Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada.

IntroductionWeight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).MethodsAdult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years.ResultsAmong 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI).ConclusionsPWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration

Life-Expectancy Disparities Among Adults With HIV in the United States and Canada: The Impact of a Reduction in Drug- and Alcohol-Related Deaths Using the Lives Saved Simulation Model.

Improvements in life expectancy among people living with human immunodeficiency virus (PLWH) receiving antiretroviral treatment in the United States and Canada might differ among key populations. Given the difference in substance use among key populations and the current opioid epidemic, drug- and alcohol-related deaths might be contributing to the disparities in life expectancy. We sought to estimate life expectancy at age 20 years in key populations (and their comparison groups) in 3 time periods (2004-2007, 2008-2011, and 2012-2015) and the potential increase in expected life expectancy with a simulated 20% reduction in drug- and alcohol-related deaths using the novel Lives Saved Simulation model. Among 92,289 PLWH, life expectancy increased in all key populations and comparison groups from 2004-2007 to 2012-2015. Disparities in survival of approximately a decade persisted among black versus white men who have sex with men and people with (vs. without) a history of injection drug use. A 20% reduction in drug- and alcohol-related mortality would have the greatest life-expectancy benefit for black men who have sex with men, white women, and people with a history of injection drug use. Our findings suggest that preventing drug- and alcohol-related deaths among PLWH could narrow disparities in life expectancy among some key populations, but other causes of death must be addressed to further narrow the disparities

Has carbohydrate-restriction been forgotten as a treatment for diabetes mellitus? A perspective on the ACCORD study design

Prior to the discovery of medical treatment for diabetes, carbohydrate-restriction was the predominant treatment recommendation to treat diabetes mellitus. In this commentary we argue that carbohydrate-restriction should be reincorporated into contemporary treatment studies for diabetes mellitus

A homozygous variant in growth and differentiation factor 2(GDF2)may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis

The etiology of nonimmune hydrops fetalis is extensive and includes genetic disorders. We describe a term-born female neonate with late onset extensive nonimmune hydrops, that is, polyhydramnios, edema, and congenital bilateral chylothorax. This newborn was successfully treated with repetitive thoracocentesis, total parenteral feeding, octreotide intravenously and finally surgical pleurodesis and corticosteroids. A genetic cause seemed plausible as the maternal history revealed a fatal nonimmune hydrops fetalis. A homozygous truncating variant inGDF2(c.451C>T, p.(Arg151*)) was detected with exome sequencing. Genetic analysis of tissue obtained from the deceased fetal sibling revealed the same homozygous variant. The parents and two healthy siblings were heterozygous for theGDF2variant. Skin and lung biopsies in the index patient, as well as the revised lung biopsy of the deceased fetal sibling, showed lymphatic dysplasia and lymphangiectasia. To the best of our knowledge, this is the first report of an association between a homozygous variant inGDF2with lymphatic dysplasia, hydrothorax and nonimmune hydrops fetalis

Genetic Variants in \u3cem\u3eHSD17B3\u3c/em\u3e, \u3cem\u3eSMAD3\u3c/em\u3e, and \u3cem\u3eIPO11\u3c/em\u3e Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P \u3c 5 × 10‐6). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q \u3c 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q \u3c 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor‐beta (TGF‐β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D

Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 x 10(-6)). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D

CeRebrUm and CardIac Protection with ALlopurinol in Neonates with Critical Congenital Heart Disease Requiring Cardiac Surgery with Cardiopulmonary Bypass (CRUCIAL):study protocol of a phase III, randomized, quadruple-blinded, placebo-controlled, Dutch multicenter trial

