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Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse β cells lacking γ-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced β cell stress. In human islets, γ-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a γ-carboxylated ER-resident Ca2+-binding protein expressed in β cells. Mechanistically, γ-carboxylation of ERGP protects cells against Ca2+ overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca2+ entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca2+ flux in β cells and in their capacity to adapt to metabolic stress. [Display omitted] • Vitamin K-dependent carboxylation regulates glucose-stimulated insulin secretion • ERGP is a γ-carboxylated protein controlling store-operated calcium entry • ERGP γ-carboxylation reduces STIM1 and Orai1 puncta formation • Decarboxylated ERGP causes calcium overfilling in β cells and hyperinsulinemia Reduced vitamin K (VK) intake is associated with an increased risk of developing type 2 diabetes. Lacombe et al. demonstrate that VK-dependent carboxylation is necessary for β cell adaptation in mice fed a high-fat diet. The underlying mechanism involves ERGP, a carboxylated protein that regulates store-operated calcium entry in β cells. [ABSTRACT FROM AUTHOR]

Defining a suitable product presentation with an acceptable stability profile over its intended shelf-life is one of the principal challenges in bioproduct development. Accelerated stability studies are routinely used as a tool to better understand long-term stability. Data analysis often employs an overall mass action kinetics description for the degradation and the Arrhenius relationship to capture the temperature dependence of the observed rate constant. To improve predictive accuracy and precision, the current work proposes a least-squares estimation approach with a single nonlinear covariate and uses a polynomial to describe the change in a product attribute with respect to time. The approach, which will be referred to as Arrhenius time-scaled ( ATS) least squares, enables accurate, precise predictions to be achieved for degradation profiles commonly encountered during bioproduct development. A Monte Carlo study is conducted to compare the proposed approach with the common method of least-squares estimation on the logarithmic form of the Arrhenius equation and nonlinear estimation of a first-order model. The ATS least squares method accommodates a range of degradation profiles, provides a simple and intuitive approach for data presentation, and can be implemented with ease. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2278-2286, 2014 [ABSTRACT FROM AUTHOR]

• Styphylococcus aureus bacteremia (SAB) is common in low and middle-income countries (LMIC). • LMIC are poorly represented in SAB research. • In-hospital mortality for SAB is much higher in LMIC than in high-income countries. Staphylococcus aureus bacteremia (SAB) is a common infection worldwide. We compared SAB mortality in low- and middle-income countries (LMIC) versus high-income countries (HIC) in a meta-analysis. We searched MEDLINE, Embase, and Cochrane Database of Systematic Reviews from 1991-2021 and included observational, single-country studies on patients with positive blood cultures for S. aureus. The main outcome was the proportion of patients with SAB who died in the hospital. A generalized linear mixed random-effects model was used to pool estimates, and a meta-regression was used to adjust for study-level characteristics. A total of 332 studies involving 517,671 patients in 39 countries were included. No study was conducted in a low-income country. Only 33 (10%) studies were performed in middle-income countries (MIC), which described 6,216 patients. The pooled in-hospital mortality was 32.4% (95% confidence interval [CI] 27.2%-38.2%, T2 = 0.3063) in MIC and 22.3% (95% CI 20.1%-24.6%, T2 = 0.3257) in HIC. In a meta-regression model, MIC had higher in-hospital mortality (adjusted odds ratio 1.37, 95% CI 1.11-1.71; P = 0.0042) than HIC. In SAB studies, LMIC are poorly represented. In-hospital mortality was significantly higher in MIC than in HIC. Research should be conducted in LMIC to characterize differences in care processes driving the mortality gap. [ABSTRACT FROM AUTHOR]

Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies. We performed a systematic review and meta-analysis to estimate all-cause mortality in SAB and explore mortality change over time. The MEDLINE and Embase databases, as well as the Cochrane Database of Systematic Reviews, were searched from January 1, 1991 to May 7, 2021. Human observational studies on patients with S. aureus bloodstream infection were included. The study analyzed data of patients with a positive blood culture for S. aureus. Two independent reviewers extracted study data and assessed risk of bias using the Newcastle–Ottawa Scale. A generalized, linear, mixed random effects model was used to pool estimates. A total of 341 studies were included, describing a total of 536,791 patients. From 2011 onward, the estimated mortality was 10.4% (95% CI, 9.0%–12.1%) at 7 days, 13.3% (95% CI, 11.1%–15.8%) at 2 weeks, 18.1% (95% CI, 16.3%–20.0%) at 1 month, 27.0% (95% CI, 21.5%–33.3%) at 3 months, and 30.2% (95% CI, 22.4%–39.3%) at 1 year. In a meta-regression model of 1-month mortality, methicillin-resistant S. aureus had a higher mortality rate (adjusted OR (aOR): 1.04; 95% CI, 1.02–1.06 per 10% increase in methicillin-resistant S. aureus proportion). Compared with prior to 2001, more recent time periods had a lower mortality rate (aOR: 0.88; 95% CI, 0.75–1.03 for 2001–2010; aOR: 0.82; 95% CI, 0.69–0.97 for 2011 onward). SAB mortality has decreased over the last 3 decades. However, more than one in four patients will die within 3 months, and continuous improvement in care remains necessary. [ABSTRACT FROM AUTHOR]