Mitochondrial Haplogroups and Weight Gain After Initiating ART in Patients With HIV.

We studied the association of mitochondrial DNA (mtDNA) haplogroups with weight and body mass index (BMI) gain at 96 weeks in 1019 treatment-naive persons with HIV (PWH) who initiated first-line antiretroviral therapy (ART) since 2014. The mean increase in weight and BMI over the study period was 2.90 kg and 0.98 kg/m2, respectively. We found a significant adjusted association between the major UK mtDNA haplogroup and lower weight and BMI increase at 96 weeks after ART initiation. Our findings reveal a potential role for mitochondrial genetics in the complex phenomenon of weight gain after initial ART in PWH.

Child-to-adult body size change and risk of type 2 diabetes and cardiovascular disease.

AIMS/HYPOTHESIS: Childhood overweight increases the risk of type 2 diabetes and cardiovascular disease in adulthood. However, the impact of childhood leanness on adult obesity and disease risk has been overlooked. We examined the independent and combined influences of child and adult body size on the risk of type 2 diabetes and cardiovascular disease. METHODS: Data from the UK Biobank on 364,695 individuals of European ancestry and free of type 2 diabetes and cardiovascular disease were divided into nine categories based on their self-reported body size at age 10 and measured BMI in adulthood. After a median follow-up of 12.8 years, 33,460 individuals had developed type 2 diabetes and/or cardiovascular disease. We used Cox regression models to assess the associations of body size categories with disease incidence. RESULTS: Individuals with low body size in childhood and high body size in adulthood had the highest risk of type 2 diabetes (HR 4.73; 95% CI 4.50, 4.99), compared to those with average body size in both childhood and adulthood. This was significantly higher than the risk in those with high body size in both childhood and adulthood (HR 4.05; 95% CI 3.84, 4.26). By contrast, cardiovascular disease risk was determined by adult body size, irrespective of childhood body size. CONCLUSIONS/INTERPRETATION: Low body size in childhood exacerbates the risk of type 2 diabetes associated with adult obesity but not the risk of cardiovascular disease. Thus, promoting healthy weight management from childhood to adulthood, among lean children, is crucial.

Activin receptor ALK4 promotes adipose tissue hyperplasia by suppressing differentiation of adipocyte precursors.

Adipocyte hyperplasia and hypertrophy are the two main processes contributing to adipose tissue expansion, yet the mechanisms that regulate and balance their involvement in obesity are incompletely understood. Activin B/GDF-3 receptor ALK7 is expressed in mature adipocytes and promotes adipocyte hypertrophy upon nutrient overload by suppressing adrenergic signaling and lipolysis. In contrast, the role of ALK4, the canonical pan-activin receptor, in adipose tissue is unknown. Here, we report that, unlike ALK7, ALK4 is preferentially expressed in adipocyte precursors, where it suppresses differentiation, allowing proliferation and adipose tissue expansion. ALK4 expression in adipose tissue increases upon nutrient overload and positively correlates with fat depot mass and body weight, suggesting a role in adipose tissue hyperplasia during obesity. Mechanistically, ALK4 signaling suppresses expression of CEBPα and PPARγ, two master regulators of adipocyte differentiation. Conversely, ALK4 deletion enhances CEBPα/PPARγ expression and induces premature adipocyte differentiation, which can be rescued by CEBPα knockdown. These results clarify the function of ALK4 in adipose tissue and highlight the contrasting roles of the two activin receptors in the regulation of adipocyte hyperplasia and hypertrophy during obesity.

Vgll2 as an integrative regulator of mitochondrial function and contractility specific to skeletal muscle.

