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Context First-degree relatives of women with polycystic ovary syndrome (PCOS) present hormonal and metabolic alterations compared to girls unrelated to PCOS. It is unknown whether glucose intolerance in the PCOS proband confers a more severe metabolic predisposition on their first-degree relatives. Objective To determine whether glucose tolerance status in women with PCOS is associated with worsened glucose metabolism and sex hormone levels in their peripubertal daughters or sisters. Design Cross-sectional study. Setting Seven academic centers in North America, South America, and Europe. Patients Sixty-four pairs of women with PCOS and their daughters or younger sisters aged between 8 and 14 years were recruited. Twenty-five mothers or older sisters with PCOS were glucose intolerant (GI) and 39 were normal glucose tolerant (NGT). Main Outcome Measures Beta-cell function estimated by the insulin secretion-sensitivity index-2 (ISSI-2) during an oral glucose tolerance test and by the disposition index during a frequently sampled IV glucose tolerance test. Free testosterone and 17-hydroxyprogesterone (17-OHP) levels. Results Being related to a GI PCOS proband was associated with a lower ISSI-2 (P-value = 0.032) after adjusting for ethnicity, body mass index z-score, and pubertal stage. They also had higher free testosterone (P-value = 0.011) and 17-OHP levels compared to girls with an NGT proband, the latter becoming significant after adjusting for confounders (P-value = 0.040). Conclusions Compared to first-degree female relatives of women with PCOS and NGT, first-degree relatives of women with PCOS and GI display lower beta-cell function and hyperandrogenemia, putting them at higher risk of GI and PCOS development.

There is a lack of cost-effective and readily available access to evidence-based information to manage healthy behaviours for pregnant individuals. Mobile health (mHealth) tools offer a cost-effective, interactive, personalized option that can be delivered anywhere at a time most convenient for the user. This study protocol was primarily developed to i) assess the feasibility of the SmartMoms Canada intervention in supporting participants to achieve gestational weight gain (GWG) guidelines. The secondary objectives are to: ii) assess user experience with the app, measured by adherence to the program via app software metrics and frequency of use; iii) determine the impact of SmartMoms Canada app usage on the adoption of healthful behaviours related to nutrition, physical activity and sleep habits, improvements in health-related quality of life, pregnancy-related complications, and symptoms of depression, and iv) investigate the potential extended effects of the app on postpartum health-related outcomes.This is a feasibility trial. Pregnant individuals aged 18-40 years with pre-gravid body mass index between 18.5 and 39.9 kg/mSmartMoms Canada is the first bilingual Canadian-centric app designed for pregnant people. This mHealth intervention, with its ability to supply frequent interactions, provides pregnancy- related health knowledge to users, potentially leading to an improvement in pregnancy-related outcomes and behaviours, and, ultimately a reduction in the present economic burden related to in-person interventions.ISRCTN, ISRCTN16254958. Registered 20 December 2019, http://www.isrctn.com/ ISRCTN16254958.

Introduction Lifestyle modifications should be the first-line treatment for improving reproductive function and preconception weight in women living with obesity who are seeking fertility treatments. Evidence is however scarce regarding the effectiveness of lifestyle programs in supporting these women. The study's objective was therefore to determine whether the Obesity-Fertility program leads to healthier lifestyle behaviours in women living with obesity and consulting at a fertility clinic. Methods Women with obesity and infertility were randomized to the control (CG=65) or intervention (IG=65) group. Based on the participant's medical record, randomization was stratified according to the polycystic ovarian syndrome status. The CG followed the usual fertility clinic approach while the IG participated in individual and group sessions with a registered dietician, a kinesiologist, and a psychologist. Before the intervention (baseline) and 6 months after (V6), frequency of food and beverages intakes, physical activity levels, sedentary time, daily sleep duration, alcohol consumption and smoking use were collected via a lifestyle behaviour questionnaire adapted from the 2009 Canadian Community Health Survey (Statistics Canada). Functional capacity was evaluated with a 6-minute walk test. Descriptive statistics, two-sample tests of means or proportions, generalized linear models and logistic regressions were performed. Results At baseline, women who had a research visit at 6±1 months (n=85) were 30±5 years old and had a BMI of 39.8±7.7 kg/m2. Most of them held no university degree (81.2%) and were primiparous (56.5%). Both groups (CG=43 and IG=42) had similar sociodemographic and anthropometric characteristics as well as lifestyle behaviours at baseline except for smokers’ proportion that was higher in CG (CG: 34.9% vs IG: 9.5%, p3 kcal/kg/day: +14.2% vs +2.3%, p=0. 03) and the time spent in sedentary behaviours (-6.7 vs -0.1 h/week, p Conclusion The Obesity-Fertility program significantly improved components of diet, physical activity levels and sedentary behaviours in women living with obesity and seeking fertility treatments. Such programs can therefore support these women to adopt healthier lifestyle behaviours and may improve their fertility as well as decrease risks of complications during pregnancy. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Background Primary care providers’ (PCPs) attitude toward obesity is often negative, and their confidence level for helping patients manage their weight is low. Continuing professional development (CPD) on the subject of obesity is often based on a single activity using a traditional passive approach such as lectures known to have little effect on performance or patient outcomes. The aim of this study was to evaluate the impact of an educational intervention for obesity management on PCPs’ attitude, self-efficacy, practice changes and patient-related outcomes. Methods Prospective interventional study with 12 months follow-up. A two-day clinical obesity preceptorship was offered where participants were actively involved in competence building using real-life situations, in addition to electronic networking tools, including a discussion forum and interactive monthly webinars. Thirty-five participants (12 nurses and 23 physicians) from seven Family medicine groups were enrolled. Questionnaires were used to evaluate the impact on primary care nurses’ and physicians’ attitudes and self-efficacy for obesity management. Practice changes and patient outcomes were evaluated using clinical vignettes, de-identified electronic patient records and qualitative analyses from group interviews. Results Physicians’ general attitude towards patients with obesity was improved (61 ± 22 mm vs 85 ± 17 mm, p P Conclusion A multimodal educational intervention for obesity management can improve PCPs’attitude and self-efficacy for obesity management and lifestyle counselling. This translates into beneficial practice changes and patient-related outcomes. Trial registration clinicaltrials.gov Identifier: NCT01385397. Retrospectively registered, 28 June 2011.

