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To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms-like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that L-kynurenine, a metabolite of L-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for L-kynurenine in placental health. However, UNx mice failed to show upregulation of L-kynurenine during pregnancy; furthermore, when UNx mice were fed L-kynurenine in drinking water throughout pregnancy, their preeclampsialike state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate L-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia., Introduction Pregnancy is an adaptive state of net sodium and volume expansion for the purpose of increasing perfusion of the placenta and fetus. Blood flow to the uterus can increase [...]

Patients with end-stage kidney disease (ESKD) have increased vascular disease. While protein-bound molecules that escape hemodialysis may contribute to uremic toxicity, specific contributing toxins remain ambiguous. In this issue of the JCI, Arinze et al. explore the role of tryptophan metabolites in chronic kidney disease-associated (CKD-associated) peripheral arterial disease. The authors used mouse and zebrafish models to show that circulating indoxyl sulfate (IS) blocked endothelial Wnt signaling, which impaired angiogenesis. Plasma levels of IS and other tryptophan metabolites correlated with adverse peripheral vascular disease events in humans. These findings suggest that lowering IS may benefit individuals with CKD and ESKD., Impaired angiogenesis and excess vascular complications in uremia The use of chronic dialysis in patients with end-stage kidney disease (ESKD) is one of the miracles of modern medicine with which [...]

The article discusses the presence of autoantibodies targeting nephrin in podocytopathies, specifically minimal change disease and focal segmental glomerulosclerosis. The authors question the direct evidence of antinephrin autoantibodies in patients and suggest the need for additional controls to confirm their presence. They also highlight the presence of antinephrin autoantibodies in patients with recurrent urinary tract infections, indicating a potential novel autoimmune etiology. The study emphasizes the importance of identifying specific epitopes to improve the specificity of diagnosing idiopathic nephrotic syndrome. [Extracted from the article]

PGC1[alpha] protects against kidney injury by upregulating enzymes that enhance nicotinamide adenine dinucleotide (NAD) and driving local accumulation of the fatty acid breakdown product [beta]-hydroxybutyrate, which leads to increased production of the renoprotective prostaglandin E.sub.2. Kidney protection by PGC1[alpha] Samir Parikh and colleagues show that the mitochondrial biogenesis regulator PGC1[alpha] protects against kidney injury by regulating NAD biosynthesis. In a mouse model, PGC1[alpha] upregulates NAMPT, an enzyme required form for NAD.sup.+ biosynthesis, and drives local accumulation of the fatty acid breakdown product [beta]-hydroxybutyrate. This, in turn, leads to increased production of the renoprotective prostaglandin PGE.sub.2. The authors further show that treatment with the NAD precursor nicotinamide (NAM) can reverse established ischaemic kidney injury. The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients.sup.1,2. Here we show that the mitochondrial biogenesis regulator, PGC1[alpha].sup.3,4, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1[alpha].sup.-/- (also known as Ppargc1a.sup.-/-) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1[alpha].sup.-/- mice. Inducible tubular transgenic mice (iNephPGC1[alpha]) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1[alpha] coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1[alpha] deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product [beta]-hydroxybutyrate, leading to increased production of prostaglandin PGE.sub.2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of [beta]-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1[alpha]-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1[alpha]-dependent stress resistance., Author(s): Mei T. Tran [sup.1] [sup.2] , Zsuzsanna K. Zsengeller [sup.1] [sup.2] [sup.3] , Anders H. Berg [sup.3] [sup.4] , Eliyahu V. Khankin [sup.1] [sup.2] , Manoj K. Bhasin [sup.2] [...]

We have investigated how chemistry textbooks use models of redox reactions in different subject areas, how they change models between and within the topics, and how they deal with specific learning difficulties identified in the literature. The textbooks examined were published for use in the natural science programme in Swedish upper secondary schools and in the UK A-level course. As a starting point, the defined redox models found in the literature were used to investigate the textbooks. The results show that all redox models are used with the addition of alternative representations. Authors exclusively use the electron and the oxidation number models in inorganic chemistry. In organic chemistry, the oxygen and hydrogen model are used, and in biochemistry mainly hydrogen and alternative representations. There is no guide to changes of models between the subject areas. However, within the inorganic chemistry, authors guide model change which was not identified in either organic or biochemistry. Regarding the learning difficulties, the authors dealt with just a few of them. (Contains 2 tables and 2 figures.)