During skeletal muscle adaptation to physiological or pathophysiological signals, contractile apparatus and mitochondrial function are coordinated to alter muscle fiber type. Although recent studies have identified various factors involved in modifying contractile proteins and mitochondrial function, the molecular mechanisms coordinating contractile and metabolic functions during muscle fiber transition are not fully understood. Using a gene-deficient mouse approach, our previous studies uncovered that vestigial-like family member 2 (Vgll2), a skeletal muscle-specific transcription cofactor activated by exercise, is essential for fast-to-slow adaptation of skeletal muscle. The current study provides evidence that Vgll2 plays a role in increasing muscle mitochondrial mass and oxidative capacity. Transgenic Vgll2 overexpression in mice altered muscle fiber composition toward the slow type and enhanced exercise endurance, which contradicted the outcomes observed with Vgll2 deficiency. Vgll2 expression was positively correlated with the expression of genes related to mitochondrial function in skeletal muscle, mitochondrial DNA content, and protein abundance of oxidative phosphorylation complexes. Additionally, Vgll2 overexpression significantly increased the maximal respiration of isolated muscle fibers and enhanced the suppressive effects of endurance training on weight gain. Notably, no additional alteration in expression of myosin heavy chain genes was observed after exercise, suggesting that Vgll2 plays a direct role in regulating mitochondrial function, independent of its effect on contractile components. The observed increase in exercise endurance and metabolic efficiency may be attributed to the acute upregulation of genes promoting fatty acid utilization as a direct consequence of Vgll2 activation facilitated by endurance exercise. Thus, the current study establishes that Vgll2 is an integrative regulator of mitochondrial function and contractility in skeletal muscle.

Weight Gain After Antiretroviral Therapy Initiation and Subsequent Risk of Metabolic and Cardiovascular Disease.

BACKGROUND: Weight gain following initiation of antiretroviral therapy (ART) is common. We assessed the impact of changes in weight in the year following ART initiation with subsequent cardiometabolic disease among AIDS Clinical Trials Group (ACTG) participants. METHODS: Linear regression models were fit to examine the association between change in weight/waist circumference (WC) in weeks 0-48 and change in metabolic parameters in weeks 0-48 and 48-96. Cox proportional hazard models were fit to examine the association between changes in weight/WC in weeks 0-48 and diabetes mellitus (DM), metabolic syndrome, or cardiometabolic and cardiovascular events after week 48. RESULTS: Participants (N = 2624) were primarily male (81%) and non-White (60%). Mean weight gain from 0-48 weeks was 3.6 kg (SD 7.3); 130 participants developed DM; 360 metabolic syndrome; 424 any cardiometabolic event; 28 any cardiovascular event, over 480 weeks of follow-up. In adjusted models, total cholesterol increased by 0.63 mg/dL (95% confidence interval [CI] [.38, .089]) and LDL by 0.39 mg/dL (0.19, 0.59) per 1 kg increase in weight from weeks 0 to48. Participants who experienced >10% weight gain (vs -5% to 5%) had an increased risk of DM (hazard ratio [HR] 2.01, 95% CI [1.30, 3.08]), metabolic syndrome (HR 2.24, 95% CI [1.55, 2.62]), and cardiometabolic outcomes (HR 1.54, 95% CI [1.22, 1.95]). Participants who lost more than 5% of their baseline weight had a lower risk of incident metabolic syndrome (HR 0.67, 95% CI [0.42, 1.07]). Trends for WC were similar. CONCLUSIONS: Weight and body composition changes in the first year following ART initiation are associated with contemporaneous changes in metabolic parameters and subsequent cardiometabolic disease.

"Short and Long-term Body Weight Change Following the Switch to or the Addition of Integrase Inhibitors in Persons with HIV Differs by Sex".

BACKGROUND: Sex-specific, long-term, body weight change in persons with HIV (PWH) following switch to regimens containing integrase strand-transfer inhibitors (INSTIs) is unknown. METHODS: We compared PWH enrolled in the MACS/WIHS Combined Cohort Study (2007-2020) who switched/added an INSTI to their antiretroviral therapy (ART) to those remaining on non-INSTI ART and to people without HIV (PWOH), by sex. Follow-up time was time since switch visit (or comparable visit in controls). Linear regression mixed effect models assessed the effects of sex, group (INSTI, non-INSTI, PWOH), and time upon weight and anthropometric measurements (waist, hip, thigh). RESULTS: Of 3464 participants included, women (411 INSTI, 709 Non-INSTI, 818 PWOH) compared to men (223 INSTI, 412 Non-INSTI, 891 PWOH) were younger (47.2 years vs 54.5), majority non-Hispanic Black (65 vs 23%), and had higher mean BMI (31.5 kg/m2 vs 26.9), respectively. Women switching to INSTIs experienced greater absolute and % weight gain compared to men at 5 years: +3.0 kg (95% CI 2.1-3.9) vs +1.8 kg (0.7-2.9) and +4.6% (3.5-5.7) vs +2.3% (1.0-3.6), respectively, [sex*time*study group interaction, p<0.01]. Compared to men, women switching to INSTIs experienced greater hip and thigh circumference gain at 5 years: +2.6 cm (95% CI 1.6-3.6) vs +1.2 cm (0.3-2.1) and +1.5 cm (0.7-2.2) vs -0.2 cm (-0.9, 0.5), respectively, but there were no significant sex differences in waist circumference or waist-hip ratio. CONCLUSIONS: Weight change among PWH over 5 years after switch to INSTI was 2-fold higher in women than men. The cardio-metabolic implications of this difference in weight gain remain unknown.