IntroductionDietary and/or physical activity interventions are often recommended for women with overweight or obesity as the first step prior to fertility treatment. However, randomised controlled trials (RCTs) so far have shown inconsistent results. Therefore, we propose this individual participant data meta-analysis (IPDMA) to evaluate the effectiveness and safety of dietary and/or physical activity interventions in women with infertility and overweight or obesity on reproductive, maternal and perinatal outcomes and to explore if there are subgroup(s) of women who benefit from each specific intervention or their combination (treatment–covariate interactions).Methods and analysisWe will include RCTs with dietary and/or physical activity interventions as core interventions prior to fertility treatment in women with infertility and overweight or obesity. The primary outcome will be live birth. We will search MEDLINE, Embase, Cochrane Central Register of Controlled Trials and trial registries to identify eligible studies. We will approach authors of eligible trials to contribute individual participant data (IPD). We will perform risk of bias assessments according to the Risk of Bias 2 tool and a random-effects IPDMA. We will then explore treatment–covariate interactions for important participant-level characteristics.Ethics and disseminationFormal ethical approval for the project (Venus-IPD) was exempted by the medical ethics committee of the University Medical Center Groningen (METc code: 2021/563, date: 17 November 2021). Data transfer agreement will be obtained from each participating institute/hospital. Outcomes will be disseminated internationally through the collaborative group, conference presentations and peer-reviewed publication.PROSPERO registration numberCRD42021266201.

Background: Preconception lifestyle interventions appear promising to reduce pregnancy complications, prevent adult cardiometabolic diseases, and prevent childhood obesity. These interventions have almost exclusively been studied in populations of obese infertile women. The development of preconception lifestyle interventions targeting a broader population of overweight and obese women without a history infertility and their partners is needed.Methods: This study is a multicenter open label parallel group randomized controlled trial. Sixty-eight non-infertile women with overweight or obesity in the preconception period and their partners will be recruited from the Sherbrooke and Quebec City regions. The couples will be randomized in a 1:1 ratio to receive the Healthy for my Baby intervention or standard care in the preconception period and pregnancy. Women and their partners will be invited to take part in this lifestyle intervention which includes motivational interviews and daily self-monitoring of lifestyle goals through a mobile phone application. The primary endpoint of this study is the diet quality of women during the preconception period, which will be evaluated using the C-HEI 2007 score at baseline, 2, 4- and 6-months following study enrolment. Women's dietary quality will also be evaluated through the measure of urinary biomarkers of habitual dietary intake at baseline and 2 months in preconception, and 24–26 weeks in pregnancy. Additional indicators of women's lifestyle as well as anthropometric measures will be documented in preconception and pregnancy. For the pregnancy period, the main secondary endpoint is the pattern of gestational weight gain. Pregnancy and neonatal complications will also be evaluated. For partners, diet quality, other lifestyle habits, and anthropometric measures will be documented in the preconception and pregnancy periods.Discussion: This study will evaluate the effectiveness of a low-cost intervention designed to improve diet and other lifestyle characteristics of women in the preconception period who are overweight or obese. If the Healthy for my Baby intervention is efficacious regarding dietary measures, larger trials will be needed to evaluate the impact of this intervention on the rates of pregnancy complications, childhood obesity, and adult cardiometabolic disease.Clinical Trial Registration:clinicaltrials.gov (NCT04242069).

Placental lipids transfer is essential for optimal fetal development, and alterations of these mechanisms could lead to a higher risk of adverse birth outcomes. Low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), and scavenger receptor class B type 1 (SCARB1) genes are encoding lipoprotein receptors expressed in the placenta where they participate in cholesterol exchange from maternal to fetal circulation. The aim of this study was thus to investigate the association between maternal lipid changes occurring in pregnancy, placental DNA methylation (DNAm) variations at LDLR, LRP1, and SCARB1 gene loci, and newborn’s anthropometric profile at birth. Sixty-nine normoglycemic women were followed from the first trimester of pregnancy until delivery. Placental DNAm was quantified at 43 Cytosine-phosphate-Guanines (CpGs) at LDLR, LRP1, and SCARB1 gene loci using pyrosequencing: 4 CpGs were retained for further analysis. Maternal clinical data were collected at each trimester of pregnancy. Newborns’ data were collected from medical records. Statistical models included minimally newborn sex and gestational and maternal age. Maternal total cholesterol changes during pregnancy (ΔT3-T1) were correlated with DNAm variations at LDLR (r = −0.32, p = 0.01) and LRP1 (r = 0.34, p = 0.007). DNAm at these loci was also correlated with newborns’ cord blood triglyceride and leptin levels. Mediation analysis supports a causal relationship between maternal cholesterol changes, DNAm levels at LRP1 locus, and cord blood leptin concentration (pmediation = 0.02). These results suggest that LRP1 DNAm link maternal blood cholesterol changes in pregnancy and offspring adiposity at birth, which provide support for a better follow-up of blood lipids in pregnancy.

The signaling mechanisms of the angiotensin II type 2 receptor (AT2R), a heptahelical receptor, have not yet been clearly and completely defined. In the present contribution, we set out to identify the molecular determinants involved in AT2R activation. Although AT2R has not been shown to engage Gq/11, G12, Gi2, and β-arrestin (βarr) pathways as does the AT1R upon angiotensin II (AngII) stimulation, the atypical positioning of helix VIII in the recently published AT2R structure may play a role in the receptor's capacity to couple to downstream effectors. In the AT2R structure, helix VIII points inwards and towards intracellular loop 3 (ICL3) to form tertiary interactions with transmembrane domain 6 (TM6), possibly impeding access to signaling effectors. On the other hand, in most class A GPCRs, helix VIII is found to be engaged in tertiary interactions with ICL1 and away from the effector binding site. Upon closer examination of the AT2R structure, we found that the residues contained within intracellular loop 1 (ICL1) may be involved in driving this unusual conformation of helix VIII. To explore this hypothesis, we designed a series of AT1R/AT2R receptor chimeras to validate the roles of ICL1 and helix VIII in AT2R signaling. Substituting the AT1R ICL1 into AT2R led to a mutant receptor that coupled to Gi2. The substitution of the helix VIII and C-terminal domains of AT2R into the AT1R backbone led to a mutant receptor that retained AT1R-like signaling properties. These results suggest that the C-terminal portion of AT2R is compatible with canonical GPCR signaling and that ICL1 of AT2R is involved in repositioning helix VIII, which impedes engagement of classical GPCR effectors such as G proteins or βarrs.

