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Sanicula (Apiaceae subfam. Saniculoideae) is a taxonomically difficult genus of medicinal value. Its distribution center is in China, where there are 18 species (11 of which are endemic). To provide plastid genome resources, whole chloroplast genomes of five Sanicula species (S. flavovirens, S. giraldii, S. lamelligera, S. odorata and S. rubriflora) were sequenced and compared to the previously published S. orthacantha plastome. These genomes exhibit a typical quadripartite structure. All contain 129 different genes, including 84 protein‐coding, 37 tRNA and 8 rRNA genes. The loci rpl2, matK, psbA and ycf1 are the most variable. Results of maximum likelihood analysis of 90 whole plastome sequences from Apioideae and Saniculoideae and the outgroup Hydrocotyle (Araliaceae) suggest sectional relationships in Sanicula different from the traditional classification system, but support the monophyly of Apioideae and its sister group relationship to Saniculoideae and show concordant topologies to nrDNA ITS and other plastome‐based phylogenies. Sanicula orthacantha and S. chinensis form a sister group to S. lamelligera and S. odorata, consecutively. These four species comprise a sister group to the clade of S. rubriflora and S. flavovirens, with this entire group sister to S. giraldii. The plastid genome resources provided herein will be important for future systematic, evolutionary, phylogenomic and population‐level studies of Sanicula. [ABSTRACT FROM AUTHOR]

We developed a three-step matching algorithm to enhance the between-group comparability for comparative drug effect studies involving prevalent new-users of the newer study drug versus older comparator drug(s). The three-step matching scheme is to match on: (1) index date of initiating the newer study drug to align the cohort entry time between study groups, (2) medication possession ratio measures that consider prior exposure to all older comparator drugs, and (3) propensity scores estimated from potential confounders. Our approach is illustrated with a comparative cardiovascular safety study of glucagon-like peptide-1 receptor agonist (GLP-1ra) versus sulfonylurea (SU) in type 2 diabetes patients using Taiwan's National Health Insurance Research Database 2003–2015. 66% of 3195 GLP-1ra users had previously exposed to SU. The between-group comparability was well-achieved after implementing the matching algorithm (i.e., standardized mean difference < 0.2 for all baseline patient characteristics). Compared to SU, the use of GLP-1ra yielded a significantly reduced risk of the primary composite cardiovascular events (hazard ratio [95% confidence interval]: 0.71 [0.54–0.95], p = 0.022). Our matching scheme can enhance the between-group comparability in prevalent new-user cohort designs to minimize time-related bias, improve confounder adjustment, and ensure the reliability and validity of study findings. [ABSTRACT FROM AUTHOR]

Background: Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain.Objective and Rationale: This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI.Search Methods: PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET).Outcomes: This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies.Wider Implications: This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions. [ABSTRACT FROM AUTHOR]

Background: Whether accelerated aging develops over the course of chronic human immunodeficiency virus (HIV) infection or can be observed before significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) before the initiation of antiretroviral therapy (ART).Methods: A total of 378 ART-naive PLWH who had CD4 T-cell counts >500/µL and were enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared with 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in PLWH compared with controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock.Results: There were a total of 56 639 DMPs and 6103 DMRs at a false discovery rate of <0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age than HIV-negative controls (P = .001), with black race, low CD4 and high CD8 T-cell counts, and duration of HIV being risk factors for age acceleration.Conclusions: PLWH before the initiation of ART and with preserved immune status show evidence of advanced methylation aging. [ABSTRACT FROM AUTHOR]

Abnormal angiogenesis and regression of the diseased retinal vasculature are key processes associated with ischemic retinopathies, but the underlying mechanisms that regulate vascular remodeling remain poorly understood. Here, we confirmed the specific expression of semaphorin 3G (Sema3G) in retinal endothelial cells (ECs), which was required for vascular remodeling and the amelioration of ischemic retinopathy. We found that Sema3G was elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and in the neovascularization regression phase of oxygen-induced retinopathy (OIR). Endothelial-specific Sema3G knockout mice exhibited decreased vessel density and excessive matrix deposition in the retinal vasculature. Moreover, loss of Sema3G aggravated pathological angiogenesis in mice with OIR. Mechanistically, we demonstrated that HIF-2α directly regulated Sema3G transcription in ECs under hypoxia. Sema3G coordinated the functional interaction between β-catenin and VE-cadherin by increasing β-catenin stability in the endothelium through the neuropilin-2 (Nrp2)/PlexinD1 receptor. Furthermore, Sema3G supplementation enhanced healthy vascular network formation and promoted diseased vasculature regression during blood vessel remodeling. Overall, we deciphered the endothelium-derived Sema3G-dependent events involved in modulating physiological vascular remodeling and regression of pathological blood vessels for reparative vascular regeneration. Our findings shed light on the protective effect of Sema3G in ischemic retinopathies. [ABSTRACT FROM AUTHOR]