Integrase strand transfer inhibitor (INSTI) related changes in BMI and risk of diabetes: a prospective study from the RESPOND cohort consortium.

BACKGROUND: With integrase strand transfer inhibitor (INSTI) use associated with increased body mass index (BMI) and BMI increases associated with higher diabetes mellitus (DM) risk, this study explored the relationship between INSTI/non-INSTI regimens, BMI changes, and DM risk. METHODS: RESPOND participants were included if they had CD4, HIV RNA, and ≥ 2 BMI measurements during follow up. Those with prior DM were excluded. DM was defined as a random blood glucose ≥ 11·1 mmol/L, HbA1c ≥ 6·5%/48 mmol/mol, use of antidiabetic medication, or site reported clinical diagnosis. Poisson regression assessed the association between natural log (ln) of time-updated BMI, current INSTI/non-INSTI, and their interactions, on DM risk. RESULTS: Among 20,865 people with HIV included, most were male (74%) and White (73%). Baseline median age was 45 years (IQR 37-52), with a median BMI of 24 kg/m2 (IQR 22-26). There were 785 DM diagnoses with a crude rate of 0·73 (95%CI 0·68-0·78)/100 PYFU. Ln(BMI) was strongly associated with DM (adjusted incidence rate ratio (aIRR) 16·54 per log increase, 95%CI 11·33-24·13; p<0·001). Current INSTI use associated with increased DM risk (IRR 1·58, 95%CI 1·37-1·82; p<0·001) in univariate analyses, only partially attenuated when adjusted for variables including ln(BMI) (aIRR 1·48, 95%CI 1·29-1·71; p<0·001). There was no interaction between ln(BMI), INSTI and non-INSTI use, and DM (p=0·130). CONCLUSIONS: In RESPOND, compared with non-INSTIs, current use of INSTIs was associated with an increased DM risk, which partially attenuated when adjusted for BMI changes and other variables.

Antiretrovirals and Weight Change: Weighing the Evidence.

Body weight is influenced by an interplay of individual and environmental factors. In people with HIV (PWH), weight is also influenced by disease status with loss accompanying disease progression that is reversed with effective antiretroviral therapy (ART). Weight changes in comparative ART trials differ by regimen, with greater gains observed with the integrase strand transfer inhibitors (INSTIs) dolutegravir and bictegravir, particularly when co-administered with tenofovir alafenamide fumarate (TAF), compared to regimens that include agents such as tenofovir disoproxil fumarate (TDF) that attenuate weight gain. We review weight changes in major randomized trials of pre-exposure prophylaxis (PrEP) and initial and switch HIV therapy, highlighting the challenges to assessing the role of ART in weight change. This examination forms the basis for a model that questions assumptions regarding an association between INSTI and TAF and excessive weight gain and calls for more careful consideration of these data when making HIV treatment decisions.

How does weight gain since the age of 18 years affect breast cancer risk in later life? A meta-analysis.

Early life factors are important risk factors for breast cancer. The association between weight gain after age 18 and breast cancer risk is inconsistent across previous epidemiologic studies. To evaluate this association, we conducted a meta-analysis according to PRISMA guidelines and the established inclusion criteria. We performed a comprehensive literature search using Medline (Ovid), Embase, Scopus, Cochrane Library, and ClinicalTrials.gov to identify relevant studies published before June 3, 2022. Two reviewers independently reviewed the articles for final inclusion. Seventeen out of 4,725 unique studies met the selection criteria. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS), and all were of moderate to high quality with NOS scores ranging from 5 to 8. We included 17 studies (11 case-control, 6 cohort) in final analysis. In case-control studies, weight gain after age 18 was associated with an increased risk of breast cancer (odds ratio [OR] = 1.25; 95% CI = 1.07-1.48), when comparing the highest versus the lowest categories of weight gain. Menopausal status was a source of heterogeneity, with weight gain after age 18 associated with an increased risk of breast cancer in postmenopausal women (OR = 1.53; 95% CI = 1.40-1.68), but not in premenopausal women (OR = 1.01; 95% CI = 0.92-1.12). Additionally, a 5 kg increase in weight was positively associated with postmenopausal breast cancer risk (OR = 1.12; 95%CI = 1.05-1.21) in case-control studies. Findings from cohort studies were identical, with a positive association between weight gain after age 18 and breast cancer incidence in postmenopausal women (relative risk [RR] = 1.30; 95% CI = 1.09-1.36), but not in premenopausal women (RR = 1.06; 95% CI = 0.92-1.22). Weight gain after age 18 is a risk factor for postmenopausal breast cancer, highlighting the importance of weight control from early adulthood to reduce the incidence of postmenopausal breast cancer.