Objectives To assess: 1—the spousal concordance of lifestyle and anthropometric characteristics between partners of infertile couples in which the woman is obese; and 2—in men, the influence of these characteristics on their conventional seminal parameters. Design Cross-sectional study. Setting Fertility clinic of the Centre hospitalier universitaire de Sherbrooke, Canada, between January 2012 and February 2015. Patients 97 infertile heterosexual couples in which women were obese and seeking fertility treatments. Intervention Not applicable. Main outcome measures Weight and percentage of fat mass were evaluated using a scale with foot-to-foot bio-impedance. Abdominal obesity was estimated with waist circumference and lifestyle habits, by a self-reported questionnaire. Seminal parameters were analysed and collected according to the WHO guidelines (Kruger’s strict criteria for seminal morphology). Results There was a significant spousal concordance for the percentage of fat mass, leisure activities and overall nutritional quality. Accordingly, male participants displayed anthropometric and lifestyle characteristics at higher risk than Canadian men of similar age. Moreover, BMI, daily consumption of fruits & vegetables and sleeping hours in men were independently associated to the total motile sperm count. Conclusion This is the first study to report concordance for anthropometric and lifestyle characteristics between partners of infertile couples in which the woman is obese. These characteristics in men were more adverse than in the general population and were associated with reduced sperm quality. Altogether, our results suggest that male partners of infertile couples could benefit from participating in the lifestyle intervention that is already recommended for their spouse affected by obesity. Capsule Because partners of subfertile couples in which the woman is obese share adverse anthropometric and lifestyle characteristics, male partners should be implicated in lifestyle interventions already indicated for their spouse.

IntroductionChildhood overweight and obesity (OWO) is a primary global health challenge. Childhood OWO prevention is now a public health priority in China. The Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI), one of four trials being undertaken by the international HeLTI consortium, aims to evaluate the effectiveness of a multifaceted, community-family-mother-child intervention on childhood OWO and non-communicable diseases risk.Methods and analysisThis is a multicentre, cluster-randomised, controlled trial conducted in Shanghai, China. The unit of randomisation is the service area of Maternal Child Health Units (N=36). We will recruit 4500 women/partners/families in maternity and district level hospitals. Participants in the intervention group will receive a multifaceted, integrated package of health promotion interventions beginning in preconception or in the first trimester of pregnancy, continuing into infancy and early childhood. The intervention, which is centred on a modified motivational interviewing approach, will target early-life maternal and child risk factors for adiposity. Through the development of a biological specimen bank, we will study potential mechanisms underlying the effects of the intervention. The primary outcome for the trial is childhood OWO (body mass index for age ≥85th percentile) at 5 years of age, based on WHO sex-specific standards. The study has a power of 0.8 (α=0.05) to detect a 30% risk reduction in the proportion of children with OWO at 5 years of age, from 24.4% in the control group to 17% in the intervention group. Recruitment was launched on 30 August 2018 for the pilot study and 10 January 2019 for the formal study.Ethics and disseminationThe study has been approved by the Medical Research Ethics Committee of the International Peace Maternity and Child Health Hospital in Shanghai, China, and the Research Ethics Board of the Centre Intégré Universitaire de Santé et Services Sociaux de l’Estrie–CHUS in Sherbrooke, Canada. Data sharing policies are consistent with the governance policy of the HeLTI consortium and government legislation.Trial registration numberChiCTR1800017773.Protocol versionNovember 11, 2020 (Version #5).

IntroductionMild motor difficulties in children are underdiagnosed despite being highly prevalent, leaving such children often underserved and at higher risk for secondary consequences such as cardiovascular disease and anxiety. Evidence suggests that early patient-oriented interventions, coaching parents and providing children with early stimulation should be provided, even in the absence of a diagnosis. Such interventions may be effectively delivered via telerehabilitation.Methods and analysisA family-centred, pragmatic randomised controlled trial will be carried out to evaluate the real-world effectiveness of a Web-based Early intervention for Children using multimodAl REhabilitation (WECARE). Families of children with motor difficulties, 3–8 years of age, living in Quebec, Canada, and receiving no public rehabilitation services (n=118) will be asked to determine up to 12 performance goals, evaluated using the Canadian Occupational Performance Measure (COPM, the primary outcome). Families will be randomised to receive either usual care or the WECARE intervention. The WECARE intervention will be delivered for 1 year via a web-based platform. Families will have access to videoconferences with an assigned rehabilitation therapist using a collaborative coaching approach, a private chat function, a forum open to all intervention arm participants and online resources pertaining to child development. Participants will be asked to re-evaluate the child’s COPM performance goals every 3 months up to 1 year post allocation. The COPM results will be analysed using a mixed Poisson regression model. Secondary outcomes include measures of the child’s functional ability, parental knowledge and skills and health-related quality of life, as well as qualitative outcomes pertaining to parental satisfaction and service delivery trajectories. Investigators and quantitative data analysts will be blinded to group allocation.Ethics and disseminationThe CIUSSS de l’Estrie—CHUS ethics committee approved this trial (2020-3429). Study results will be communicated via peer-reviewed journal publications, conference presentations and stakeholder-specific knowledge transfer activities.Trial registration numberNCT04254302.

