Pharmacokinetics and Safety of Remdesivir in Pregnant and Non-Pregnant Women with COVID-19: Results from IMPAACT 2032.

BACKGROUND: Pregnant people with COVID-19 experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. METHODS: IMPAACT 2032 was a phase IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI 1.35, 3.03) with each additional infusion in non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two Grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. CONCLUSIONS: Plasma remdesivir PK parameters were comparable between pregnant and non-pregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.

Metformin use associated with lower rate of hospitalization for influenza in individuals with diabetes.

AIM: To investigate if patients with diabetes taking metformin have better outcomes versus those not taking metformin following an emergency room visit for influenza. METHODS: Using electronic medical records, we performed a retrospective chart review of all adult patients with a diagnosis of diabetes seen in any Duke University Medical Center-affiliated emergency department for influenza over a 6-year period. We documented patient characteristics and comorbidities, and compared outcomes for patients taking metformin versus patients not taking metformin using both univariable and multivariable analyses. Our primary outcome was hospital admission rate. Secondary outcomes were in-hospital length of stay and in-hospital death. RESULTS: Our cohort included 1023 adult patients with diabetes, of whom 59.9% were female. The mean age was 62.9 years, 58.4% were African American, 36.1% were White, and 81.9% were obese or overweight. Of these patients, 347 (34%) were taking metformin. Patients with diabetes taking metformin were less likely to be hospitalized following an emergency department visit for influenza than patients with diabetes not taking metformin (56.8% vs. 70.1%; p < 0.001). Of those patients admitted, there was no statistically significant difference in length of stay or death. CONCLUSIONS: In patients with diabetes, metformin use is associated with lower rate of hospitalization following an emergency department visit for influenza.

Dietary inclusion of phytase and stimbiotic decreases mortality and lameness in a wire ramp challenge model in broilers.

RESEARCH HIGHLIGHTS: Wire ramp model reproducibly induced lameness/BCO in broilers.Treatments did not affect growth, but phytase with stimbiotic significantly reduced BCO.Phytase increased circulating inositol, and wire flooring decreased bone inositol.

"What Is the Point of Human Beings?"

Climate change caused by human activities is a serious threat to the survival of our species, and one that we have not yet mustered the perspective and the will to address. Our vision tends to focus on what is useful to ourselves as individuals in the short term, instead of more broadly on what is needed for the long-term good of our species. We do not consider what our purpose and role could be in the life of our planet. We do not ask "What is the point of human beings?" In this time of climate crisis, answering this question by developing a shared sense of purpose, a purpose centered on caring for the world as a whole, might give our species the perspective and will we need to survive.

Potential non-invasive detection of lesions in broiler femur heads: application of the DXA imaging system.

Leg health is a significant economic and welfare concern for the poultry industry. Current methods of detection rely on visual assessment of the legs and gait scores and bone scoring during necropsy for full characterization. Additionally, the current scoring of femurs only examines the external surface of the femoral head. Through the use of the dual-energy X-ray absorptiometry (DXA) imaging system, we show the presence of a necrotic region in the femurs that would otherwise be considered healthy based on the current evaluation procedures. Importantly, these lesions were present in almost 60% (22 of 37) of femurs that scored normal for femoral head necrosis (FHN). Additionally, these femurs showed greater bone mineral content (BMC) relative to weight compared to their counterparts with no lucent lesions (6.95% ± 0.20% vs. 6.26% ± 0.25; p = 0.038). Identification of these lesions presents both a challenge and an opportunity. These subclinical lesions are likely to be missed in routine scoring procedures for FHN and can inadvertently impact the characterization of the disease and genetic selection programs. Furthermore, this imaging system can be used for in vivo, ex vivo, and embryonic (egg) studies and, therefore, constitutes a potential non-invasive method for early detection of bone lesions in chickens and other avian species.

Effects of an herbal adaptogen feed-additive on feeding-related hypothalamic neuropeptides in chronic cyclic heat-stressed chickens.