Objective: Glycated hemoglobin (HbA1c) can predict risk for microvascular complications in patients with diabetes. However, HbA1c's reliability in chronic kidney disease (CKD) has been questioned, with concerns including competition from another posttranslational protein modification, carbamylation, acting on the same amino groups as glycation, and anemia with reduced erythrocyte lifespans leading to altered glycation accumulation. We investigated whether carbamylation and anemia modify the impact of HbA1c on renal outcomes in patients with diabetes and CKD.Research Design and Methods: In 1,516 participants from the Chronic Renal Insufficiency Cohort study with diabetes and CKD, Cox regression models were applied to evaluate the association between HbA1c and CKD progression (composite of end-stage kidney disease or 50% decline in estimated glomerular filtration rate [eGFR]), stratified by carbamylated albumin (C-Alb) quartiles and anemia.Results: The mean eGFR was 38.1 mL/min/1.73 m2, mean HbA1c was 7.5% (58 mmol/mol), and median C-Alb was 8.4 mmol/mol. HbA1c was lower in the higher C-Alb quartiles. During a median follow-up of 6.9 years, 763 participants experienced CKD progression. Overall, higher HbA1c was associated with an increased risk of CKD progression (adjusted hazard ratio 1.07 [95% CI 1.02-1.13]). However, using stratified analyses, HbA1c was no longer associated with CKD progression in the highest C-Alb quartile, but did show a monotonic increase in CKD progression risk across each lower C-Alb quartile (P-interaction = 0.022). Anemia also modified the association between HbA1c and CKD progression (P-interaction = 0.025).Conclusions: In patients with coexisting diabetes and CKD, the association between HbA1c and CKD progression is modified by carbamylation and anemia.Article Highlights: HbA1c's reliability in chronic kidney disease (CKD) has been questioned, with concerns including competition between carbamylation and glycation and anemia affecting glycation accumulation. We investigated whether carbamylation and anemia modify the impact of HbA1c on renal outcomes in patients with diabetes and CKD. In 1,516 participants from the Chronic Renal Insufficiency Cohort (CRIC) study with diabetes and CKD, we found that the association between HbA1c and CKD progression was significantly diminished in patients with high carbamylation levels or presence of anemia. This finding may explain why HbA1c is less reliable in patients with CKD compared with the general population with diabetes. [ABSTRACT FROM AUTHOR]

Background The multiple mutations comprising the epsilon variant demonstrate the independent convergent evolution of severe acute respiratory syndrome coronavirus (SARS-CoV-2), with its spike protein mutation L452R present in the delta (L452R), kappa (L452R), and lambda (L452Q) variants. Methods Coronavirus disease 2019 (COVID-19) variants were detected in 1017 patients using whole-genome sequencing and were assessed for outcome and severity. The mechanistic effects of the epsilon versus non-epsilon variants were investigated using a multiomic approach including cellular response assays and paired cell and host transcriptomic and proteomic profiling. Results We found that patients carrying the epsilon variant had increased mortality risk but not increased hospitalizations (P <.02). Cells infected with live epsilon compared with non-epsilon virus displayed increased sensitivity to neutralization antibodies in all patients but a slightly protective response in vaccinated individuals (P <.001). That the epsilon SARS-CoV-2 variant is more infectious but less virulent is supported mechanistically in the down-regulation of viral processing pathways seen by multiomic analyses. Importantly, this paired transcriptomics and proteomic profiling of host cellular response to live virus revealed an altered leukocyte response and metabolic messenger RNA processing with the epsilon variant. To ascertain host response to SARS-CoV-2 infection, primary COVID-19–positive nasopharyngeal samples were transcriptomically profiled and revealed a differential innate immune response (P <.001) and an adjusted T-cell response in patients carrying the epsilon variant (P <.002). In fact, patients infected with SARS-CoV-2 and those vaccinated with the BNT162b2 vaccine have comparable CD4+/CD8+ T-cell immune responses to the epsilon variant (P <.05). Conclusions While the epsilon variant is more infectious, by altering viral processing, we showed that patients with COVID-19 have adapted their innate immune response to this fitter variant. A protective T-cell response molecular signature is generated by this more transmissible variant in both vaccinated and unvaccinated patients. [ABSTRACT FROM AUTHOR]