The Long-Term Associations of Perinatal Obesogenic Environment with Offspring Biological Aging.

Biological age (BA), reflecting aging-related health decline beyond chronological age, varies among individuals. While previous research explored associations of maternal pregnancy-related body size with offspring health outcomes, its implications for BA in young adults remain unclear. Utilizing longitudinal data of 1,148 mother-offspring pairs from the Jerusalem Perinatal Study, we analyzed associations of maternal pre-pregnancy BMI and gestational weight gain (GWG) with offspring Klemera-Doubal method (KDM)-based BA at age 32, and potential familial life-course underlying mechanisms. Maternal pregnancy-related body size, adjusted for sociodemographic/lifestyle factors was associated with offspring BA (ßmaternal pre-pregnancy BMI=0.183,95%CI:0.098,0.267;ßGWG=0.093,95%CI:0.021,0.165). Association of GWG with BA was largely direct (90%,95%CI,44%,100%), while association with maternal pre-pregnancy BMI was partially mediated through adolescent BMI (36%,95%CI=18%,75%), with both associations eliminated after adjustment for offspring adult BMI. Associations persisted after adjusting for offspring polygenic risk score for BMI (ßmaternal pre-pregnancy BMI=0.128;95%CI=0.023,0.234; ßGWG=0.102;95%CI=0.006,0.198), and somewhat altered after adjustment for maternal cardiometabolic conditions (ßmaternal pre-pregnancy BMI=0.144,95%CI=0.059, 0.230). Impact on GWG associations was negligible. Thus, perinatal obesogenic environment contributes to offspring BA beyond sociodemographic factors and maternal cardiometabolic history, yet intergenerational transmission of obesity seems to underlie these associations. Nonetheless, the period between adolescence and young adulthood could be targeted for weight-reducing interventions, ultimately promoting healthy aging.

Impact of preconception and antenatal supplementation with myo-inositol, probiotics, and micronutrients on offspring BMI and weight gain over the first 2 years.

BACKGROUND: Nutritional intervention preconception and throughout pregnancy has been proposed as an approach to promoting healthy postnatal weight gain in the offspring but few randomised trials have examined this. METHODS: Measurements of weight and length were obtained at multiple time points from birth to 2 years among 576 offspring of women randomised to receive preconception and antenatally either a supplement containing myo-inositol, probiotics, and additional micronutrients (intervention) or a standard micronutrient supplement (control). We examined the influence on age- and sex-standardised BMI at 2 years (WHO standards, adjusting for study site, sex, maternal parity, smoking and pre-pregnancy BMI, and gestational age), together with the change in weight, length, BMI from birth, and weight gain trajectories using latent class growth analysis. RESULTS: At 2 years, there was a trend towards lower mean BMI among intervention offspring (adjusted mean difference [aMD] - 0.14 SD [95% CI 0.30, 0.02], p = 0.09), and fewer had a BMI > 95th percentile (i.e. > 1.65 SD, 9.2% vs 18.0%, adjusted risk ratio [aRR] 0.51 [95% CI 0.31, 0.82], p = 0.006). Longitudinal data revealed that intervention offspring had a 24% reduced risk of experiencing rapid weight gain > 0.67 SD in the first year of life (21.9% vs 31.1%, aRR 0.76 [95% CI 0.58, 1.00], p = 0.047). The risk was likewise decreased for sustained weight gain > 1.34 SD in the first 2 years of life (7.7% vs 17.1%, aRR 0.55 [95% CI 0.34, 0.88], p = 0.014). From five weight gain trajectories identified, there were more intervention offspring in the "normal" weight gain trajectory characterised by stable weight SDS around 0 SD from birth to 2 years (38.8% vs 30.1%, RR 1.29 [95% CI 1.03, 1.62], p = 0.029). CONCLUSIONS: Supplementation with myo-inositol, probiotics, and additional micronutrients preconception and in pregnancy reduced the incidence of rapid weight gain and obesity at 2 years among offspring. Previous reports suggest these effects will likely translate to health benefits, but longer-term follow-up is needed to evaluate this. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02509988 (Universal Trial Number U1111-1171-8056). Registered on 16 July 2015.