Background : Obesity in women of childbearing age is associated with infertility and increases significantly the risks of many pregnancy and neonatal complications. Adopting a healthy lifestyle prior conception and maintaining it during pregnancy may reduce these complications. Our aim was therefore to determine whether a lifestyle program targeting women with obesity and infertility and maintained during pregnancy improves gestational and neonatal outcomes. Methods : We report on 46 women who became pregnant and had available outcome data during pregnancy and at birth, among 127 women with infertility and obesity (body mass index, BMI ≥30 kg/m²), or overweight with PCOS (BMI ≥27 kg/m²), who were enrolled in a lifestyle randomized-controlled trial. Participants were randomized to the control group (CG, n=20), who received standard of care, or the lifestyle group (LSG, n=26), who followed a lifestyle program alone for 6 months, and then in combination with usual fertility care for 18 months or until the end of pregnancy. Pregnancy and neonatal outcomes were retrospectively retrieved from mothers’ and newborns’ medical records. Results : At enrollment, both groups were similar for age (29.3 vs 31.0 years), BMI (38.7 vs 38.4 kg/m2) and waist circumference (113.7 vs 112.7 cm). Preconception weight loss was significantly higher in the LSG compared to the CG (4.86 kg vs 1.21 kg, p=0.013), but gestational weight gains were similar (+10.83 vs +10.52 kg, p=0.987). During pregnancy, groups did not differ for the rates of preeclampsia, gestational diabetes or other clinical outcomes, but significantly less women in the LSG required insulin for treatment of their gestational diabetes (12.5% vs 42.1%, p=0.027) as well as urgent cesarean section due to failure of vaginal delivery (0.0% vs 21.1%, p=0.021). Regarding neonatal outcomes, there was no significant difference between groups for gestational age, weight at birth and head circumference, as well as rates of prematurity, LGA, SGA, birth defects or other clinical outcomes, but babies from the LSG displayed significantly lower tricipital skinfolds (4.73 mm vs 5.72 mm, p=0.031) and trends for lower sum of four skinfolds (16.61 mm vs 19.06 mm, p=0.056) and increased length at birth (50.82 cm vs 49.63 cm, p=0,053). Conclusion : In women with obesity and infertility, our lifestyle program initiated prior to fertility treatments and maintained throughout pregnancy improved their preconception weight and lifestyle, but not their gestational weight gain. Such intervention was nonetheless effective to reduce significantly some clinically relevant pregnancy and neonatal complications. If these results are replicated in a larger sample, it would strongly suggest that women with obesity should be supported to adopt a healthy lifestyle prior conception in order to increase their likelihood of giving birth to a healthy baby.

Polycystic ovary syndrome (PCOS) is a common and significant condition associated with hyperandrogenism, infertility, low quality of life, and metabolic comorbidities. One possible explanation of PCOS development is cellular dysfunction induced by nonesterified fatty acids (NEFAs), that is, lipotoxicity, which could explain both the hyperandrogenemia and insulin resistance that characterize women with PCOS. The literature suggests that androgen biosynthesis may be induced by overexposure of androgen-secreting tissues to NEFA and/or defective NEFA metabolism, leading to lipotoxic effects. Indeed, lipotoxicity could trigger androgenic hyperresponsiveness to insulin, LH, and ACTH. In most PCOS women, lipotoxicity also causes insulin resistance, inducing compensatory hyperinsulinemia, and may thus further increase hyperandrogenemia. Many approaches aimed at insulin sensitization also reduce lipotoxicity and have been shown to treat PCOS hyperandrogenemia. Furthermore, our group and others found that angiotensin II type 2 receptor (AT2R) activation is able to improve lipotoxicity. We provided evidence, using C21/M24, that AT2R activation improves adipocytes’ size and insulin sensitivity in an insulin-resistant rat model, as well as androgen levels in a PCOS obese rat model. Taken together, these findings point toward the important role of lipotoxicity in PCOS development and of the RAS system as a new target for the treatment of PCOS.

Background We and others have observed that young girls predisposed to polycystic ovary syndrome (PCOS) display defective insulin sensitivity, beta-cell function and non-esterified fatty acids (NEFA) suppressibility during early pubertal years, compared to controls. Our objective is to assess whether these differences in glucose and NEFA metabolisms persist after 5 years in late/post-puberty. Methods We conducted a prospective cohort study between 2007 and 2015 with 4–6 years of follow-up in an academic institution research center. We compared 8 daughters and sisters of PCOS women (PCOSr) to 8 age-matched girls unrelated to PCOS (±1.5 years). Girls were assessed initially at 8–14 years old and re-assessed after a median follow-up of 5.4 years, at 13–21 years old. Our main measures were a frequently sampled intravenous glucose tolerance test (FSivGTT)-derived insulin sensitivity (IS) and beta-cell function (disposition index, DIFSivGTT); and indices of NEFA suppression during FSivGTT (logn-linear slope of NEFA and T50 of NEFA suppression). Results At follow-up, both PCOSr and controls had similar results: IS = 3.2 vs 3.4 (p = 0.88), DIFSivGTT = 1926 vs 1380 (p = 0.44), logn-linear slope = −0.032 vs −0.032 (p = 0.88) and T50NEFA = 18.1 vs 20.8 min (p = 0.57). IS, DIFSivGTT and NEFA suppressibility were stable in PCOSr after 5 years, but decreased significantly in controls (all p

Placental lipids transfer is essential for optimal fetal development, and alterations of these mechanisms could lead to a higher risk of adverse birth outcomes. Low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), and scavenger receptor class B type 1 (SCARB1) genes are encoding lipoprotein receptors expressed in the placenta where they participate in cholesterol exchange from maternal to fetal circulation. The aim of this study was thus to investigate the association between maternal lipid changes occurring in pregnancy, placental DNA methylation (DNAm) variations at LDLR, LRP1, and SCARB1 gene loci, and newborn's anthropometric profile at birth. Sixty-nine normoglycemic women were followed from the first trimester of pregnancy until delivery. Placental DNAm was quantified at 43 Cytosine-phosphate-Guanines (CpGs) at LDLR, LRP1, and SCARB1 gene loci using pyrosequencing: 4 CpGs were retained for further analysis. Maternal clinical data were collected at each trimester of pregnancy. Newborns' data were collected from medical records. Statistical models included minimally newborn sex and gestational and maternal age. Maternal total cholesterol changes during pregnancy (ΔT3-T1) were correlated with DNAm variations at LDLR (r = -0.32, p = 0.01) and LRP1 (r = 0.34, p = 0.007). DNAm at these loci was also correlated with newborns' cord blood triglyceride and leptin levels. Mediation analysis supports a causal relationship between maternal cholesterol changes, DNAm levels at LRP1 locus, and cord blood leptin concentration (pmediation = 0.02). These results suggest that LRP1 DNAm link maternal blood cholesterol changes in pregnancy and offspring adiposity at birth, which provide support for a better follow-up of blood lipids in pregnancy.