Objective: To compare the composite neonatal and maternal adverse outcomes among low-risk pregnant women who labor and subsequently deliver at different time shifts.Methods: This was a population-based retrospective cohort study using the U.S. vital statistics data set on Period Linked Birth-Infant Death Data from 2012 to 2016. The study population was restricted to live births from low-risk women with nonanomalous singletons who labored and delivered at 37 0/7 to 41 6/7 weeks of gestation. Time of delivery was categorized as the first shift (7:00-15:00), the second shift (15:00-23:00), and the third shift (23:00-7:00). The primary outcome was composite neonatal adverse outcome, and the secondary outcome was composite maternal adverse outcome. Multivariable Poisson regression models were used to estimate the association between the time of delivery and adverse outcomes (using adjusted relative risk [aRR] and 95% CI).Results: Of 19.9 million live births during the study period, 58.8% (more than 11.6 million) met the inclusion criteria. The overall composite neonatal adverse outcome was 6.6 per 1,000 live births. The multivariable adjusted analysis demonstrated that, compared with neonates delivered at the first shift, the risk of composite neonatal adverse outcome was higher at the second shift (relative risk [RR] 1.15, aRR 1.07, 95% CI 1.05-1.09), and the third shift (RR 1.28, aRR 1.24, 95% CI 1.22-1.27). The overall composite maternal adverse outcome was 2.45 per 1,000 live births. After adjustment, there was no significant difference in the risk of composite maternal adverse outcome based on the time of delivery.Conclusion: Among low-risk singleton pregnancies, compared with delivery at 7:00-15:00, the composite neonatal adverse outcome is marginally but significantly higher if the delivery occurs at the second (15:00-23:00) and the third (23:00-7:00) shifts. The composite maternal adverse outcome is similar among the three different time shifts. [ABSTRACT FROM AUTHOR]

Older people with multimorbidity are usually required to manage multiple medications and complex medication regimens. However, clinical guidelines for medication management almost entirely focus on a single disease. Further research is needed to assess the efficacy of medication self-management interventions for older people with multimorbidity. This study aimed to evaluate the effectiveness of a nurse-led medication self-management intervention on medication adherence and health outcomes in older people with multimorbidity. A single-blind, two-arm randomised controlled trial. Three community health centres in Changsha, China. Older people with multimorbidity. A total of 136 participants were recruited and randomly allocated into either a 6-week nurse-led medication self-management intervention group (n = 67) or usual care group (n = 69). The intervention consisted of three one-on-one educational sessions on medication-related information, motivation and self-management skills and two follow-up phone calls. The primary outcome was medication adherence. Secondary outcomes included medication self-management capacity, treatment experiences, quality of life and utilisation of health care services. Outcomes were measured at baseline, post-intervention and 3-month follow-up. The intervention effects were assessed using generalised estimating equation models. Statistically significant improvements were found in medication adherence (β = 1.63, p = 0.034), medication knowledge (β = 2.61, p < 0.001), beliefs about harm of medication (β = − 1.83, p < 0.001), medication self-efficacy (β = 3.22, p < 0.001) and satisfaction with convenience of medication use (β = 5.02, p = 0.005) for the intervention group compared with the control group immediately post-intervention. Compared with the control group at 3 months follow-up, the intervention group demonstrated significantly greater improvements in medication knowledge (β = 2.26, p < 0.001), beliefs about necessity of medication (β = 2.68, p = 0.002) and concerns about medication (β = − 2.44, p = 0.002), medication self-efficacy (β = 1.87, p = 0.015) and medication burden (β = − 3.96, p = 0.004). Improved medication adherence was observed in the intervention group at 3 months follow-up compared with baseline, although the differences between the groups were not significant. No statistically significant effects were found on quality of life and utilisation of health care services at either time point. A 6-week medication self-management intervention significantly improved medication adherence immediately post-intervention, suggesting a short-term intervention effect. A longer intervention period and continuous follow-up support may be required to achieve sustained improvements in medication adherence and health outcomes in older people with multimorbidity. ChiCTR.org.cn (ChiCTR2000030011); Start of recruitment: June 2020. [ABSTRACT FROM AUTHOR]