Objectives: Manufacturer recalls and altered supply chains during the coronavirus disease 2019 (COVID-19) pandemic caused a nationwide shortage of blue-top tubes (BTTs). Most non-point-of-care coagulation tests use these tubes, leaving laboratories and health care facilities in short supply. The Department of Pathology and Laboratory Medicine at Cedars-Sinai Medical Center implemented interventions to conserve supply without sacrificing patient safety.Methods: In a retrospective quality improvement analysis, we examined coagulation testing and BTT utilization over the 3-month interval during which our interventions were applied. Our study assessed the interventions' effectiveness by evaluating changes in BTT utilization, coagulation testing volume, and patient impact.Results: Average daily use (ADU) of BTT before and after the intervention were 476 and 403, respectively-a 15.2% reduction. Notably, the Emergency Department had a reduction in ADU of 43.3%. Average daily volumes of coagulation assays performed decreased from 949 to 783-a 17.5% reduction. No adverse events from the Pharmacy Department were identified during the study period.Conclusions: Interventions resulting in significant reductions were in divisions with effective management and supervision. Success in navigating the BTT shortage stemmed from timely announcements, action, and effective communication. Our recommendations established more effective coagulation assay utilization, decreased overall BTT use, and prevented patients with coagulopathic disorders from experiencing adverse consequences. [ABSTRACT FROM AUTHOR]

Background: The objective of this analysis was to compare the performance sensitivity and specificity of manufacturer-recommended signal-to-cutoff (S/Co) thresholds with modified S/Co values to estimate the prevalence of SARS-CoV-2-specific antibodies in a cohort of firefighters with a known infection history. Methods: Plasma venipuncture samples were used for serologic analysis of firefighters in Los Angeles, CA, USA, in October 2020. Seropositivity was assessed using the manufacturer's recommended S/Co (≥1.4 IgG) and modified S/Co thresholds based on measured antibody levels in 178 negative control patients who had blood drawn prior to the emergence of COVID-19. Optimal S/Co threshold was determined by receiver operating characteristic (ROC) curve analysis. Results: Of 585 firefighters included in the study, 52 (8.9%) reported having a PCR-positive test history prior to antibody testing. Thirty-five (67.3%) firefighters with a previous PCR-positive test were seropositive based on the manufacturer S/Co thresholds, consistent with an estimated 67.3% sensitivity and 100% specificity. After evaluating multiple modified S/Co thresholds based on pre-pandemic negative samples, a modified S/Co of 0.36 was found to yield optimal sensitivity (88.5%) and specificity (99.4%) by ROC curve analysis. This modified threshold improved serostatus classification accuracy by 21.2%. Conclusions: S/Co thresholds based on known negative samples significantly increase seropositivity and more accurately estimate cumulative incidence of disease compared to manufacturer-based thresholds. [ABSTRACT FROM AUTHOR]

Fatty acid-binding proteins (FABPs) facilitate the diffusion of fatty acids within cellular cytoplasm. Compared with C57B1/6J mice maintained on a high-fat diet, adipose-FABP (A-FABP) null mice exhibit increased fat mass, decreased lipolysis, increased muscle glucose oxidation, and attenuated insulin resistance, whereas overexpression of epithelial-FABP (E-FABP) in adipose tissue results in decreased fat mass, increased lipolysis, and potentiated insulin resistance. To identify the mechanisms that underlie these processes, real-time PCR analyses indicate that the expression of hormone-sensitive lipase is reduced, while perilipin A is increased in A-FABP/aP2 null mice relative to E-FABP overexpressing mice. In contrast, de novo lipogenesis and expression of genes encoding lipoprotein lipase, CD36, long-chain acyl-CoA synthetase 5, and diacylglycerol acyltransferase are increased in A-FABP/aP2 null mice relative to EFABP transgenic animals. Consistent with an increase in de novo lipogenesis, there was an increase in adipose C16:0 and C16:1 acyl-.CoA pools. There were no changes in serum free fatty acids between genotypes. Serum levels of resistin were decreased in the E-FABP transgenic mice, whereas serum and tissue adiponectin were increased in A-FABP/ aP2 null mice and decreased in E-FABP transgenic animals; leptin expression was unaffected. These results suggest that the balance between lipolysis and lipogenesis in adipocytes is remodeled in the FABP null and transgenic mice and is accompanied by the reprogramming of adipokine expression in fat cells and overall changes in plasma adipokines. fatty acids; adipocytes; adipokines