Background and Objectives: Current recommendation is to change insulin pump catheters every 3 days. The rational supporting this recommendation is weak, mostly historical or anecdotical, and based on habits. Our objective was to determine catheter length of wearing under day-to-day condition. Methods: Participants with type 1 diabetes (T1D) worn their usual catheter during 2 periods as long as glycemic control was acceptable and insertion site remained comfortable. Data are presented as means ± standard deviations. Hypoglycemia (≤ 3.5 mmol/L) and hyperglycemia (≥ 13.8 mmol/L) were recorded via self-monitoring of blood glucose or continuous glucose monitoring. Each experimental period was separated by a 1-week washout, consisting of the usual catheter management. Results: Participants (n=22, 12 males, age: 47.1±16.2 years, BMI: 26.6±4.1 kg/m2, duration of T1D: 27.5±14.3 years, pump therapy: 8.8±6.2 years, 14 using Medtronic, 8 using Animas, usual catheter wearing: 3.5±0.5 days, insulin: 51.7±15.5 units/day, A1c: 7.4±0.8%) completed 41/44 periods (348.7 experimental days; one subject quitted, 2 catheters accidentally ripped-out). Catheters were worn 8.18±2.93 days, the shortest and the longest periods were respectively 3.81 and 15.61 days. Reasons for removal were uncontrolled glycemia despite bolusing (73%), discomfort (15%), or both (12%). Number of hypoglycemia and hyperglycemia per day were 0.18±0.17 and 0.90±0.56, respectively. No severe hypoglycemia, nor hyperglycemia ≥ 20 mmol/L or ketosis were observed over the study. Conclusions: Catheters might be worn beyond 3 days, up to 8 days and possibly more, significantly reducing patients and financial burden. Longer-term data are required to ensure that longer catheter wearing is not associated with impact on glucose control or lipohypertrophy. Disclosure J. Ardilouze: None. F. Gobeil: None. J. Menard: None. D. Bovan: None. V. Messier: Other Relationship; Self; Eli Lilly and Company. M. Savard: None. J. Baillargeon: None. R. Rabasa-Lhoret: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Novo Nordisk A/S. Funding JDRF

Recommendation to insulin pump users is to change catheters every 3 days. Convergent data point to inflammation for catheter-related insertion site problems. Objective: to explore if adding a tiny amount of non-steroidal anti-inflammatory drug (NSAID) into insulin solution increases catheter wearing time compare to insulin alone. Methods: Double-blinded randomized study in insulin pump users with type 1 diabetes. Participants were instructed to keep catheters as long as glycemic control was acceptable and insertion site remained comfortable. Subjects performed 4 experiments: 2 testing lispro and 2 testing the mixed solution (lispro: 90 units/ml + ketorolac: 3 mg/ml), each experimental period separated by a 1-week washout. Safety parameters were measured at entry vs. end of study (including plasma ketorolac concentration). We defined responders as participants wearing catheter ≥ 1 day using lispro+ketorolac vs. lispro. Results: Fourteen subjects completed the study (males: 7, age: 43.5±18.0 years, diabetes duration: 29.6±13.9 years, pump therapy: 9.0±4.5 years, A1c: 7.1±0.6%). There was no catheter wearing time difference (lispro+ketorolac: 7.45±2.99 vs. lispro: 7.82±2.64 days). The daily doses of insulin and ketorolac were respectively 46.44±12.39 units and 1.55±0.41 mg. Ketorolac plasmatic concentration was at 19.7±17.6 ng/ml (1000 times lower than after clinically indicated doses). From entry vs. end of study, creatinine increased (70±17 vs. 81±19 µmol/L, p=0.018) and glomerular filtration rate declined (119±33 vs. 109±34 ml/min/1.73m2, p=0.028). Wearing time improved in responders (n=7, 50%): 6.04±1.38 vs. 7.97±1.68 days (p=0.018). Conclusions: While no difference was observed overall, a large sub-group of patients could be responders to the addition of some NSAID to insulin. Due to the small sample size, the true magnitude of kidney function deterioration is unknown and might not be clinically significant. Disclosure J. Ardilouze: None. F. Gobeil: None. J. Menard: None. D. Bovan: None. V. Messier: Other Relationship; Self; Eli Lilly and Company. M. Savard: None. J. Baillargeon: None. R. Rabasa-Lhoret: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Novo Nordisk A/S. Funding JDRF

Obesity reduces fertility and the effectiveness of fertility treatments in women, in addition to increasing pregnancy complications and programming of childhood obesity. Since studies have suggested that weight loss and lifestyle management could improve the fertility of women with obesity, obesity management with lifestyle modification is recommended for these women. Objectives: To evaluate the impacts of a lifestyle program in women with obesity and infertility on: 1) fertility outcomes, and 2) anthropometric and lifestyle measures. Methods: Women with obesity and infertility consulting at the fertility clinic of an academic hospital were randomized to the lifestyle program group (LPG) or control group (CG). Women in the CG began usual fertility care directly. Those in the LPG received the lifestyle intervention alone, without fertility treatments, for the first 6 months, and then in association with fertility treatments, if not pregnant. The lifestyle intervention combined individual and group sessions with a nutritionist and a kinesiologist in order to support progressive and sustainable lifestyle modifications. Per-protocol analyses including women who completed at least 6 months of the trial, or became pregnant, are presented. The maximal duration of follow-up, and intervention in the LPG, was 18 months or the end of pregnancy. Proportions were compared using chi-squared tests and means, using Student’s t tests. Results: Among 130 randomized women, 108 completed at least 6 months of the study or became pregnant (83%, 51 LPG and 57 CG). In these women, the lifestyle program increased by 58% the pregnancy rate as compared to controls (60.8% vs 38.6%, p=0.021) and almost tripled the proportion of women who conceived spontaneously, without fertility treatments (33.3% vs 12.3%, p=0.009). The lifestyle program also increased the live birth rate by 39% (51.0% vs 36.8%), although this was not statistically significant (p=0.139). When comparing participants with measures at 6 months of follow-up or at first pregnancy visit if before 6 months (75%, 46 LPG; 51 CG), women in the LPG lost significantly more % of weight (-3.4 ± 4.5% vs -0.89 ± 3.7, p=0.003), waist circumference (-2.9 ± 4.3 cm vs -0.97 ± 4.4, p=0.036) and % of fat mass (-1.3 ± 2.1% vs -0.47 ± 1.3%, p=0.033) compared to the CG. They also improved significantly more their lifestyle habits than the CG (healthy eating index: +18.2 ± 13.7 points vs +5.3 ± 12.4, p