Heat stress (HS) is a global serious issue in the poultry industry with numerous adverse effects, including increased stress, depressed feed intake (FI), poor growth performance and higher mortality. Herbal adaptogens, plant extracts considered as stress response modifiers, are metabolic regulators that improve an organism's ability to adapt to and minimize damage from environmental stresses. Previously, we showed that herbal adaptogen supplementation increased FI and body weight (BW) of broiler (meat-type) chickens reared under HS conditions. Therefore, we hypothesized that these effects may be mediated through modulation of hypothalamic feeding-related neuropeptides. Male Cobb 500 chicks were reared in 12 environmental chambers with three diets: a corn-soybean-based diet (C) and two herbal adaptogen-supplemented diets at 500 g/1000 kg (NR-PHY-500) and 1 kg/1000 kg (NR-PHY-1000). Broilers in 9 chambers were exposed to chronic cyclic HS (35 °C for 8 h/day) from d29 to d42, while 3 chambers were maintained at 24 °C (thermoneutral, TN) for all 42 days. Hypothalamic samples were collected on d42 from each group, both before the onset of HS (Pre-HS) that day and after 3 h of HS (post-HS). Hypothalamic expressions of neuropeptide Y (NPY) receptors Y4 and Y7, Corticotropin-releasing hormone (CRH), orexin receptor 1 (ORXR1), melanocortin receptors (MC1R, MC4R, and MC5R), visfatin and neurosecretory protein GL (NPGL) genes were significantly upregulated by adaptogen supplementation. The hypothalamic expression of MC2R was affect by period, with a significant upregulation during post-HS phase. There was a significant period by treatment interaction for hypothalamic orexin and adiponectin expression. The hypothalamic expression of NPY, Y1, Y2, Y5, Y6, proopiomelanocortin (POMC), cocaine and amphetamine regulated transcript (CART), agouti-related peptide (AgRP), ORXR2, AdipR1/2, MC3R, and ghrelin was not affected by diet supplementation nor by HS exposure. In conclusion, these findings suggest that in-feed supplementation of adaptogen might improve FI and growth via modulation of hypothalamic feeding-related neuropeptides in heat-stressed broilers.

Effect of a microencapsulated phyto/phycogenic blend supplementation on growth performance, processing parameters, meat quality, and sensory profile in male broilers.

Powered by consumer taste, value, and preferences, natural products including phytogenics and algae are increasingly and separately used in the food systems where they have been reported to improve growth performance in poultry and livestock. The present study aimed to determine the effects of a new feed additive, microencapsulated NUQO© NEX, which contains a combination of phytogenic and phycogenic, on broiler growth performance, blood chemistry, bone health, meat quality and sensory profile. Male Cobb500 chicks (n = 1,197) were fed a 3-phase feeding intervals; 1-14d starter, 15-28d grower, and 29-40d finisher. The dietary treatments included a corn-soy basal Control (CON), basal diet supplemented with NUQO© NEX at 100 g/ton from 1 to 28d then 75 g/ton from d 28 to 40 (NEX75), and basal diet supplemented with NUQO© NEX at 100 g/ton from 1 to 40d (NEX100). The NEX100 supplemented birds had 62 g more BWG increase and 2.1-point improvement in FCR compared with CON in the finisher and overall growth phase (p < 0.05), respectively. Day 40 processing body weights and carcass weights were heavier for the NEX100 supplemented birds (p < 0.05). The incidences of muscle myopathies were also higher in NEX treatments, which could be associated with the heavier weights, but the differences were not detected to be significant. The NEX75 breast filets had more yellowness than other dietary treatments (p = 0.003) and the NEX 100 treatment reduced the levels of breast filet TBARS at 7 days-post harvest (p = 0.053). Finally, both NEX treatments reduced the incidence of severe bone (tibia and femur) lesions. In conclusion, the supplementation of the phytogenic NUQO© NEX improved finisher performance parameters, whole phase FCR, processing carcass weights, and breast filet yellowness, at varying inclusion levels.