The adipocyte exerts an important role in energy homeostasis, both as depot for energy-rich triglycerides and as a source for metabolic hormones. Adipocytes also contribute to inflammation and the innate immune response. Although it can be physiologically beneficial to combine these two functions in a single cell type under some circumstances, the proinflammatory signals emanating from adipocytes in the obese state can have local and systemic effects that promote atherosclerosis and insulin resistance. The transcriptional machinery in the adipocyte that mediates these pro-inflammatory responses has remained poorly characterized to date. In particular, no information is currently available on the NF-[kappa]B family of transcription factors. Here, we show that adipogenesis is associated with changes in amount and subunit composition of the NF-[kappa]B complexes. NF-[kappa]B subunits p65 (RelA), p68 (RelB), and I[kappa]B are upregulated during fat cell differentiation. Correspondingly, basal NF-[kappa]B nuclear gel shift and luciferase reporter assays are induced in parallel during differentiation. Surprisingly, endotoxin sensitivity of the classical NF-[kappa]B pathway is substantially delayed and attenuated despite increased overall inflammatory response in the mature adipocyte, as judged by induction of IL-6 and TNF-[alpha]. As a reflection of the constitutively elevated NF-[kappa]B activity in the mature adipocyte, adipocytes (but not preadipocytes) exert a strong inflammatory stimulus on macrophages in vitro, suggesting a cross talk between adipocytes and interstitial macrophages in adipose tissue in vivo. These effects are mediated by a secretory product of adipocytes that is unlikely to be IL-6 or TNF-[alpha]. nuclear factor-[kappa]B; inflammation

Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep [sup.ob/ob] mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A [sup.y]/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis., Author(s): Yong Qi [1]; Nobuhiko Takahashi [1]; Stanley M Hileman [2]; Hiralben R Patel [1]; Anders H Berg [3]; Utpal B Pajvani [3]; Philipp E Scherer [3]; Rexford S Ahima [...]

Acrp30 is a circulating protein synthesized in adipose tissue. A single injection in mice of purified recombinant Acrp30 leads to a 2-3-fold elevation in circulating Acrp30 levels, which triggers a transient decrease in basal glucose levels. Similar treatment in ob/ob, NOD (non-obese diabetic) or streptozotocin-treated mice transiently abolishes hyperglycemia. This effect on glucose is not associated with an increase in insulin levels. Moreover, in isolated hepatocytes, Acrp30 increases the ability of sub-physiological levels of insulin to suppress glucose production. We thus propose that Acrp30 is a potent insulin enhancer linking adipose tissue and whole-body glucose metabolism., Author(s): Anders H. Berg [1, 4]; Terry P. Combs [1, 4]; Xueliang Du [2]; Michael Brownlee [2, 3]; Philipp E. Scherer (corresponding author) [1, 3] Adipose tissue, in addition to [...]

Background Protein carbamylation is a post-translational protein modification caused, in part, by exposure to urea's dissociation product cyanate. Carbamylation is linked to cardiovascular outcomes and mortality in dialysis-dependent end-stage kidney disease (ESKD), but its effects in earlier pre-dialysis stages of chronic kidney disease (CKD) are not established. Methods We conducted two nested case–control studies within the Chronic Renal Insufficiency Cohort Study. First, we matched 75 cases demonstrating CKD progression [50% estimated glomerular filtration rate (eGFR) reduction or reaching ESKD] to 75 controls (matched on baseline eGFR, 24-h proteinuria, age, sex and race). In the second study, we similarly matched 75 subjects who died during follow-up (cases) to 75 surviving controls. Baseline carbamylated albumin levels (C-Alb, a validated carbamylation assay) were compared between cases and controls in each study. Results At baseline, in the CKD progression study, other than blood urea nitrogen (BUN) and smoking status, there were no significant differences in any matched or other parameter. In the mortality group, the only baseline difference was smoking status. Adjusting for baseline differences, the top tertile of C-Alb was associated with an increased risk of CKD progression [odds ratio (OR) = 7.9; 95% confidence interval (CI) 1.9–32.8; P = 0.004] and mortality (OR = 3.4; 95% CI 1.0–11.4; P = 0.05) when compared with the bottom tertile. C-Alb correlated with eGFR but was more strongly correlated with BUN. Conclusions Our data suggest that protein carbamylation is a predictor of CKD progression, beyond traditional risks including eGFR and proteinuria. Carbamylation's association with mortality was smaller in this limited sample size. [ABSTRACT FROM AUTHOR]