Background: People with human immunodeficiency virus (PWH) have an increased risk of developing chronic obstructive pulmonary disease (COPD).Methods: We phenotyped lung macrophages in 4 subgroups-M1 (CD40+CD163-), M2 (CD40-CD163+), double positives (CD40+CD163+), and double negatives and (CD40-CD163-)-and we determined their phagocytic capacity in PWH with and without COPD.Results: People with human immunodeficiency virus with COPD have more double-negative macrophages (84.1%) versus PWH without (54.3%) versus controls (23.9%) (P=.004) and reduced phagocytosis (P=.012). Double-negative macrophages had the worst phagocytic capacity (P<.001).Conclusions: People with human immunodeficiency virus with COPD have an abundance of nonpolarized macrophages, which have poor phagocytic capacity and therefore predispose PWH to increased risk of disease progression. [ABSTRACT FROM AUTHOR]

Abstract: Heat transfer performance assessment was made for forced convection in a heated tube with a porous medium core and a tube with a wall covered with a porous medium layer, so as to investigate effectiveness of porous material insertion within a tube. Both local thermal and non-thermal equilibrium analyses were carried out for the two cases of partial porous medium filling, to investigate the validity of local thermal equilibrium assumption. It has been found that the local thermal non-equilibrium analysis is essential for the case of forced convection in a tube with a heated wall surface covered with a porous medium layer, whereas the local thermal equilibrium analysis suffices to capture transport phenomena for the case of forced convection in a tube with a porous medium core. In a comparatively low range of pumping power, the heat transfer performance of the tube with a porous medium core is higher than that of the tube with a wall covered with a porous medium layer. However, in a high range of pumping power, the latter performance exceeds the former. [Copyright &y& Elsevier]

Tomographic reconstruction from noisy projections do not yield adequate results. Mathematically, this tomographic reconstruction represents an ill-posed problem due to information missing caused by the presence of noise. Maximum a posteriori (MAP) or Bayesian reconstruction methods offer possibilities to improve the image quality as compared with analytical methods in particular by introducing a prior to guide the reconstruction and regularize the noise. With an aim to achieve robust utilization of continuity/connectivity information and overcome the heuristic weight update for other nonlocal prior methods, this paper proposes a novel patch similarity based mixture (PSM) prior model for tomographic reconstruction. This prior is defined by a weighted Gaussian distance between neighborhood intensities. The weight quantifies the similarity between local neighborhoods and is computed using a maximization entropy constraint. This prior is then introduced within a joint image/weight MAP computed tomography reconstruction algorithm. Several acceleration trials including Compute Unified Device Architecture (CUDA) parallelization is applied to alleviate the intensive patch distance computation involved in the joint algorithm. The method was tested with both synthetic phantoms and clinical computed tomography data and compared in accuracy with five other reconstruction algorithms which are filtered back-projection and Bayesian-based. Reconstruction results show that the proposed reconstructions are able to produce high-quality images with ensured iteration convergence. [ABSTRACT FROM AUTHOR]

Background: Ankle sprain is a common sports injury. While the effects of static constraints in stabilizing the ankle joint are relatively well understood, those of dynamic constraints are less clear and require further investigation.Purpose: This study was undertaken to evaluate the dynamic stability of the ankle joint during the landing phase of running and stop-jump maneuvers in athletes with and without chronic ankle instability (CAI).Study Design: Controlled laboratory study.Methods: Fifteen athletes with CAI and 15 age-matched athletes without CAI performed running and stop-jump landing tasks. The dynamic ankle joint stiffness, tibialis anterior (TA)/peroneus longus (PL) and TA/gastrocnemius lateralis (GL) co-contraction indices, ankle joint angle, and root-mean-square (RMS) of the TA, PL, and GL electromyographic signals were measured during each task.Results: During running, the CAI group exhibited a greater ankle inversion angle than the control group in the pre-landing phase (P = .012-.042) and a lower dynamic ankle joint stiffness in the post-landing phase (CAI: 0.109 ± 0.039 N·m/deg; control: 0.150 ± 0.068 N·m/deg; P = .048). In the stop-jump landing task, athletes with CAI had a significantly lower TA/PL co-contraction index during the pre-landing phase (CAI: 49.1 ± 19; control: 64.8 ± 16; P = .009). In addition, the CAI group exhibited a greater ankle inversion (P = .049), a lower peak eversion (P = .04), and a smaller RMS of the PL electromyographic signal in the post-landing phase (CAI: 0.73 ± 0.32; control: 0.51 ± 0.22; P = .04).Conclusion: Athletes with CAI had a relatively inverted ankle, reduced muscle co-contraction, and a lower dynamic stiffness in the ankle joint during the landing phase of sports maneuvers and this may jeopardize the stability of the ankle.Clinical Relevance: Sports training or rehabilitation programs should differentiate between the pre-landing and post-landing phases of sports maneuvers, and should educate athletes to land with an appropriate ankle position and muscle recruitment. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether abnormal plasma placental growth factor (PlGF) level is associated with adverse neonatal and maternal outcomes.Methods: This was a secondary analysis of the Preeclampsia Triage by Rapid Assay Trial (PETRA), a prospective, multicenter, observational study that enrolled women with suspected preeclampsia. Our analysis included women age 18-45 years with a singleton pregnancy between 20 and 41 weeks of gestation. Plasma collected at enrollment was used for PlGF measurement. Abnormal PlGF was defined as low (100 pg/mL or less) or very low (less than 12 pg/mL). The primary outcomes were composite adverse neonatal and maternal outcomes. We used multivariable Poisson regression models to examine the association between PlGF and outcomes.Results: Of 1,112 women who met the inclusion criteria, plasma PlGF was low in 742 (67%) and very low in 353 (32%). In the cohort, the overall rates of the composite adverse neonatal and maternal outcomes were 6.4% and 4.8%, respectively. Compared with normal PlGF (more than 100 pg/mL), low PlGF was significantly associated with an increased risk of the composite neonatal outcome (9.2% vs 0.8%; adjusted relative risk [aRR] 17.2, 95% CI 5.2-56.3), and the composite maternal outcome (6.2% vs 1.9%; aRR 3.6, 95% CI 1.7-8.0). Very low PlGF was also significantly associated with both neonatal and maternal outcomes. The sensitivity and specificity of low PlGF were 95.8% and 35.3%, respectively, for the composite neonatal outcome, and 86.8% and 34.3% for the composite maternal outcome. Although the positive predictive values were low (9.2% and 6.2%, respectively), the negative predictive value of low PlGF for neonatal and maternal outcomes was 99.2% and 98.1%, respectively.Conclusion: Among women being evaluated for preeclampsia, those with abnormal PlGF are significantly more likely to experience adverse neonatal and maternal outcomes. These outcomes occur infrequently when the PlGF is normal. These findings suggest that PlGF may be useful for risk stratification of women with suspected preeclampsia.Funding Source: No funding was received for this study. The original PETRA study was supported by funding from Alere. [ABSTRACT FROM AUTHOR]

An excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remain incompletely studied. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D. By performing BA-related metabolic and metagenomic analyses in 290 IBS-D patients and 89 healthy volunteers, we found that 24.5% of IBS-D patients exhibited excessive excretion of total BAs and alteration of BA-transforming bacteria in feces. Notably, the increase in Clostridia bacteria (e.g., C. scindens) was positively associated with the levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4), but negatively correlated with serum fibroblast growth factor 19 (FGF19) concentration. Furthermore, colonization with Clostridia-rich IBS-D fecal microbiota or C. scindens individually enhanced serum C4 and hepatic conjugated BAs but reduced ileal FGF19 expression in mice. Inhibition of Clostridium species with vancomycin yielded opposite results. Clostridia-derived BAs suppressed the intestinal FGF19 expression in vitro and in vivo. In conclusion, this study demonstrates that the Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients, which provides a mechanistic hypothesis with testable clinical implications. [ABSTRACT FROM AUTHOR]

Background: Shared links between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) have been well-known. A high concentration of advanced glycation end products (AGEs) has been reported to contribute to impaired mobility in patients with AD, but there is limited understanding regarding the longitudinal impact of AGEs on cognitive performance.Objective: This study aims to explore whether the concentrations of AGEs mediate the clinical progression of cognitive performance in patients with AD and T2DM.Methods: Twenty-five patients aged 79.0±5.8 years who were diagnosed with probable AD with a Clinical Dementia Rating (CDR) of 0.5 or 1 and T2DM were enrolled in this study. When patients participated in the study, the concentration of plasma AGEs was tested. A series of neuropsychological tests, namely the Mini-Mental Status Examination (MMSE), Cognitive Assessment Screening Instrument (CASI), and CDR, were performed annually during follow-up. The association between the concentration of AGEs and changes in overall cognition and cognition related daily living performance was analyzed.Results: After the mean 48.6±2.1 months of follow-up, AGEs were found to be significantly associated with a change in CDR. A total of 12 (48%) patients experienced a decline in CDR; they had a significantly higher concentration of AGEs than did those whose CDR did not deteriorate (100.5 ± 14.2 versus 81.5 ± 17.7; p = 0.007). This difference in CDR remained significant after adjustment for age, sex, education level, and apolipoprotein E4 status (adjusted p = 0.023).Conclusion: In conclusion, this study indicates that a high concentration of AGEs may be a predictor of a long-term decline in cognition related daily living performance in patients with AD and T2DM. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of oral carbohydrate at 2 h before elective cesarean section on postoperative recovery indicators such as the time to colostrum and vaginal bleeding. Methods: Women undergoing elective cesarean section under spinal‐epidural anesthesia, aged 20–40 years, with a body mass index (BMI) of 19–30 kg/m2 and an American Society of Anesthesiology (ASA) score of II were randomized to the oral carbohydrate group (the OC group), the oral placebo group (the OP group), or the control group (the C group). The OC group underwent oral carbohydrate preloading (300 mL/bottle), the OP group orally consumed 300 mL of distilled water, and the C group was forbidden from drinking or eating on the day of the operation. The time to colostrum, vaginal bleeding, time to exhaust, and complications were recorded. Results: A total of 38 participants in the OC group, 37 in the OP group, and 37 in the C group completed the study. Compared with the OP group and the C group, the OC group produced colostrum significantly earlier, had a lower amount of 24‐h vaginal bleeding, and had a higher 24‐h consumption of analgesics. Compared with OP and OC groups, the C group took longer to exhaust. No significant intergroup difference was observed for any other indicator. Conclusion: Oral carbohydrates loading 2 h before elective cesarean section significantly reduces the time to produce colostrum and the amount of vaginal bleeding, which contributes to postoperative recovery. [ABSTRACT FROM AUTHOR]