BACKGROUND: Neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of brain injury that may result in adverse neurodevelopment. To date, no therapy is available to improve long-term neurodevelopmental outcomes of CCHD neonates. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of reactive oxygen and nitrogen species, thereby limiting cell damage during reperfusion and reoxygenation to the brain and heart. Animal and neonatal studies suggest that allopurinol reduces hypoxic-ischemic brain injury and is cardioprotective and safe. This trial aims to test the hypothesis that allopurinol administration in CCHD neonates will result in a 20% reduction in moderate to severe ischemic and hemorrhagic brain injury. METHODS: This is a phase III, randomized, quadruple-blinded, placebo-controlled, multicenter trial. Neonates with a prenatal or postnatal CCHD diagnosis requiring cardiac surgery with CPB in the first 4 weeks after birth are eligible to participate. Allopurinol or mannitol-placebo will be administered intravenously in 2 doses early postnatally in neonates diagnosed antenatally and 3 doses perioperatively of 20 mg/kg each in all neonates. The primary outcome is a composite endpoint of moderate/severe ischemic or hemorrhagic brain injury on early postoperative MRI, being too unstable for postoperative MRI, or mortality within 1 month following CPB. A total of 236 patients (n = 188 with prenatal diagnosis) is required to demonstrate a reduction of the primary outcome incidence by 20% in the prenatal group and by 9% in the postnatal group (power 80%; overall type 1 error controlled at 5%, two-sided), including 1 interim analysis at n = 118 (n = 94 with prenatal diagnosis) with the option to stop early for efficacy. Secondary outcomes include preoperative and postoperative brain injury severity, white matter injury volume (MRI), and cardiac function (echocardiography); postnatal and postoperative seizure activity (aEEG) and regional cerebral oxygen saturation (NIRS); neurodevelopment at 3 months (general movements); motor, cognitive, and language development and quality of life at 24 months; and safety and cost-effectiveness of allopurinol. DISCUSSION: This trial will investigate whether allopurinol administered directly after birth and around cardiac surgery reduces moderate/severe ischemic and hemorrhagic brain injury and improves cardiac function and neurodevelopmental outcome in CCHD neonates. TRIAL REGISTRATION: EudraCT 2017-004596-31. Registered on November 14, 2017. ClinicalTrials.gov NCT04217421. Registered on January 3, 2020 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-022-06098-y

Clinical Course of TGA After Arterial Switch Operation in the Current Era

Background: The number of patients with an arterial switch operation (ASO) for transposition of the great arteries (TGA) is steadily growing; limited information is available regarding the clinical course in the current era. Objectives: The purpose was to describe clinical outcome late after ASO in a national cohort, including survival, rates of (re-)interventions, and clinical events. Methods: A total of 1,061 TGA-ASO patients (median age 10.7 years [IQR: 2.0-18.2 years]) from a nationwide prospective registry with a median follow-up of 8.0 years (IQR: 5.4-8.8 years) were included. Using an analysis with age as the primary time scale, cumulative incidence of survival, (re)interventions, and clinical events were determined. Results: At the age of 35 years, late survival was 93% (95% CI: 88%-98%). The cumulative re-intervention rate at the right ventricular outflow tract and pulmonary branches was 36% (95% CI: 31%-41%). Other cumulative re-intervention rates at 35 years were on the left ventricular outflow tract (neo-aortic root and valve) 16% (95% CI: 10%-22%), aortic arch 9% (95% CI: 5%-13%), and coronary arteries 3% (95% CI: 1%-6%). Furthermore, 11% (95% CI: 6-16%) of the patients required electrophysiological interventions. Clinical events, including heart failure, endocarditis, and myocardial infarction occurred in 8% (95% CI: 5%-11%). Independent risk factors for any (re-)intervention were TGA morphological subtype (Taussig-Bing double outlet right ventricle [HR: 4.9, 95% CI: 2.9-8.1]) and previous pulmonary artery banding (HR: 1.6, 95% CI: 1.0-2.2). Conclusions: TGA-ASO patients have an excellent survival. However, their clinical course is characterized by an ongoing need for (re-)interventions, especially on the right ventricular outflow tract and the left ventricular outflow tract indicating a strict lifelong surveillance, also in adulthood.</p