Background: Bioavailable 25-hydroxyvitamin D (25OHD) may be a better indicator of vitamin D sufficiency than total 25OHD. This report describes a novel assay for measuring serum bioavailable 25OHD. Methods: We developed an assay for 25OHD % bioavailability based on competitive binding of 25OHD tracer between vitamin D-binding protein (DBP)-coated affinity chromatography beads and serum DBP. Bioavailable 25OHD, total 25OHD, albumin, and DBP protein concentrations were measured in 89 samples from hospitalized patients and 42 healthy controls to determine how the DBP binding assay responds to differences in concentrations of DBP and compares to calculated bioavailable 25OHD values. Results: DBP binding assay showed a linear relationship between DBP-bound 25OHD tracer recovered from bead supernatant and DBP calibrator concentrations (y = 0.0017x +0.731, R2 = 0.9961, p<0.001). Inversion of this relationship allowed interpolation of DBP binding equivalents based upon 25OHD tracer recovered. The relationship between DBP binding equivalents and % bioavailability fits a non-linear curve, allowing calculation of % bioavailable 25OHD from DBP binding equivalents (y = 10.625x-0.817, R2 = 0.9961, p<0.001). In hospitalized patient samples, there were linear relationships between DBP protein concentrations and DBP binding equivalents (y = 0.7905x + 59.82, R2 = 0.8597, p<0.001), between measured vs. calculated % bioavailability (y = 0.9528 + 0.0357, R2 = 0.7200, p<0.001), and between absolute concentrations of measured vs. calculated bioavailable 25OHD (y = 1.2403 + 0.1221, R2 = 0.8913, p<0.001). Conclusions: The DBP-binding assay for bioavailable 25OHD shows expected changes in 25OHD % bioavailability in response to changes in DBP concentrations and concordance with calculated bioavailable 25OHD concentrations. [ABSTRACT FROM AUTHOR]

Background: Depression is a common complication of pregnancy and vitamin D deficiency is one biological risk factor for postpartum depression (PPD). Materials and Methods: We evaluated the ratio of 24,25(OH)2D and 25(OH)D serum concentrations referred to as the Vitamin D Metabolite Ratio (VMR), a new candidate biomarker during pregnancyand its relationship with PPD. Women were enrolled in the first trimester of pregnancy and followed through four timepoints. Results: A total of 89 women had complete depression, biomarker and demographic data and 34% were at risk for PPD (CES-D≥16). Stepwise multiple logistic regression models for PPD risk were carried out with eight predictors. Results showed that only lower VMR, OR = 1.43, 95% CI 1.10–1.86, p = 0.007, and Hispanic/Latina identification, OR = 3.83, 95% CI 1.44–10.92, p = 0.007 were significantly associated with higher PPD risk. Conclusion: Routine prenatal screening for vitamin D metabolites, particularly in Hispanic/Latina women, may identify women at risk for PPD. [ABSTRACT FROM AUTHOR]

Introduction: This study examines the metabolomic profile in humans following acetaminophen (APAP) induced subclinical hepatoxicity in the presence and absence of propylene glycol (PG), a cytochrome P450 2E1 inhibitor. Methods: Plasma samples were collected during a previously performed randomized, cross-over trial where 21 subjects received APAP, four grams daily for two weeks in one arm and APAP, four grams daily with 20 mL PG in a second arm. Plasma collected at baseline and at day nine of each arm(time of peak elevation of liver function tests) underwent metabolomic analysis. Results: There were reduced phase two metabolites in subjects who displayed liver injury. There was also decreased sulfonation capacity in all subjects as well as in subjects displaying liver injury relative to subjects not displaying liver injury as evidenced by decreased sulfonation of hepatically derived steroids. There were decreased levels of acylcarnitines in subjects who displayed liver injury relative to subjects not displaying liver injury, indicating inhibition of mitochondrial fatty acid β-oxidation. Conclusions: Daily APAP dosing led to saturation of metabolic pathways and inhibition of mitochondrial function in subjects displaying subclinical liver injury. [ABSTRACT FROM AUTHOR]