Purpose: To provide practice recommendations for the diagnosis and management of hypoparathyroidism in adults. Methods: Key questions pertaining to the diagnosis and management of hypoparathyroidism were addressed following a literature review. We searched PubMed, MEDLINE, EMBASE and Cochrane databases from January 2000 to March 2018 using keywords ‘hypoparathyroidism, diagnosis, treatment, calcium, PTH, calcidiol, calcitriol, hydrochlorothiazide and pregnancy’. Only English language papers involving humans were included. We excluded letters, reviews and editorials. The quality of evidence was evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These standards of care for hypoparathyroidism have been endorsed by the Canadian Society of Endocrinology and Metabolism. Results: Hypoparathyroidism is a rare disease characterized by hypocalcemia, hyperphosphatemia and a low or inappropriately normal serum parathyroid hormone level (PTH). The majority of cases are post-surgical (75%) with nonsurgical causes accounting for the remaining 25% of cases. A careful review is required to determine the etiology of the hypoparathyroidism in individuals with nonsurgical disease. Hypoparathyroidism is associated with significant morbidity and poor quality of life. Treatment requires close monitoring as well as patient education. Conventional therapy with calcium supplements and active vitamin D analogs is effective in improving serum calcium as well as in controlling the symptoms of hypocalcemia. PTH replacement is of value in lowering the doses of calcium and active vitamin D analogs required and may be of value in lowering long-term complications of hypoparathyroidism. This manuscript addresses acute and chronic management of hypoparathyroidism in adults. Main conclusions: Hypoparathyroidism requires careful evaluation and pharmacologic intervention in order to improve serum calcium and control the symptoms of hypocalcemia. Frequent laboratory monitoring of the biochemical profile and patient education is essential to achieving optimal control of serum calcium.

Although lifestyle modification is considered as the first-line treatment for women with obesity and infertility, these women generally do not have access to a program supporting them in adopting healthy habits that is integrated to fertility care. Implementing such a program requires to demonstrate its efficiency. The purpose of this study was to conduct a cost-effectiveness analysis (CEA) of an interdisciplinary lifestyle intervention (Fit-for-Fertility (FFF) program) for women with obesity and infertility, in comparison with the usual care protocol, i.e. fertility treatments. Methods: A CEA was conducted alongside a randomized controlled trial, recruiting women at the fertility clinic of the Centre hospitalier universitaire de Sherbrooke. Women were randomized to: i) the intervention group (IG): FFF program alone for 6 months (individual follow-ups every 6 weeks and 12 group sessions), and in combination with usual care for infertility after 6 months if not pregnant; or ii) control group (CG): usual care from the outset. Data were collected in both groups, during 18 months or until the end of the pregnancy for those who became pregnant. Costs related to the management of infertility, obesity, pregnancy and childbirth, and the FFF program were considered and collected by self-reported questionnaires, review of medical records and administrative databases. Live birth (LB) rate was used to assess effectiveness. The CEA’s parameter of interest was the incremental cost-effectiveness ratio (ICER), calculated by non-parametric bootstrap with 5,000 iterations. All costs are in Canadian dollars, 2019. Results: A total of 130 women were randomized (65 CG, 65 IG). We present results for the 108 women (57 CG, 51 IG) who completed at least 6 months in the study. We observed an absolute difference of 14.2% (p=0.328) in LB rate between groups (IG: 51.0%; CG: 36.8%). Total mean costs per patient were significantly higher in the IG vs the CG for healthcare system’s ($5,660 ± $3,200 vs $3,631 ± $3,389; p=0.002) and society’s ($9,745 ± $5,899 vs $6,898 ± 7,021; p=0.026) perspectives. We observed an ICER of $12,633 per additional LB [$5,319-$19,947] from the healthcare system’s perspective, and $5,980 [$3,086-$8 874] from the patients’ perspective. Overall, the ICER for the society’s perspective, which includes both previous perspectives, was estimated at $24,393 per additional LB [$15,509-$33,276]. Conclusion: According to our results, a lifestyle intervention may be clinically more effective than the usual protocol of care for women with obesity and infertility, but generates higher costs as well, resulting in a positive ICER (of $12,600 per additional life birth for the healthcare system). Such an intervention could be considered efficient compared to the usual standard of care, but studies are needed to assess the willingness to pay of stakeholders for this type of intervention.

Polycystic ovary syndrome (PCOS) is a common condition affecting women of reproductive age. This disorder is characterized by hyperandrogenism and anovulation and is frequently associated with comorbidities such as infertility, metabolic syndrome, type 2 diabetes, and cardiovascular risk factors. Although the causes of PCOS are unknown, this review focuses on the most accepted theory involving insulin action but will also elaborate on a novel concept: the role of lipotoxicity in the development of androgen overproduction, in addition to its known role in insulin resistance. This review will also shed a spotlight on 2 drugs that target lipotoxicity and are, therefore, known or promising for the treatment of PCOS manifestations: peroxisome proliferator-activated receptor γ and angiotensin II type 2 receptor agonists. This paper, therefore, emphasizes the need to further explore the pathophysiology of PCOS and particularly the role of lipotoxicity. Indeed, this new mechanism deserves attention to develop therapeutic approaches that will directly target the root of this condition and not only bandage its associated consequences.