Effect of heat stress on the hypothalamic expression of water channel- and noncoding RNA biogenesis-related genes in modern broilers and their ancestor red jungle fowl.

Genetic selection for high growth rate has resulted in spectacular progress in feed efficiency in chickens. As feed intake and water consumption (WC) are associated and both are affected by environmental conditions, we evaluated WC and its hypothalamic regulation in three broiler-based research lines and their ancestor jungle fowl (JF) under heat stress (HS) conditions. Slow growing ACRB, moderate growing 95RB, fast growing MRB, and JF were exposed to daily chronic cyclic HS (36 °C, 9 h/d) or thermoneutral temperature (24 °C). HS increased WC in the MRB only. Arginine vasopressin (AVP) mRNA levels were decreased by HS in the MRB. Within the renin-angiotensin-aldosterone system (RAAS) system, renin expression was increased by HS in the JF, ACRB, and 95RB, while angiotensin I-converting enzyme (ACE), angiotensin II receptors (type 1, AT1, and type 2, AT2) were affected by line. The expression of aquaporin (AQP2, 7, 9, 10, 11, and 12) genes was upregulated by HS, whereas AQP4 and AQP5 expressions were influenced by line. miRNA processing components (Dicer1, Ago2, Drosha) were significantly different among the lines, but were unaffected by HS. In summary, this is the first report showing the effect of HS on hypothalamic water channel- and noncoding RNA biogenesis-related genes in modern chicken populations and their ancestor JF. These results provide a novel framework for future research to identify new molecular mechanisms and signatures involved in water homeostasis and adaptation to HS.

Effect of heat stress on the hypothalamic expression profile of water homeostasis-associated genes in low- and high-water efficient chicken lines.

With climate change, selection for water efficiency and heat resilience are vitally important. We undertook this study to determine the effect of chronic cyclic heat stress (HS) on the hypothalamic expression profile of water homeostasis-associated markers in high (HWE)- and low (LWE)-water efficient chicken lines. HS significantly elevated core body temperatures of both lines. However, the amplitude was higher by 0.5-1°C in HWE compared to their LWE counterparts. HWE line drank significantly less water than LWE during both thermoneutral (TN) and HS conditions, and HS increased water intake in both lines with pronounced magnitude in LWE birds. HWE had better feed conversion ratio (FCR), water conversion ratio (WCR), and water to feed intake ratio. At the molecular level, the overall hypothalamic expression of aquaporins (AQP8 and AQP12), arginine vasopressin (AVP) and its related receptor AVP2R, angiotensinogen (AGT), angiotensin II receptor type 1 (AT1), and calbindin 2 (CALB2) were significantly lower; however, CALB1 mRNA and AQP2 protein levels were higher in HWE compared to LWE line. Compared to TN conditions, HS exposure significantly increased mRNA abundances of AQPs (8, 12), AVPR1a, natriuretic peptide A (NPPA), angiotensin I-converting enzyme (ACE), CALB1 and 2, and transient receptor potential cation channel subfamily V member 1 and 4 (TRPV1 and TRPV4) as well as the protein levels of AQP2, however it decreased that of AQP4 gene expression. A significant line by environment interaction was observed in several hypothalamic genes. Heat stress significantly upregulated AQP2 and SCT at mRNA levels and AQP1 and AQP3 at both mRNA and protein levels, but it downregulated that of AQP4 protein only in LWE birds. In HWE broilers, however, HS upregulated the hypothalamic expression of renin (REN) and AVPR1b genes and AQP5 proteins, but it downregulated that of AQP3 protein. The hypothalamic expression of AQP (5, 7, 10, and 11) genes was increased by HS in both chicken lines. In summary, this is the first report showing improvement of growth performances in HWE birds. The hypothalamic expression of several genes was affected in a line- and/or environment-dependent manner, revealing potential molecular signatures for water efficiency and/or heat tolerance in chickens.