Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Oxidative stress after antenatal betamethasone: acute downregulation of glutathione peroxidase-3

BACKGROUND: Human and experimental data show that antenatal exposure to glucocorticoids (GC) temporarily reduces fetal well-being and impairs the fetal response to hypoxemia. AIMS: We tested the hypothesis that antenatal betamethasone provokes transient oxidative stress, which may be triggered directly by the GC or indirectly by metabolic signals such as increased glucose and free fatty acid (FFA) concentrations. STUDY DESIGN: Prospective (single center, 18 months) cohort study in newborns <34 weeks gestational age at birth. METHODS: We studied 105 newborns and measured oxidative damage to lipids [malondialdehyde (MDA)] and proteins (protein carbonyls), as well as glutathione peroxidase-3 (GPx3), an important antioxidant enzyme, in umbilical vein (UV) plasma. In addition, we measured umbilical artery and UV blood gases, and metabolic indices (plasma glucose, FFA and insulin) in UV. RESULTS: MDA but not protein carbonyl concentrations was inversely related to time elapsed since the first or last betamethasone administration (p=0.006); MDA remained elevated by 69-96% for at least 72 h after the last betamethasone. By contrast, GPx3 concentrations were repressed in newborns who received betamethasone < or =24h before birth. GPx3 and MDA concentrations were correlated (r=-0.38, p<0.001). Labor, GA, sex, size at birth, blood gases or metabolic indices did not explain the effects of betamethasone on MDA and GPx3. CONCLUSIONS: Antenatal GC elicit a rapid suppression of the GPx3 antioxidant defense system which may contribute to a longer-lasting but also transient rise in lipid oxidative damage.status: publishe

Oxidant balance markers at birth in relation to glycemic and acid-base parameters at birth

In diabetic pregnancies, suboptimal glycemic control is a risk factor for fetal acidemia and stillbirth. We hypothesized that the diabetic intrauterine milieu (hyperglycemia, hyperinsulinemia, changes in acid-base status) might predispose to oxidative stress. We studied 70 newborns whose mothers had pregestational diabetes (58 with type 1 diabetes mellitus) and 71 control newborns from nondiabetic mothers. Protein carbonyls (PCs), malondialdehyde, and 8-hydroxy-2'deoxyguanosine were measured in umbilical vein plasma as a reflection of protein, lipid, and DNA oxidative damage, respectively; glutathione peroxidase-3 (GPx3), an important circulating antioxidant enzyme, was also assayed. Despite satisfactory glycemic control in the majority of diabetic mothers, their newborns showed higher birth weight and relative hyperglycemia, hyperinsulinemia, and respiratory acidemia. The oxidant balance marker concentrations were not different at the P < .05 level between the 2 groups, and there was no relationship to maternal hemoglobin A(₁C) levels in the diabetic group. However, in the entire sample, increasing glucose levels at birth were related to lower GPx3 and higher PC concentrations; and GPx3 and PC concentrations were inversely correlated. In addition, a depressed pH or larger base-deficit at birth was related to higher PC and 8-hydroxy-2'deoxyguanosine concentrations. In conclusion, oxidant balance markers at birth are not affected by maternal diabetes per se and its long-term glycemic control, yet some markers are acutely tuned to metabolic cues including glucose and the acid-base environment.status: publishe

Maternal body size and birth weight: can insulin or adipokines do better?