Objective. For investigating the efficacy and mechanism of Roxadustat + oral iron in the treatment of elderly chronic kidney disease (CKD) complicated with anemia. Methods. A total of 100 elderly patients with CKD and anemia admitted to our hospital between April 2020 and December 2021 were enrolled as research subjects, and the patients were assigned to control group (Con group, n = 50) or experimental group (Exp group, n = 50). The patients in the Con group were given oral iron, and those in the Exp group were given Roxadustat capsule based on the Con group. Both groups were given subcutaneous injection of recombinant human erythropoietin. The clinical efficacy, anemia indexes, iron metabolism indexes, inflammatory indexes, and adverse reactions were compared between the two groups. Results. The Exp group showed a notably higher treatment effective rate than the Con group (P < 0.05). After treatment, the anemia indexes, iron metabolism indexes, and inflammatory indexes in the Exp group were notably better than those in the Con group (P < 0.05). The Exp group showed a notably lower incidence of adverse reactions during treatment than the Con group (P < 0.05). Conclusion. Roxadustat plus oral iron yields a pronounced clinical efficacy in the therapy of elderly patients with CKD and anemia. [ABSTRACT FROM AUTHOR]

Objectives: Bacterial antibiotic tolerance is responsible for the recalcitrance of chronic infections. This study aims to investigate a potential drug that can effectively kill antibiotic-tolerant bacteria and evaluate the ability of this drug on the eradication of tolerant cells both in vitro and in vivo.Methods: The in vitro effect of econazole on eradicating starvation-induced tolerant bacterial populations was studied by testing the amount of survival bacteria in the presence of econazole combining conventional antibiotics. Proton motive force (PMF) was determined after econazole treatment by DiOC2(3). Finally, mouse infection models were used to detect the ability of econazole on killing the tolerant populations in vivo.Results: Econazole eradicated starvation-induced tolerant cells of various bacterial species within 24 or 96 h when used in combination with conventional antibiotics. Moreover, mouse survival rate drastically increased along with the decrease of in vivo bacterial count after treatment of infected mice with the econazole and ceftazidime combination for 72 h. PMF was found to have dissipated almost completely in econazole-treated cells.Conclusions: Econazole could act in combination with conventional antibiotics to effectively eradicate bacterial tolerant cells. The combined use of econazole and ceftazidime was shown to be effective for eradicating tolerant cells in a mouse infection model. The ability of econazole to eradicate tolerant cells was due to its ability to cause dissipation of bacterial transmembrane PMF. Econazole-mediated PMF disruption is a feasible strategy for the treatment of chronic and recurrent bacterial infections. [ABSTRACT FROM AUTHOR]