Importance: Certain individuals, when infected by SARS-CoV-2, tend to develop the more severe forms of Covid-19 illness for reasons that remain unclear. Objective: To determine the demographic and clinical characteristics associated with increased severity of Covid-19 infection. Design: Retrospective observational study. We curated data from the electronic health record, and used multivariable logistic regression to examine the association of pre-existing traits with a Covid-19 illness severity defined by level of required care: need for hospital admission, need for intensive care, and need for intubation. Setting: A large, multihospital healthcare system in Southern California. Participants: All patients with confirmed Covid-19 infection (N = 442). Results: Of all patients studied, 48% required hospitalization, 17% required intensive care, and 12% required intubation. In multivariable-adjusted analyses, patients requiring a higher levels of care were more likely to be older (OR 1.5 per 10 years, P<0.001), male (OR 2.0, P = 0.001), African American (OR 2.1, P = 0.011), obese (OR 2.0, P = 0.021), with diabetes mellitus (OR 1.8, P = 0.037), and with a higher comorbidity index (OR 1.8 per SD, P<0.001). Several clinical associations were more pronounced in younger compared to older patients (Pinteraction<0.05). Of all hospitalized patients, males required higher levels of care (OR 2.5, P = 0.003) irrespective of age, race, or morbidity profile. Conclusions and relevance: In our healthcare system, greater Covid-19 illness severity is seen in patients who are older, male, African American, obese, with diabetes, and with greater overall comorbidity burden. Certain comorbidities paradoxically augment risk to a greater extent in younger patients. In hospitalized patients, male sex is the main determinant of needing more intensive care. Further investigation is needed to understand the mechanisms underlying these findings. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP)‐induced liver injury is initiated by metabolism of APAP by the cytochrome P‐450 (CYP) system, primarily CYP2E1. We previously demonstrated CYP inhibition following administration of a liquid APAP formulation containing propylene glycol, a CYP2E1 inhibitor, and other excipients. This study was undertaken to determine if propylene glycol specifically inhibits production of CYP‐derived metabolites and if propylene glycol reduces the rise in alanine aminotransferase (ALT) seen following prolonged APAP dosing. Human subjects were randomized to receive 4 g of APAP daily in one arm of the study or 4 g of APAP with 5 mL of 99% propylene glycol in the other arm, both for 14 days. After a washout period of at least 14 days, subjects were crossed over between arms. Outcomes were rise of ALT greater than 2 times baseline (responders) and proportion of randomly sampled CYP‐derived metabolites relative to total metabolites produced. There was no difference in percentage of responders between treatment groups: 6 of 21 in the APAP group (29%) compared with 8 of 20 in the APAP + propylene glycol group (40%); chi‐square, P = .59. For all subjects, the mean percentage of CYP‐derived metabolites produced was 5.8% (APAP) versus 4.3% (APAP + propylene glycol); P = .018. This effect was solely attributable to the responders: the mean percentage of CYP metabolites of responders was 7.7% (APAP) versus 4.6% (APAP + propylene glycol), P = .050, whereas there was no difference for the nonresponders. Five subjects were responders in both arms (2% probability of random occurrence). Our data indicates that propylene glycol inhibits CYP2E1 metabolism of APAP in some subjects but does not effect hepatocellular indury at the dose given. [ABSTRACT FROM AUTHOR]