Overweight gravidas and gravidas with a robust weight gain have an accrued risk of delivering a large-for-gestational age (LGA) baby. Here, we examined whether the measurement of insulin and adipokines--peptides secreted mainly by adipose tissue--at the glucose challenge test (GCT) improves the prediction of birth weight. We studied 631 singleton pregnancies at 24 to 29 weeks' gestational age (GA) with data on height, baseline body weight (BW), and BW change between baseline and the GCT. In addition to glucose and insulin, we measured adiponectin, leptin, soluble leptin receptor (the main leptin-binding protein), and tumor necrosis factor alpha. We found that birth weight was related to maternal height, baseline BW, and BW change, and also--albeit less strongly--to insulin, adiponectin, leptin, and soluble leptin receptor concentrations. In multiple regression analyses, body size parameters explained approximately 10% of the variance in birth weight, of which BW change was the most important correlate, but the metabolic markers added only approximately 2% variance, with leptin alone adding 1.4%. Gravidas carrying a small-for-GA (SGA) fetus were more likely to have a leptin value in the highest quartile than those with an appropriate-for-GA fetus (odds ratio, 2.6; 95% confidence interval, 1.1-6.3; P = .04), but there were no other differences in the metabolic markers between SGA or LGA and appropriate-for-GA pregnancies. In conclusion, measuring insulin and adipokines at the GCT has limited, if any, clinical benefit to predict which fetuses will be SGA or LGA at birth.status: publishe

Adipokine profile and C-reactive protein in pregnancy: effects of glucose challenge response versus body mass index

OBJECTIVE: To test the hypothesis that gravidas who have an abnormal response to glucose loading have dysfunctional adipose tissue cells that produce more insulin resistance-inducing and proinflammatory adipokines but less insulin-sensitizing adipokines. METHODS: We performed a nested case-control study within a larger sample of gravidas who had a glucose challenge test (GCT) at 24-29 weeks; we compared 73 cases with an abnormal GCT (>8.3 mM) and 146 controls with a strictly normal GCT (<7.2 mM) matched for body mass index (BMI) and height (mean difference between cases and controls: 0.1 kg/m(2) and 1 cm, respectively). We measured plasma insulin, adipokines (leptin, adiponectin, resistin, tumor necrosis factor [TNF]-alpha, interleukin [IL]-6), soluble leptin receptor (sOb-R), the main leptin-binding protein, and C-reactive protein (CRP). RESULTS: The cases showed a 48% increase in insulin concentrations and a 27% increase in TNF-alpha concentrations compared to the controls (both P < .0001), but leptin, sOb-R, IL-6, and adiponectin, as well as CRP, concentrations were comparable between cases and controls. In the whole group (n = 219), BMI was correlated with insulin, leptin, IL-6, and CRP, and inversely with sOb-R and adiponectin concentrations (all P < .0003). CONCLUSIONS: Plasma leptin, sOb-R, IL-6, and adiponectin, as well as CRP, are strongly related to BMI in gravidas at 24-29 weeks gestational age but not to the glucose loading response. However, TNF-alpha is higher in women with an abnormal GCT. Further studies should disclose the source of increased TNF-alpha in these women, and to assess whether TNF-alpha is causally related to glucose intolerance during pregnancy.status: publishe

Chronic tumor necrosis factor-alpha infusion in gravid C57BL6/J mice accelerates adipose tissue development in female offspring

OBJECTIVE: Tumor necrosis factor (TNF)-alpha is thought to mediate, in part, the link between obesity and insulin resistance, and women with gestational diabetes mellitus (GDM) have raised serum TNF-alpha concentrations. Our objective was to investigate whether systemic TNF-alpha administration into gravid C57BL6/J mice causes a GDM-like syndrome and affects growth and adipose tissue (AT) development in the offspring. METHODS: We assessed glucose tolerance and reproductive outcome in mice infused with saline, or 2 mug or 4 mug recombinant mouse (rm)TNF-alpha by subcutaneous mini-osmotic pumps between days (d)11.5 and 18.5 of gestation. Subsequently, we studied the effects of the 2-mug dose on maternal AT metabolism. Finally, the growth of offspring exposed to 2 mug rmTNF-alpha in utero was followed until 8 weeks postnatal age. At 8 weeks, we assessed AT accumulation, as well as adipocyte area in white AT and insulin sensitivity in males, and adipokine mRNA levels in various AT depots in females. RESULTS: The peak glucose response to an intraperitoneal glucose stimulus in late-gravid mice and fetal weight were higher with 2 mug but not 4 mug rmTNF-alpha compared with saline; however, 2 mug TNF-alpha did not affect AT parameters. The female but not male offspring of these mice showed accelerated growth, hyperadiposity, robustly increased leptin expression in all AT depots, and raised fasting blood glucose. CONCLUSIONS: TNF-alpha infusion (2 mug for 7 days) in gravid mice resulted in a mild GDM syndrome and accelerated AT development in the offspring in a sex-specific manner. The data suggest that TNF-alpha mediates in part the effects of GDM on fetal growth and postnatal adiposity, and constitutes a potential mediator of intrauterine programming.status: publishe