Rethinking causal assumptions about maternal BMI, gestational weight gain, and adverse pregnancy outcomes.

BACKGROUND: The aim of this study was to evaluate commonly assumed causal relationships between body mass index (BMI), gestational weight gain (GWG), and adverse pregnancy outcomes, which have formed the basis of guidelines and interventions aimed at limiting GWG in women with overweight or obesity. We explored relationships between maternal BMI, total GWG (as a continuous variable and as 'excessive' GWG), and pregnancy outcomes (including infant birthweight measures and caesarean birth). METHODS: Analysis of individual participant data (IPD) from the i-WIP (International Weight Management in Pregnancy) Collaboration, from randomised trials of diet and/or physical activity interventions during pregnancy reporting GWG and maternal and neonatal outcomes. Women randomised to the control arm of 20 eligible randomised trials (4370 of 8908 participants) from the i-WIP dataset of 36 randomised trials (total 12,240 women). The main research questions were to characterise the relationship between maternal BMI and (a) total GWG, (b) the risk of 'excessive' GWG (using the Institute of Medicine's guidelines), and (c) adverse pregnancy outcomes as mediated via GWG versus other pathways to determine the extent to which the observed effect of maternal BMI on pregnancy outcomes is mediated via GWG. We utilised generalised linear models and regression-based mediation analyses within an IPD meta-analysis framework. RESULTS: Mean GWG decreased linearly as maternal BMI increased; however, the risk of 'excessive' GWG increased markedly at BMI category thresholds (i.e. between the normal and overweight BMI category threshold and between the overweight and obese BMI category threshold). Increasing maternal BMI was associated with increased risk of all pregnancy outcomes assessed; however, there was no evidence that this effect was mediated via effects on GWG. CONCLUSIONS: There is evidence of a meaningful relationship between maternal BMI and GWG and between maternal BMI and adverse pregnancy outcomes. There is no evidence that the effect of maternal BMI on outcomes is via an effect on GWG. Our analyses also cast doubt on the existence of a relationship between 'excessive' GWG and adverse pregnancy outcomes. Our findings challenge the practice of actively managing GWG throughout pregnancy.

Assessment of weight gain in adult patients living with HIV receiving first-line dolutegravir-based or efavirenz-based ART regimens in routine care clinics in Tshwane district, South Africa: An observational study.

INTRODUCTION: Although dolutegravir (DTG) is deemed stable, safe, cost-effective, and clinically beneficial, it also carries the risk of side effects, including observed weight gain among patients on DTG-based antiretroviral therapy (ART) regimens. We compared weight changes among adults (≥18 years) initiating tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) or tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TEE) regimens and those switching from TEE to TLD (TEE-to-TLD switchers) in three large primary care facilities in South Africa METHODS: We conducted a retrospective longitudinal record review using patient medical records, extracting relevant demographic and clinical data from October 2018 to June 2021 from randomly selected adults who initiated TLD or TEE (initiators) and adult TEE-to-TLD switchers. We assessed weight, body mass index (BMI), and percentage weight changes for both groups and fitted linear regression and generalized linear models to determine factors associated with weight and BMI change and percentage weight change ≥10%, respectively, among treatment initiators. We fitted linear mixed-effect models among TEE-to-TLD switchers to consider repeated measures. RESULTS: Of 860 initiators, 450 (52.3%) initiated on TEE and 410 (47.7%) on TLD, with median follow-up of 1.4 years and 1.0 year, respectively. At initiation, 43.3% on TEE and 40.8% on TLD were overweight or obese. TLD initiators had an adjusted higher mean weight gain of 1.6 kg (p < 0.001) and mean BMI gain of 0.51 kg/m2 (p < 0.001) than TEE initiators. Independent risk factors for higher mean weight and BMI included age ≥50 years, male, on ART for >12 months, initial BMI of <18.5 kg/m2, and CD4 counts <200 cells/µL. Of 298 TEE-to-TLD switchers, 36.6% were overweight or obese at TEE initiation. Comparing before and after TLD switch, TEE-to-TLD switchers had an adjusted mean weight of 1.2 kg less while on TLD (p = 0.026). Being overweight and CD4 counts >350 cells/µL were independent risk factors for lower weight gain after TLD switch. CONCLUSIONS: We report more weight gain among TLD than among TEE initiators, although to a lesser extent than previously reported. TEE-to-TLD switchers experienced less weight gain after TLD switch; return to health before receiving TLD may be a contributory factor. The current findings are reassuring for those switching to a DTG-based regimen.

