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ContextIt has been well established that the human gut microbiome plays a critical role in the regulation of important biological processes and the mechanisms underlying numerous complex diseases. Although researchers have only recently begun to study the relationship between the gut microbiota and bone metabolism, early efforts have provided increased evidence to suggest an important association.Evidence AcquisitionIn this study, we attempt to comprehensively summarize the relationship between the gut microbiota and bone metabolism by detailing the regulatory effects of the microbiome on various biological processes, including nutrient absorption and the intestinal mucosal barrier, immune system functionality, the gut–brain axis, and excretion of functional byproducts. In this review, we incorporate evidence from various types of studies, including observational, in vitro and in vivo animal experiments, as well as small efficacy clinic trails.Evidence SynthesisWe review the various potential mechanisms of influence for the gut microbiota on the regulation of bone metabolism and discuss the importance of further examining the potential effects of the gut microbiota on the risk of osteoporosis in humans. Furthermore, we outline some useful tools/approaches for metagenomics research and present some prominent examples of metagenomics association studies in humans.ConclusionCurrent research efforts, although limited, clearly indicate that the gut microbiota may be implicated in bone metabolism, and therefore, further exploration of this relationship is a promising area of focus in bone health and osteoporosis research. Although most existing studies investigate this relationship using animal models, human studies are both needed and on the horizon.We summarized potential mechanisms of gut microbiota on regulation of bone mass, outlined some useful tools for metagenomics, and presented examples of metagenome-wide association studies.

Calcium is an important integrative component of the human body and critical for human health. It has been well established that calcium intake is helpful in the prevention and treatment of osteoporosis, which has become one of the most serious public health problems across the world. However, community-dwelling adults with and without osteoporosis are rarely concerned or even not aware of the potential side effects of high or inappropriate doses of calcium intake. Some recent studies have revealed that excessive calcium intake might increase the risks of cardiovascular diseases. The purpose of this article was to review the health benefits, costs, and consequences of calcium supplementation on osteoporosis/osteoporotic fractures, cardiovascular events, kidney stones, gastrointestinal diseases, and other important diseases. In the end, we suggest that calcium supplementation should be prescribed and taken cautiously, accounting for individual patients' risks and benefits. Clearly, further studies are needed to examine the health effects of calcium supplementation to make any solid recommendations for people of different genders, ages, and ethnicities.

Although the gut microbiota has been reported to influence osteoporosis risk, the individual species involved, and underlying mechanisms, remain largely unknown. We performed integrative analyses in a Chinese cohort of peri-/post-menopausal women with metagenomics/targeted metabolomics/whole-genome sequencing to identify novel microbiome-related biomarkers for bone health. Bacteroides vulgatus was found to be negatively associated with bone mineral density (BMD), which was validated in US white people. Serum valeric acid (VA), a microbiota derived metabolite, was positively associated with BMD and causally downregulated by B. vulgatus . Ovariectomized mice fed B. vulgatus demonstrated increased bone resorption and poorer bone micro-structure, while those fed VA demonstrated reduced bone resorption and better bone micro-structure. VA suppressed RELA protein production (pro-inflammatory), and enhanced IL10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells and enhanced maturation of osteoblasts in vitro. The findings suggest that B. vulgatus and VA may represent promising targets for osteoporosis prevention/treatment. Gut microbiota has been reported to influence osteoporosis risk, but the individual species, and underlying mechanisms, remain largely unknown. Here, the authors identify Bacteroides vulgatus and serum valeric acid as potential targets for osteoporosis prevention/treatment.