Introduction Among conventional hemodialysis (CHD) patients, carbamylated serum albumin (C-Alb) correlates with urea and amino acid deficiencies and is associated with mortality. We postulated that reduction of C-Alb by intensive HD may correlate with improvements in protein metabolism and cardiac function. Methods One-year observational study of in-center nocturnal extended hemodialysis (EHD) patients and CHD control subjects. Thirty-three patients receiving 4-hour CHD who converted to 8-hour EHD were enrolled, along with 20 controls on CHD. Serum C-Alb, biochemistries, and cardiac MRI parameters were measured before and after 12 months of EHD. Findings EHD was associated with reduction of C-Alb (average EHD change −3.20 mmol/mol [95% CI −4.23, −2.17] compared to +0.21 [95% CI −1.11, 1.54] change in CHD controls, P < 0.001). EHD was also associated with increases in average essential amino acids (in standardized units) compared to CHD (+0.38 [0.08, 0.68 95%CI]) vs. −0.12 [−0.50, 0.27, 95% CI], P = 0.047). Subjects who reduced C-Alb more than 25% were found to have reduced left ventricular mass, increased urea reduction ratio, and increased serum albumin compared to nonresponders, and % change in C-Alb significantly correlated with % change in left ventricular mass. Discussion EHD was associated with reduction of C-Alb as compared to CHD, and reduction of C-Alb by EHD correlates with reduction of urea. Additional studies are needed to test whether reduction of C-Alb by EHD also correlates with improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Changes in Arctic sea ice have raised questions about changes in sea ice drift patterns. Reduced sea ice coverage may open up the Arctic to further exploration of maritime activities, particularly during the summer months. Given such changes, it is important to investigate differences between available sea ice drift products. Products based on synthetic aperture radar (SAR), radar scatterometer, and radiometer are compared for both motion speed and direction within this study. Two C-band SAR and one L-band SAR product are used in the comparison. Differences in temporal and spatial resolutions of the drift estimates spanning from July 2010 until June 2011 are investigated. High temporal and spatial resolution was proven useful to fully capture the sea ice drift in the Fram Strait. For summer coverage, SAR data are a prerequisite and L-band is desirable. The two C-band SAR products have a mean speed correlation of 0.90 and exhibit high conformity, despite being generated by separate processing methods. The L-band SAR product and the scatterometer and radiometer products are to a lower degree in agreement with each other and the C-band SAR products, which may be attributed to the products’ dependency on the temporal baseline. Depending on the choice of sensor or combination of sensors, the resulting 12-month mean drift varies between 0.09 and 0.12 m/s excluding L-band SAR. The latter shows a particularly low drift of 0.05 m/s, which we attribute to an over-representation of slow ice. [ABSTRACT FROM PUBLISHER]

Objective: Angiogenic factors are strongly associated with adverse maternal and fetal outcomes among women with preterm preeclampsia (PE) in developed countries. We evaluated the role of angiogenic factors and their relationship to adverse outcomes among Haitian women with PE. Material and Methods: We measured plasma antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) levels in women with PE (n=35) compared to controls with no hypertensive disorders (NHD) (n=43) among subjects with singleton pregnancies that delivered at Hospital Albert Schweitzer (HAS) in Haiti. We divided the preeclamptic women into two groups, early onset (≤ 34 weeks) and late onset (>34 weeks) and examined relationships between sFlt1/PlGF ratios on admission and adverse outcomes (abruption, respiratory complications, stroke, renal insufficiency, eclampsia, maternal death, birth weight <2500 grams, or fetal/neonatal death) in women with PE subgroups as compared to NHD groups separated by week of admission. Data are presented as median (25th-75th centile), n (%), and proportions. Results: Among patients with PE, most (24/35) were admitted at term. Adverse outcome rates in PE were much higher among the early onset group compared to the late onset group (100.0% vs. 54.2%, P=0.007). Plasma angiogenic factors were dramatically altered in both subtypes of PE. Angiogenic factors also correlated with adverse outcomes in both subtypes of PE. The median sFlt1/PlGF ratios for subjects with early onset PE with any adverse outcome vs. NHD <=34 weeks with no adverse outcome were 703.1 (146.6, 1614.9) and 9.6 (3.5, 58.6); P<0.001). Among late onset group the median sFlt1/PlGF ratio for women with any adverse outcome was 130.7 (56.1, 242.6) versus 22.4 (10.2, 58.7; P=0.005) in NHD >34 weeks with no adverse outcome. Conclusion: PE-related adverse outcomes are common in women in Haiti and are associated with profound angiogenic imbalance regardless of gestational age at presentation. [ABSTRACT FROM AUTHOR]