Insulin-like growth factor-II regulates maternal hemodynamic adaptation to pregnancy in rats

The relationship between maternal plasma volume (PV) expansion and fetal growth is well established, but the underlying mechanisms remain unclear. Here, we examined the influence of maternal body weight and fetoplacental mass on gestational PV increment in the rat. Because IGF-I and IGF-II have growth-promoting and vasoactive properties, their relationship to PV expansion and fetoplacental growth was also studied. In normal rats, the gradual expansion of PV (+35% at day 22, i.e., term) was accompanied by a rise in circulating IGF-II (+45%) and a considerable drop in IGF-I (-73%). Increased maternal body weight induced by an obesogenic diet did not influence PV and circulating IGFs compared with rats on the standard diet. Combining the results from both diets, circulating IGF-II was the principal correlate of PV. A second experiment examined the effect of fetoplacental mass reduction by surgically removing half of the gestational sacs at day 16. This procedure reduced maternal PV and circulating IGF-II at term by 14% and 20%, respectively. We then investigated the effect of a constant infusion of IGF-II (1 mgxkg(-1)xday(-1)) from day 16, which raised circulating IGF-II by 38% and found increased PV (+19%) and a larger placental trophospongial area (+29%) at term. Our results indicate that the placenta, the primary source of IGF-II synthesis in pregnancy, drives PV expansion, and that IGF-II is among the regulatory factors of the gestational PV increment. Further studies should clarify whether IGF-II directly affects vascular function and/or indirectly promotes the secretion of placenta-derived vasoactive substances.status: publishe

Is low-dose streptozotocin in rats an adequate model for gestational diabetes mellitus?

OBJECTIVE: To examine the use of streptozotocin (SZ) in rats as a model for gestational diabetes mellitus (GDM). METHODS: We studied various doses of SZ, either as a single administration (30, 35, 40, or 50 mg/kg, intraperitoneally) on day 1 of pregnancy or as 2 low doses (30 and 20 or 30 and 30 mg/kg) administered 2 days before mating and on day 1 of pregnancy. We examined the effect on maternal and fetal glucose and insulin concentrations and on fetal weight on day 20 of pregnancy. In a second series of experiments, we studied two groups (SZ 30/20 and SZ 35) with fetal hyperinsulinemia on day 20 of pregnancy. We performed an intravenous glucose tolerance test (IVGTT) on day 20, and in separate groups we reassessed fetal weight and insulin concentrations at term (day 22). RESULTS: There was considerable variability in glucose concentrations with most SZ doses. Lower doses of SZ (30, 30/20, and 35 mg/kg) did not significantly increase maternal and fetal glucose levels, in contrast to higher doses of SZ (30/30 and 50 mg/kg). Fetuses were smaller on day 20 with all doses except SZ 30 and SZ 30/20; fetal insulin concentrations were elevated with SZ 30, 30/20, and 35. The IVGTT showed glucose intolerance in SZ 35 and SZ 30/20, but the insulin response was unaffected in either group. Fetuses were smaller on day 22 in both these SZ groups, whereas fetal insulin levels at term were not different compared with controls. CONCLUSIONS: Low-dose SZ is not a good model for GDM because of the high variability in glucose levels, the normal insulin response to a glucose load, the absence of fetal macrosomia, and the inconsistent effect on fetal insulin concentrations.status: publishe