Schwann cells (SCs) support axonal function and promote nerve regeneration. This study investigated how various glucose concentrations influence SC viability, oxidative stress, and autophagy, which contribute to diabetic neuropathy. RSC96 SCs were cultured under five glucose conditions (0, 2.5, 5.5, 50, or 100 mM) for 24, 48, and 72 h. Cell viability was assessed by MTT; ROS levels were determined by DCFDA staining, and apoptosis and ER stress markers, as well as autophagy‐related proteins were assessed by Western blotting. Autophagic flux was also analyzed using bafilomycin A1 and Cyto‐ID. The results revealed time‐dependent increases in cell death across all glucose conditions, especially under deprivation and low glucose (LG) conditions. ROS, CHOP, Bax, and cleaved caspase‐3 levels increased from 24 to 72 h. The initial increase in the LC3B‐II/I ratio indicated that autophagy was overactivated under glucose deprivation or LG conditions but impaired by 72 h, as indicated by reduced Lamp‐2 expression. High glucose conditions led to early and persistent autophagy suppression, with minimal autophagic flux and vacuole formation. These findings demonstrate that SCs are sensitive to glucose levels and undergo distinct autophagic impairments through different mechanisms under persistent low or high glucose environments.

We have studied the characteristics of frequency response at 850-nm GaAs high-speed vertical-cavity surface-emitting lasers (VCSELs) with different kinds of oxide aperture sizes and cavity length using the PICS3D simulation program. Using 5-μm oxide aperture sizes, the frequency response behavior can be improved from 18.4 GHz and 15.5 GHz to 21.2 GHz and 19 GHz in a maximum of 3 dB at 25 °C and 85 °C, respectively. Numerical simulation results also suggest that the frequency response performances improved from 21.2 GHz and 19 GHz to 30.5 GHz and 24.5 GHz in a maximum of 3 dB at 25 °C and 85 °C due to the reduction of cavity length from 3λ/2 to λ/2. Consequently, the high-speed VCSEL devices were fabricated on a modified structure and exhibited 50-Gb/s data rate at 85 °C.

Background Taiwan is a super-aged society, and the shortage of hospital doctors; nurse practitioners (NPs) became vital healthcare providers to fulfill the healthcare demands of the population. The purpose of this study was to explore the key determinates of job satisfaction for NPs in acute care practices using significant practice variables, such as empowerment and burnout. Methods Participants of this descriptive survey study were recruited from a national sample of NPs with membership in the Taiwan Association of Nurse Practitioners. The data were collected utilizing an online questionnaire based on demographic and practice variables, the Misener Nurse Practitioner Job Satisfaction Scale (MNPJSS), the Condition for Work Effectiveness Questionnaire II (CWEQ II), and the Copenhagen Burnout Inventory (CBI). A total of 1,211 NPs completed the online survey. A multiple regression model with the stepwise selection was used to explore job satisfaction. Results The mean overall satisfaction score indicated that the level of satisfaction was between slightly dissatisfied and slightly satisfied. Regression results indicated that formal power, work-related burnout, access to information, and needed resources were critical components of job satisfaction, and accounted for 63% of the variance. Moreover, NPs who were married, had a higher annual salary, worked only during the day shift, and had lower patients-related burnout showed better job satisfaction. Conclusions This study provides evidence for healthcare organizations to formulate policies to strengthen NP job satisfaction. Empowerment and burnout are vital factors in NPs’ job satisfaction. Healthcare organizations have an obligation to implement policies to empower NPs in practice and provide interventions to mitigate burnout. Implementing these changes will improve job satisfaction and with it the quality of patient care.

Abstract Context Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. Objective We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri- and postmenopausal women. Design and Methods We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. Results Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. Dodecanoic acid treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (eg,10, 100 μM). Conclusions This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