Effects of Early Enteral to Parenteral Protein Ratios on Brain Volume and Somatic Growth in Very Low Birth Weight Infants.

OBJECTIVE: To evaluate whether a higher proportion of enteral vs parenteral protein ratio (E:P ratio) in the first 28 days after birth is associated with increased brain volume and somatic growth in very low birth weight (VLBW; birth weight <1500 g) infants. STUDY DESIGN: This was a retrospective analysis of a subcohort of VLBW infants (n = 256, gestational age mean 28.07 [SD 2.17] weeks, birth weight 1038.80 [SD 262.95] grams) from the Cincinnati Infant Neurodevelopment Early Prediction Study, a regional prospective study of infants born at ≤32 weeks' gestation. Brain magnetic resonance imaging was obtained at term-equivalent age. Macronutrient intake and growth metrics for the first 28 days were collected retrospectively. The primary outcome was total brain tissue volume. The relationships between E:P ratio, total and regional brain tissue volumes, and somatic growth were analyzed by multivariable linear regression models; composite variables were used to adjust for potential confounders including pregnancy risk factors and initial severity of illness. RESULTS: Higher E:P ratio was associated with increased total brain tissue volume but was not associated with change in head circumference z score. In secondary analyses, higher E:P ratio was associated with increased weight velocity. There were no significant associations between E:P ratio and change in weight or length z scores or regional brain volumes. CONCLUSIONS: Higher E:P ratio in the first 28 days was positively associated with total brain volume and weight gain. Promoting the provision of enteral over parenteral protein may improve brain and somatic growth in VLBW infants.

Association of Growth During Infancy with Neurodevelopment and Obesity in Children Born Very Preterm: The Environmental Influences on Child Health Outcomes Cohort.

OBJECTIVE: To evaluate associations between change in weight z score after neonatal intensive care unit (NICU) discharge and neurodevelopmental outcomes and obesity at 12-48 months of age among individuals born very preterm. STUDY DESIGN: This secondary analysis used data from infants born very preterm participating in the Environmental influences on Child Health Outcomes cohort (n = 1400). Growth during infancy was calculated as change in weight z score between NICU discharge and follow-up at a mean of 27 months of age. Very low weight gain was defined as a change in weight z score <-1.67; very high weight gain was a change in weight z score >1.67. Neurodevelopmental outcomes included the Bayley Scales of Infant and Toddler Development, Child Behavior Checklist 1.5-5 years, and Modified Checklist for Autism in Toddlers. Multivariable linear regression was used to estimate associations between increase in weight z score and neurodevelopmental outcomes. RESULTS: Very low weight gain between NICU discharge and follow-up (experienced by 6.4% of participants) was associated with lower scores on cognitive (adjusted mean difference: -4.26; 95% CI: -8.55, -0.04) and language (adjusted mean difference: -4.80; 95% CI: -9.70, -0.11) assessments. Very high weight gain (experienced by 13.6% of participants) was associated with an increased obesity risk (adjusted relative risk: 6.20; 95% CI: 3.99, 9.66) but not with neurodevelopmental outcomes. CONCLUSIONS: Very high weight gain in the first 12-48 months after NICU discharge was associated with a higher risk of obesity at follow-up; very low weight gain was associated with lower scores on cognitive and language assessments.

JAK inhibitors in refractory juvenile rheumatic diseases: Efficacy, tolerance and type-I interferon profiling, a single center retrospective study.

OBJECTIVES: - Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment. METHODS: - We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology. RESULTS: - 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment. CONCLUSION: - JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.

Weight change and risk of incident type 2 diabetes: short, medium and long-term follow-up in tehran lipid and glucose study.