PEGylated recombinant human endostatin (M2ES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A non-clinical study was performed to evaluate the toxicokinetics and safety of M2ES in rhesus monkeys. After intravenous (IV) infusions of M2ES at a dose level of 3, 10, and 30mg/kg in rhesus monkeys, the concentration-time curves of M2ES were best fitted to a non-compartment model, and area under the curve (AUC) was positively correlated with the dosage. M2ES had a tendency to accumulate in vivo following successive IV infusions. Serum anti-M2ES IgG antibodies were generated quickly during IV administration, and the antibody level in serum did not significantly decrease after four-week recovery period. Animals administered IV infusions twice weekly (M2ES at 10 or 30mg/kg body weight per day) for 3 months developed mild or moderate vacuolation of proximal tubule epithelial cell in proximal convoluted tubule of kidney, but this adverse-effect was reversible. In summary, M2ES was well tolerated and did not cause any serious toxicity. These pre-clinical safety data contribute to the initiation of the ongoing clinical study. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin E (IgE) belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor (FcεR1) in pathological cardiac remodeling and heart failure are unknown.Methods: Serum IgE levels and cardiac FcεR1 expression were assessed in diseased hearts from human and mouse. The role of FcεR1 signaling in pathological cardiac remodeling was explored in vivo by FcεR1 genetic depletion, anti-IgE antibodies, and bone marrow transplantation. The roles of the IgE-FcεR1 pathway were further evaluated in vitro in primary cultured rat cardiomyocytes and cardiac fibroblasts (CFs). RNA sequencing and bioinformatic analyses were used to identify biochemical changes and signaling pathways that are regulated by IgE/FcεR1.Results: Serum IgE levels were significantly elevated in patients with heart failure as well as in 2 mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin II infusion. Interestingly, FcεR1 expression levels were also significantly upregulated in failing hearts from human and mouse. Blockade of the IgE-FcεR1 pathway by FcεR1 knockout alleviated transverse aortic constriction- or angiotensin II-induced pathological cardiac remodeling or dysfunction. Anti-IgE antibodies (including the clinical drug omalizumab) also significantly alleviated angiotensin II-induced cardiac remodeling. Bone marrow transplantation experiments indicated that IgE-induced cardiac remodeling was mediated through non-bone marrow-derived cells. FcεR1 was found to be expressed in both cardiomyocytes and CFs. In cultured rat cardiomyocytes, IgE-induced cardiomyocyte hypertrophy and hypertrophic marker expression were abolished by depleting FcεR1. In cultured rat CFs, IgE-induced CF activation and matrix protein production were also blocked by FcεR1 deficiency. RNA sequencing and signaling pathway analyses revealed that transforming growth factor-β may be a critical mediator, and blocking transforming growth factor-β indeed alleviated IgE-induced cardiomyocyte hypertrophy and cardiac fibroblast activation in vitro.Conclusions: Our findings suggest that IgE induction plays a causative role in pathological cardiac remodeling, at least partially via the activation of IgE-FcεR1 signaling in cardiomyocytes and CFs. Therapeutic strategies targeting the IgE-FcεR1 axis may be effective for managing IgE-mediated cardiac remodeling. [ABSTRACT FROM AUTHOR]

Background: With the increasing incidence of mobile phone addiction, mobile phone addiction has been considered to be related to adolescents' psychological distress. However, the underlying mechanisms of this relation were still unclear. The present study tested the mediating role of rumination and the moderating role of the capacity to be alone in the relation between mobile phone addiction and psychological distress.Methods: 754 middle school students were recruited to complete measures of mobile phone addiction, rumination, the capacity to be alone, psychological distress and demographic variables.Results: Mobile phone addiction was significantly and positively associated with psychological distress, and this link could be mediated by rumination. Moreover, the direct effect of mobile phone addiction on psychological distress and the indirect effect of rumination in this link were moderated by the capacity to be alone. Both these two effects were stronger for adolescents with lower capacity to be alone.Limitations: The present study is limited in terms of its sample selection, cross-sectional design, and self-reported instruments.Conclusions: The present study advances our understanding of how and when or for whom mobile phone addiction is related to serious psychological distress. Education professionals and parents should pay special attention to the psychological distress of adolescents suffering from mobile phone addiction, particularly for those with lower capacity to be alone. [ABSTRACT FROM AUTHOR]

Extracting effective features for texture classification is always a difficult problem in texture analysis. We present a method for texture features extraction by independent component analysis (ICA) of Gabor features (called ICAG). It has three distinguished aspects. First, Gabor wavelet transformation first produces distinct textural features characterized by spatial locality, scale, and orientation selectivity. Second, principal component analysis (PCA) and ICA then reduce the dimensionality and redundancy of these features. Thus, the resulting independent components are taken as texture features for classification. Third, in the ICA procedure, two different frameworks are discussed. Framework I, called ICAG I, regards pixels as random variables and represents them as a column vector by reshaping all the transformed images row by row, while framework II, called ICAG II, treats the statistical features, namely, the mean and standard deviation, as random variables. Thus, the statistical features of all the transformed images construct a column vector. Finally, comparative experiments between ICAG and the other traditional methods—ICA and Gabor wavelets—are performed on two composite images (five narrowband textures and five natural textures with broader bands). The results indicate that ICAG provides the best performance and ICAG II is more efficient and applicable. [ABSTRACT FROM AUTHOR]