•Three doses of amphotericin B colloidal dispersion (ABCD) (0.5, 1.0, and 1.5 mg/kg) were well tolerated in the healthy Chinese subjects, and the plasma concentrations fitted a three-compartment model of PK.•PPK modeling extrapolated the exposure of standard dose (3 and 4 mg/kg) ABCD in patients.•PK/PD analysis and Monte Carlo simulations predicted that 3 or 4 mg/kg qd for 14-28 days after intravenous injection of ABCD will be efficacious against IFIs caused by C. albicans with an MIC≤2 or 4 mg/L (PTA>90% and CFR>98%). Amphotericin B colloidal dispersion (ABCD) is a less toxic formulation of amphotericin B for the treatment of invasive fungal infections. The pharmacokinetic (PK) profile and safety of a generic ABCD were investigated after a single dose (0.5 to 1.5 mg/kg) administered as an intravenous infusion in 30 healthy Chinese subjects. PK data from healthy Chinese male subjects were applied for developing a population PK model to predict the PK profiles of standard doses (3 or 4 mg/kg) in patients. A 5000-time Monte Carlo simulation of AUC0–24/MIC target was implemented to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) under standard doses. The PK profiles of intravenous administration of ABCD were best described by a 3-compartmental model with a time-varying clearance and a dose-dependent volume of distribution in the peripheral compartment. PK/pharmacodynamic (PK/PD) analysis revealed that 3 or 4 mg/kg ABCD once a day resulted in favorable CRF (>98%) with 2-log reduction of Candida albicans. A high PTA (>90%) was achieved at MIC ≤2 mg/L for the dosing regimen of ABCD 3 mg/kg and 4 mg/kg for MIC ≤4 mg/L. PK/PD analysis indicated that a favorable efficacy of ABCD could be reached at a dose of 3 or 4 mg/kg once daily for 14 to 28 days to treat invasive fungal infections caused by C albicans. ClinicalTrials.gov identifier: NCT03577509.

Many respiratory but few arterial blood pharmacokinetics of desflurane uptake and disposition have been investigated. We explored the pharmacokinetic parameters in piglets by comparing inspiratory, end-tidal, arterial blood, and mixed venous blood concentrations of desflurane. Seven piglets were administered inspiratory 6% desflurane by inhalation over 2 h, followed by a 2-h disposition phase. Inspiratory and end-tidal concentrations were detected using an infrared analyzer. Femoral arterial blood and pulmonary artery mixed venous blood were sampled to determine desflurane concentrations by gas chromatography at 1, 3, 5, 10, 20, 30, 40, 50, 60, 80, 100, and 120 min during each uptake and disposition phase. Respiratory and hemodynamic parameters were measured simultaneously. Body uptake and disposition rates were calculated by multiplying the difference between the arterial and pulmonary artery blood concentrations by the cardiac output. The rates of desflurane body uptake increased considerably in the initial 5 min (79.8 ml.min ) and then declined slowly until 120 min (27.0 ml.min ). Similar characteristics of washout were noted during the subsequent disposition phase. Concentration-time curves of end-tidal, arterial, and pulmonary artery blood concentrations fitted well to zero-order input and first-order disposition kinetics. Arterial and pulmonary artery blood concentrations were best fitted using a two-compartment model. After 2 h, only 21.9% of the desflurane administered had been eliminated from the body. Under a fixed inspiratory concentration, desflurane body uptake in piglets corresponded to constant zero-order infusion, and the 2-h disposition pattern followed first-order kinetics and best fitted to a two-compartment model.

Previous studies have demonstrated the genetic correlations between type 2 diabetes, obesity and dyslipidemia, and indicated that many genes have pleiotropic effects on them. However, these pleiotropic genes have not been well-defined. It is essential to identify pleiotropic genes using systematic approaches because systematically analyzing correlated traits is an effective way to enhance their statistical power. To identify potential pleiotropic genes for these three disorders, we performed a systematic analysis by incorporating GWAS (genome-wide associated study) datasets of six correlated traits related to type 2 diabetes, obesity and dyslipidemia using Meta-CCA (meta-analysis using canonical correlation analysis). Meta-CCA is an emerging method to systematically identify potential pleiotropic genes using GWAS summary statistics of multiple correlated traits. 2,720 genes were identified as significant genes after multiple testing (Bonferroni corrected p value < 0.05). Further, to refine the identified genes, we tested their relationship to the six correlated traits using VEGAS-2 (versatile gene-based association study-2). Only the genes significantly associated (Bonferroni corrected p value < 0.05) with more than one trait were kept. Finally, 25 genes (including two confirmed pleiotropic genes and eleven novel pleiotropic genes) were identified as potential pleiotropic genes. They were enriched in 5 pathways including the statin pathway and the PPAR (peroxisome proliferator-activated receptor) Alpha pathway. In summary, our study identified potential pleiotropic genes and pathways of type 2 diabetes, obesity and dyslipidemia, which may shed light on the common biological etiology and pathogenesis of these three disorders and provide promising insights for new therapies.