BACKGROUND: Despite the high burden of obesity and Type 2 diabetes (T2DM) in the Middle East/West Asia region, the effect of weight change on the development of T2DM is poorly addressed. Therefore, we aimed to assess the impact of 3-year body weight change on incident of T2DM over 3-, 6-, and 9-year periods among Iranian adults. METHODS: A total of 6930 participants (men = 2567) aged ≥ 20 years free of T2DM or cancer at baseline were included. Weight measurements were taken at baseline (2002-2005) and approximately 3 years later. Participants were categorized based on their weight change ratio into ≥ 5% loss, stable (± 5%), and ≥ 5% gain. Generalized estimating equations (GEE), adjusted with age, sex, education levels, baseline measurements of fasting plasma glucose, weight, waist circumference, triglycerides to high-density lipoprotein cholesterol ratio, family history of diabetes, current smoker, hypertension, and prevalent cardiovascular disease were applied to estimate the Odds ratios (ORs) and 95% confidence intervals (CIs) of weight change categories for incident T2DM, considering stable weight as a reference. RESULTS: During median follow-ups of 3-, 6-, and 9-year, 295, 505, and 748 cases of T2DM occurred, respectively. Weight gain of ≥ 5%, as compared to stable weight group (± 5%), was associated with increased T2DM risk, with ORs of 1.58 (95% CI 1.16-2.14), 1.76 (1.41-2.20), and 1.70 (1.40-2.05) for the 3-, 6-, and 9-year follow-ups, respectively, in multivariable analysis; corresponding values for weight loss ≥ 5% were 0.48 (0.29-0.80), 0.57 (0.40-0.81), and 0.51 (0.38-0.68), respectively. This association persisted even after adjusting for attained weight. Subgroup analysis showed consistent associations across age, gender, and body mass index categories. CONCLUSION: Weight gain and loss of ≥ 5% were associated with increased and decreased risks of incident T2DM, respectively, regardless of attained weight. This association was consistent over various follow-up durations among the Iranian population as recommended by guidelines.

Intra-patient analysis of individual weight gain or loss between IVF cycles: cycle now and transfer later.

STUDY QUESTION: What is the impact of clinically significant weight change on outcomes related to IVF cycle performance? SUMMARY ANSWER: While individual weight loss did not significantly impact ovarian response to stimulation or other cycle outcome parameters in our study, some positive associations were found for individual weight gain. WHAT IS KNOWN ALREADY: The role of weight-change in patients undergoing IVF has been largely studied by comparing weight loss in different cohorts of patients stratified by a static BMI. Specifically, obesity has been extensively studied in relation to its negative effects on assisted or unassisted conception outcomes and ovulatory function. Previous research has shown conflicting results, while BMI, which is commonly used as a marker of obesity, may not accurately reflect the underlying factors affecting fertility in obese patients. STUDY DESIGN, SIZE, DURATION: This study utilized a retrospective within-patient repeated measurement analysis design to assess the impact of weight change on IVF outcomes in cycles where all embryos were cryopreserved at the blastocyst stage for transfer at a later date. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at an academically affiliated fertility center. The data included 961 women who underwent at least two IVF cycles between December 2014 and June 2020, with documented short-term weight gain (n = 607) or weight loss (n = 354) within 1 year from their initial IVF cycle. Multivariable generalized estimating equations (GEE) and generalized linear mixed models (GLMM) were employed to assess associations between weight change and outcomes across cycles. MAIN RESULTS AND THE ROLE OF CHANCE: The multivariable models indicated that weight loss did not show any significant associations with the numbers of oocytes retrieved, or mature oocytes, the fertilization rate or the blastulation rate. However, weight gain demonstrated a minor positive association with the number of oocytes retrieved in both GEE models (coefficient: 0.01, 95% CI: 0.00-0.01) and GLMM models (0.01, 95% CI: 0.01-0.00). There was also a potential increase in the fertilization rate with weight gain, as indicated by a positive coefficient in both GEE models (coefficient: 0.01, 95% CI: 0.00-0.02) and GLMM models (coefficient: 0.01, 95% CI: 0.00-0.01). However, the association between weight gain and the embryo blastulation rate was not statistically significant in any model. LIMITATIONS, REASONS FOR CAUTION: This study focused on cycle performance parameters instead of reproductive outcomes, which restricted our ability to evaluate the impact of weight change on cumulative live birth rates. Additionally, the study did not account for variables such as stimulation protocols, potentially introducing confounding factors and limiting the generalizability of the results. WIDER IMPLICATIONS OF THE FINDINGS: Although obesity is associated with adverse obstetrical risks, there is less evidence of adverse reproductive outcomes in IVF cycles. We therefore recommend that an IVF cycle should not be delayed due to weight, so that the patient is not adversely affected by increasing age. The IVF cycle should aim to freeze all embryos, so that embryo transfer can then occur after weight loss, so as to limit the recognized obstetrical risks. STUDY FUNDING/COMPETING INTEREST(S): The study was not funded and there were no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Effects of L-Carnitine Supplementation on the Rate of Weight Gain and Biomarkers of Environmental Enteric Dysfunction in Children with Severe Acute Malnutrition: A Double-Blind Randomized Controlled Clinical Trial.