Objectives To compare: 1) 75 g oral glucose tolerance test (OGTT) and self-monitoring of blood glucose (SMBG) in identifying gestational diabetes mellitus (GDM) and other hyperglycemic statuses in pregnant women; 2) pregnancy outcomes according to glycemic status; and 3) participants’ opinions regarding both methods. Methods A prospective study in women with a 50 g glucose load test ≥7.2 mmol/L at 24 to 28 weeks’ gestation and singleton pregnancy. Women underwent OGTT (blinded) at day 1, followed by 7 days of SMBG (4 daily measurements: fasting and 2 h postprandially) without modifying diet or lifestyle. GDM (OGTT+) was diagnosed using the criteria of the International Association of the Diabetes and Pregnancy Study Groups, while pregnancy hyperglycemia (SMBG+) was defined as ≥4/7 glucose values ≥5.3 after fasting or ≥6.7 mmol/L 2 h postprandially for any meal of the day. Equivalent management was provided to women with GDM and/or pregnancy-related hyperglycemia. Results We divided 103 participants (age: 29.5±5.0 years; prepregnancy body mass index: 25.3±5.4 kg/m2) into 4 groups according to test results: OGTT+/SMBG+ (n=12, 11.7%); OGTT+/SMBG– (n=14, 13.6%); OGTT–/SMBG+ (n=9, 8.7%); and OGTT–/SMBG– (n=68, 66.0%). Clinical characteristics and maternal outcomes were statistically similar between groups. Neonatal complication rates were greater in groups with hyperglycemia than in the OGTT–/SMBG– group, notably neonatal hypoglycemia (9/12, 7/14, 5/9 vs. 6/68; p Conclusions More than half of the women with OGTT+ were normoglycemic in daily life. Conversely, 11.7% of women with OGTT– had pregnancy hyperglycemia. OGTT+ and/or SMBG+ were equally associated with greater neonatal complications. This study suggests that alongside OGTT, SMBG could improve the care of pregnant women.

KEY POINTS Infertility, defined as a failure to achieve a pregnancy after at least 12 months of regular and unprotected sexual intercourse, affects 15% of all couples in Canada.[1][1] Costs associated with assisted reproductive technologies are growing, such that equitable access to high-quality

Acetylcholine (Ach) has vasodilatory actions. However, data are conflicting about the role of Ach in regulating blood flow in subcutaneous adipose tissue (ATBF). This may be related to inaccurate ATBF recording or to the responder/nonresponder (R/NR) phenomenon. We showed previously that healthy individuals are R (ATBF increases postprandially by >50% of baseline BF) or NR (ATBF increases ≤50% postprandially). Our objective was to assess the role of the cholinergic system on ATBF in R and NR subjects. ATBF was manipulated by in situ microinfusion of vasoactive agents (VA) in AT and monitored by the133Xenon washout technique (both recognized methods) at the VA site and at the control site. We tested incrementally increasing doses of Ach (10−5, 10−3, and 10−1mol/l; n = 15) and Ach receptor antagonists (Ra) before and after oral administration of 75-g glucose using atropine (muscarinic Ra; 10−4mol/l, n = 13; 10−5mol/l, n = 22) and mecamylamine (nicotinic Ra; 10−3mol/l, n = 15; 10−4mol/l, n = 10). Compared with baseline [2.41 (1.36–2.83) ml·100 g−1·min−1], Ach increased ATBF dose dependently [3.32 (2.80–5.09), 6.46 (4.36–9.51), and 10.31 (7.98–11.52), P < 0.0001], with no difference between R and NR. Compared with control side, atropine (both concentrations) had no effect on fasting ATBF; only atropine 10−4mol/l decreased post-glucose ATBF [iAUC: 1.25 (0.32–2.91) vs. 1.98 (0.64–2.94); P = 0.04]. This effect was further apparent in R. Mecamylamine had no impact on fasting and postglucose ATBF in R and NR. Our results suggest that the cholinergic system is implicated in ATBF regulation, although it has no role in the blunting of ATBF response in NR.

Oral 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid was used to determine whether an increase in cardiac dietary fatty acid (DFA) metabolism in impaired glucose tolerance (IGT) is different in men and women. Myocardial DFA partitioning after 6 h was higher in IGT versus control subjects (P = 0.006) in both men (2.14 [95% CI 1.70–2.18] vs. 1.28 standard uptake value [SUV] units [0.80–1.76]) and women (1.95 [1.57–2.33] vs. 1.64 SUV units [1.32–1.96]) without difference between sexes. Myocardial DFA fractional uptake (Ki) between time 90 and 120 min postprandially was also higher in IGT versus control subjects (P < 0.001) in men (0.063 [0.032–0.095] vs. 0.016 min−1 [0.007–0.025]) and women (0.050 [0.024–0.077] vs. 0.030 min−1 [0.013–0.047]) without significant sex difference. Men had higher net myocardial DFA uptake between time 90 and 120 min driven by higher chylomicron-triglyceride (TG) levels. IGT-associated increased cardiac DFA partitioning was directly related to obesity in women, whereas it was associated with IGT per se in men. We conclude that early cardiac DFA uptake is higher in men driven by change in postprandial chylomicron-TG level but that increase in 6-h postprandial cardiac DFA partitioning nevertheless occurs with IGT both in men and women.

