals recruited 2177 patients, with 2116 confirmed as having ACS. Mean age was 61.4±11.8 years (range 20-95) and 58.7% (n=1242) were males. There were 813 (38.4%) patients with unstable angina, 695 (32.8%) with non-ST-elevation myocardial infarction (NSTEMI) and 608 (28.7%) with ST-elevation myocardial infarction (STEMI). Both STEMI (69.9%) and NSTEMI (61.4%) were more in males (P<0.001). Aspirin, clopidogrel and statins were given to over 90% in acute setting and on discharge. In STEMI, 407 (66.9%) were reperfused; 384 (63.2%) were given fibrinolytics and only 23 (3.8%) underwent primary percutaneous coronary intervention (PCI). Only 42.3 % had thrombolysis in <30 min and 62.5% had PCI in <90 min. On discharge, beta-blockers and ACE inhibitors/angiotensin II receptor blockers were given to only 50.7% and 69.2%, respectively and only 17.6% had coronary interventions planned. CONCLUSIONS: In patients with ACS, aspirin, clopidogrel and statin use met audit standards in acute setting and on discharge. Vast majority of patients with STEMI underwent fibrinolyisis than PCI, due to limited resources. Primary PCI, planned coronary interventions and timely thrombolysis need improvement in Sri Lanka.