BACKGROUND: Severe acute malnutrition (SAM) is a major public health concern among low- and middle-income countries, where the majority of the children encountering this acute form of malnutrition suffer from environmental enteric dysfunction (EED). However, evidence regarding the effects of L-carnitine supplementation on the rate of weight gain and EED biomarkers in malnourished children is limited. OBJECTIVES: We aimed to investigate the role of L-carnitine supplementation on the rate of weight gain, duration of hospital stays, and EED biomarkers among children with SAM. METHODS: A prospective, double-blind, placebo-controlled, randomized clinical trial was conducted at the Nutritional Rehabilitation Unit (NRU) of Dhaka Hospital, International Centre for Diarrheal Disease Research, Bangladesh. Children with SAM aged 9-24 mo were randomly assigned to receive commercial L-carnitine syrup (100 mg/kg/d) or placebo for 15 d in addition to standard of care. A total of 98 children with Weight-for-Length-z-score (WLZ) < -3 Standard deviation were enrolled between October 2021 and March 2023. Analyses were conducted on an intention-to-treat basis. RESULTS: The primary outcome variable, "rate of weight gain," was comparable between L-carnitine and placebo groups (2.09 ± 2.23 compared with 2.07 ± 2.70; P = 0.973), which was consistent even after adjusting for potential covariates (age, sex, Weight-for-Age z-score, asset index, and WASH practices) through linear regression [ß: 0.37; 95% confidence interval (CI): -0.63,1.37; P = 0.465]. The average hospital stay was ∼4 d. The results of adjusted median regression showed that following intervention, there was no significant difference in the EED biomarkers among the treatment arms; Myeloperoxidase (ng/mL) [ß: -1342.29; 95% CI: -2817.35, 132.77; P = 0.074], Neopterin (nmol/L) [ß: -153.33; 95% CI: -556.58, 249.91; P = 0.452], alpha-1-antitrypsin (mg/mL) [ß: 0.05; 95% CI: -0.15, 0.25; P = 0.627]. Initial L-carnitine (µmol/L) levels (median, interquartile range) for L-carnitine compared with placebo were 54.84 (36.0, 112.9) and 59.74 (45.7, 96.0), whereas levels after intervention were 102.05 (60.9, 182.1) and 105.02 (73.1, 203.7). CONCLUSIONS: Although our study findings suggest that L-carnitine bears no additional effect on SAM, we recommend clinical trials with a longer duration of supplementation, possibly with other combinations of interventions, to investigate further into this topic of interest. This trial was registered at clinicaltrials.gov as NCT05083637.

Weight change in people with depression and the risk of dementia: a nationwide cohort study.

BACKGROUND: Depression is a risk factor for dementia and weight change can appear as a symptom of depression. However, the association between weight change after the diagnosis of depression and the risk of dementia is poorly established. This study aimed to investigate the association between weight change before and after a diagnosis of depression with the subsequent risk of dementia. METHODS: The National Health Insurance Sharing Service database was used. 1 308 730 patients aged ⩾40 years diagnosed with depression were identified to be eligible. Weight changes after their depression diagnosis were categorized and subsequent incidence of dementia was followed up. RESULTS: During an average follow-up period of 5.2 years (s.d., 2.0 years), 69 373 subjects were newly diagnosed with all-cause dementia (56 351 were Alzheimer's disease and 6877 were vascular dementia). Regarding all outcomes, compared to those with a minimal weight change (-5 to 5%), all groups with weight gain or loss showed increased risks of dementia after adjusting potential risk factors for dementia, in all analysis models with a dose-response relationship, showing a U-shaped association. CONCLUSIONS: Weight change as a symptom of depression could be a predictor for the future development of dementia.