Background: Several studies have reported higher levels of Alanine aminotransferase (ALT) in women with polycystic ovary syndrome (PCOS) compared with control subjects. Plasma ALT levels are considered a marker of hepatic lipotoxicity because of their significant associations with different hepatic metabolic dysfunctions, such as hepatic steatosis and hepatic insulin resistance. Methods: Retrospective chart review aiming to assess, in PCOS women, the relationship between ALT levels and measures of lipotoxicity consequences that are available clinically, both during fasting and using the oral glucose tolerance test. Results: Women (n = 132) with PCOS, were in average 27.9 years of age, with a mean body mass index of 34.1 kg/m2 and 49% had a metabolic syndrome (MetS). ALT levels were significantly correlated with homeostatic model assessment for insulin resistance (r = 0.42, P

Myoinositol (MI) and d-chiroinositol (DCI) are 2 stereoisomers and insulin sensitizers. Their physiological ratio differs from tissue to tissue, and they are regulated by an insulin-dependent epimerase whose activity is drastically reduced in conditions of insulin resistance. Based on literature data and on the fact that MI phospholipids are follicle-stimulating hormone (FSH) second messengers, we speculated that patients with polycystic ovary syndrome (PCOS) having hyperinsulinemia, present an enhanced MI to DCI epimerization in the ovary, leading to MI deficiency that impairs FSH signaling, resulting in reduced oocyte quality. In the present study, 20 patients with PCOS and 20 healthy women were enrolled for measurement of MI and DCI levels in their follicular fluid. Follicular fluid samples were taken using a vaginal probe and both MI and DCI were quantified analytically. Results showed that the ratio of MI-DCI dropped from 100:1 in healthy participants to 0.2:1 in patients with PCOS who additionally displayed significantly higher levels of insulin resistance, hyperinsulinemia, and luteinizing hormone. This study is the first one to analyze the misbalance in the MI-DCI ratio in the ovary of patients with PCOS, supporting the concept that maintaining the physiological levels of the 2 stereoisomers is crucial, in restoring the ovarian functionality.

Using a novel positron emission tomography (PET) method with oral administration of 14( R, S)-[18F]-fluoro-6-thia-heptadecanoic acid (18FTHA), we recently demonstrated that subjects with impaired glucose tolerance (IGT) display an impairment in cardiac function associated with increased myocardial uptake of dietary fatty acids. Here, we determined whether modest weight loss induced by lifestyle changes might improve these cardiac metabolic and functional abnormalities. Nine participants with IGT, enrolled in a one-year lifestyle intervention trial, were invited to undergo determination of organ-specific postprandial dietary fatty acids partition using the oral 18FTHA method, and cardiac function and oxidative metabolic index using PET [11C]acetate kinetics with ECG-gated PET ventriculography before and after the intervention. The intervention resulted in significant weight loss and reduction of waist circumference, with reduced postprandial plasma glucose, insulin, and triglycerides excursion. We observed a significant increase in stroke volume, cardiac output, and left ventricular ejection fraction associated with reduced myocardial oxidative metabolic index and fractional dietary fatty acid uptake. Modest weight loss corrects the exaggerated myocardial channeling of dietary fatty acids and improves myocardial energy substrate metabolism and function in IGT subjects.

The objective of this systematic review was to appraise current knowledge on the impact of physical activity (PA) and physical fitness (PF) on the health of class II and III obese subjects and bariatric surgery (BS) patients. All original studies were searched using four databases (Medline®, Scopus®, CINAHL and Sportdiscus). Two independent investigators selected studies assessing the impact of PA or PF on specific health outcomes (anthropometric parameters, body composition, cardiometabolic risk factors, PF, wellness) in adults with a body mass index ≥35 kg m(-2) or in BS patients. Conclusions were drawn based on a rating system of evidence. From 3,170 papers identified, 40 papers met the inclusion criteria. The vast majority of studies were recently carried out with a predominance of women. Less than one-third of these studies were experimental and only three of them were of high quality. Each study reported at least one beneficial effect of PA or PF. However, a lack of high-quality studies and heterogeneity in designs prevented us from finding high levels of evidence. In conclusion, although results support the importance of PA and PF to improve the health of this population, higher-quality trials are required to strengthen evidence-based recommendations.

Aims: To determine whether placental IGF1R, IGFBP3, INSR and IGF1 DNA methylation and mRNA levels were dysregulated when exposed to maternal impaired glucose tolerance (IGT) and investigate whether the epigenetic profile is associated with feto-placental developmental markers. Patients & methods: The IGT diagnosis was made according to the WHO criteria (IGT: n = 34; normal glucose tolerance [NGT]: n = 106). DNA methylation and mRNA levels were quantified using bisulfite pyrosequencing and qRT-PCR, respectively. Results: IGF1R and IGFBP3 DNA methylation levels were lower in placentas exposed to IGT compared with NGT (-4.3%; p = 0.021 and -2.5%; p = 0.006 respectively) and correlated with 2-h post-oral glucose tolerance test (OGTT) glycemia (r = -0.23; p = 0.010 and r = -0.20; p = 0.028, respectively). IGF1R mRNA levels were associated with newborns’ growth markers (e.g., birth weight; r = 0.20; p = 0.032). Conclusion: These results support the growth-promoting role of the IGF system in placental/fetal development and suggest that the IGF1R and IGFBP3 DNA methylation profiles are dysregulated in IGT, potentially affecting the fetal metabolic programming.

Placental lipoprotein lipase (LPL) is crucial for placental lipid transfer. ImpairedLPLgene expression and activity were reported in pregnancies complicated by gestational diabetes mellitus (GDM) and intra-uterine growth restriction. We hypothesized that placentalLPLDNA methylation is altered by maternal metabolic status and could contribute to fetal programming. The objective of this study was thus to assess whether placentalLPLDNA methylation is associated with GDM and both maternal and newborn lipid profiles. Placenta biopsies were sampled at delivery from 126 women including 27 women with GDM diagnosed following a post 75 g-oral glucose tolerance test (OGTT) between weeks 24 and 28 of gestation. PlacentalLPLDNA methylation and expression levels were determined using bisulfite pyrosequencing and quantitative real-time PCR, respectively. DNA methylation levels withinLPLproximal promoter region (CpG1) and intron 1 CpG island (CpGs 2 and 3) were lower in placenta of women with GDM. DNA methylation levels atLPL-CpG1 and CpG3 were also negatively correlated with maternal glucose (2-h post OGTT;r=–0.22;P=0.02) and HDL-cholesterol levels (third trimester of pregnancy;r=–0.20;p=0.03), respectively. Moreover, we report correlation betweenLPL-CpG2 DNA methylation and cord blood lipid profile. DNA methylation levels within intron 1 CpG island explained up to 26% (r⩽–0.51;PLPLmRNA expression variance. Overall, we showed that maternal metabolic profile is associated with placentalLPLDNA methylation dysregulation. Our results suggest that site-specificLPLepipolymorphisms in the placenta are possibly functional and could potentially be involved in determining the future metabolic health of the newborn.