In this work, tetra-n-butyl ammoniumbromide (TBAB) semiclathrate hydrate was employed in a batch operationto separate CH4from low-concentration coal mine methane(CMM) gas with a mole composition of 30% CH4,60% N2, and 10% O2. TBAB semiclathrate hydrate formedfrom the low-concentration CMM gas has more favorable incipient equilibriumconditions than gas hydrates formed from the same gas mixture. Theexperiments were carried out at a fixed pressure of 4.0 MPa, threeTBAB mole concentrations of 0.29, 0.62, and 1.38 %, and in the temperaturerange of 274.75–283.35 K. The effects of TBAB concentrationsand subcoolings (ΔTsub) on CH4separation from the low-concentration CMM gas were investigated.The results indicated that CH4was preferentially incorporatedinto the hydrate crystals rather than N2and O2in the presence of TBAB. The experimental conditions of the TBABconcentration of 1.38%, 4.0 MPa, and ΔTsub= 7.0 K were most favorable for TBAB semiclathrate hydrateto separate CH4from the low-concentration CMM gas. TheCH4recovery obtained at these conditions was approximately27%. Compared with CH4content in the low-concentrationCMM gas, the mole fraction of CH4in TBAB semiclathratehydrate was increased to 41%. [ABSTRACT FROM AUTHOR]

Objective: Diabetes is one of the most distinct comorbidities of COVID-19. Here, we describe the clinical characteristics of and outcomes in patients with diabetes in whom COVID-19 was confirmed or clinically diagnosed (with typical features on lung imaging and symptoms) and their association with glucose-lowering or blood pressure-lowering medications.Research Design and Methods: In this retrospective study involving 904 patients with COVID-19 (136 with diabetes, mostly type 2 diabetes), clinical and laboratory characteristics were collected and compared between the group with diabetes and the group without diabetes, and between groups taking different medications. Logistic regression was used to explore risk factors associated with mortality or poor prognosis.Results: The proportion of comorbid diabetes is similar between cases of confirmed and of clinically diagnosed COVID-19. Risk factors for higher mortality of patients with diabetes and COVID-19 were older age (adjusted odds ratio [aOR] 1.09 [95% CI 1.04, 1.15] per year increase; P = 0.001) and elevated C-reactive protein (aOR 1.12 [95% CI 1.00, 1.24]; P = 0.043). Insulin usage (aOR 3.58 [95% CI 1.37, 9.35]; P = 0.009) was associated with poor prognosis. Clinical outcomes of those who use an ACE inhibitor (ACEI) or angiotensin II type-I receptor blocker (ARB) were comparable with those of patients who do not use ACEI/ARB among COVID-19 patients with diabetes and hypertension.Conclusions: C-reactive protein may help to identify patients with diabetes who are at greater risk of dying during hospitalization. Older patients with diabetes were prone to death related to COVID-19. Attention needs to be paid to patients with diabetes and COVID-19 who use insulin. ACEI/ARB use showed no significant impact on patients with diabetes and hypertension who have COVID-19. [ABSTRACT FROM AUTHOR]

It is estimated that ∼1% of European ancestry patients clinically diagnosed with type 1 diabetes (T1D) actually have monogenic forms of the disease. Because of the much lower incidence of true T1D in East Asians, we hypothesized that the percentage would be much higher. To test this, we sequenced the exome of 82 Chinese Han patients clinically diagnosed with T1D but negative for three autoantibodies. Analysis focused on established or proposed monogenic diabetes genes. We found credible mutations in 18 of the 82 autoantibody-negative patients (22%). All mutations had consensus pathogenicity support by five algorithms. As in Europeans, the most common gene was HNF1A (MODY3), in 6 of 18 cases. Surprisingly, almost as frequent were diallelic mutations in WFS1, known to cause Wolfram syndrome but also described in nonsyndromic cases. Fasting C-peptide varied widely and was not predictive. Given the 27.4% autoantibody negativity in Chinese and 22% mutation rate, we estimate that ∼6% of Chinese with a clinical T1D diagnosis have monogenic diabetes. Our findings support universal sequencing of autoantibody-negative cases as standard of care in East Asian patients with a clinical T1D diagnosis. Nonsyndromic diabetes with WSF1 mutations is not rare in Chinese. Its response to alternative treatments should be investigated. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoids (GC) therapeutic response in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) varies markedly. Aims/Objectives: To compare the utility between subjective and objective assessment of GC sensitivity in reflecting the impact of GC on systemic and local eosinophilia in CRSwNP patients. Material and methods: Twenty-six patients with CRSwNP were enrolled. All patients were given 30 mg of prednisone once daily for 7 days and subsequently classified into subjectively GC-sensitive and -insensitive subgroup or objectively GC-sensitive and -insensitive subgroup. The numbers of eosinophils and neutrophils in blood and polyp tissues were compared between GC-sensitive and GCinsensitive subgroup. Results: 17/26 (65.4%) patients were subjectively and 8/26 (30.8%) patients objectively sensitive to GC treatment. The absolute number and percentage of eosinophils in blood were decreased both in GCsensitive and -insensitive subjects after GC treatment. In addition, a significant reduction in tissue eosinophil percentage was only observed in objectively GC-sensitive subjects after GC treatment. Furthermore, the change of tissue eosinophil percentage in objectively GC-sensitive subjects was significantly higher than that in objectively GC-insensitive subjects. Conclusions and significance: Objective assessment may better reflect oral GC response in tissue eosinophilic inflammation than subjective assessment in patients with CRSwNP. [ABSTRACT FROM AUTHOR]

Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease.Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis.Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information.Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration.Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, the minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition. [ABSTRACT FROM AUTHOR]

Importance: Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections. However, whether winter supplementation of vitamin D reduces the risk among children is unknown.Objective: To determine whether high-dose vs standard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children.Design, Setting, and Participants: A randomized clinical trial was conducted during the winter months between September 13, 2011, and June 30, 2015, among children aged 1 through 5 years enrolled in TARGet Kids!, a multisite primary care practice-based research network in Toronto, Ontario, Canada.Interventions: Three hundred forty-nine participants were randomized to receive 2000 IU/d of vitamin D oral supplementation (high-dose group) vs 354 participants who were randomized to receive 400 IU/d (standard-dose group) for a minimum of 4 months between September and May.Main Outcome Measures: The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months. Secondary outcomes included the number of influenza infections, noninfluenza infections, parent-reported upper respiratory tract illnesses, time to first upper respiratory tract infection, and serum 25-hydroxyvitamin D levels at study termination.Results: Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91-1.19) for the high-dose group and 1.03 (95% CI, 0.90-1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, -0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80-1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months (95% CI, 3.02-5.95 months) for the high-dose group vs 3.29 months (95% CI, 2.66-4.14 months) for the standard-dose group, or number of parent-reported upper respiratory tract illnesses between groups (625 for high-dose vs 600 for standard-dose groups, incidence RR, 1.01; 95% CI, 0.88-1.16). At study termination, serum 25-hydroxyvitamin D levels were 48.7 ng/mL (95% CI, 46.9-50.5 ng/mL) in the high-dose group and 36.8 ng/mL (95% CI, 35.4-38.2 ng/mL) in the standard-dose group.Conclusions and Relevance: Among healthy children aged 1 to 5 years, daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections. These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections.Trial Registration: clinicaltrials.gov Identifier: NCT01419262. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), extensive experimental studies have demonstrated a negative impact of chronic stress during various stages of life (including prenatal phase) on some aspects of AD pathology. Nevertheless, presently, few studies have been involved in the learning and memory impairments, as well as neuropathology elicited by the chronic prenatal stress (CPS) and the chronic offspring stress (COS) exposures simultaneously, particularly for the adult male APPswe/PS1dE9 murine offspring. Therefore, the aim of the present study was to investigate the influence of CPS on learning and memory impairments induced by COS in 6-month-old male APPswe/PS1dE9 offspring mice and the related mechanism. Our study firstly demonstrates that 14-day exposure to CPS could exacerbate the learning and memory impairments, as well as neuropathological damages in the CA3 regions of the hippocampus and cortex neurons, which is induced by the 28-day exposure to COS in 6-month-old male APPswe/PS1dE9 offspring mice. In addition, CPS could potentiate the production of AβPP, Aβ42, and corticosterone in 6-month-old male APPswe/PS1dE9 offspring that also suffer COS. In conclusion, our novel findings strongly implicate the synergistic roles of the CPS and COS exposures in impairing offspring learning and memory. Moreover, CPS potentiating the production of Aβ42 might be mediated by glucocorticoids through increasing the expression of APP and BACE1 gene. [ABSTRACT FROM AUTHOR]

Background: Life expectancy at birth (LE) is a comprehensive measure that accounts for age-specific death rates in a population. Shanghai has ranked first in LE in China mainland for decades. Understanding the reasons behind its sustained gain in LE provides a good reflection of many other cities in China. The aim of this study is intended to explore temporal trend in age- and cause-specific gains in LE in Shanghai and the probable reasons lay behind.Methods: Joinpoint regression was applied to evaluate temporal trend in LE and the long time span was then divided accordingly. Contributions to change in LE (1973-2015) were decomposed by age and cause at corresponding periods.Results: LE in Shanghai could be divided into four phases ie., descent (1973-1976), recovery (1976-1998), rapid rise (1998-2004) and slow rise (2004-2015). The growing LE was mainly attributed to reductions in mortality from the elderly populations and chronic diseases such as cerebrovascular disease, chronic lower respiratory disease, and gastrointestinal cancers (stomach, liver and esophageal cancer).Conclusions: The four-decade sustained gain in LE in Shanghai is due to the reductions in mortality from the elderly and chronic diseases such as cerebrovascular disease, chronic lower respiratory disease, and gastrointestinal cancers. Further growth momentum still comes from the elderly population. [ABSTRACT FROM AUTHOR]

A theoretical explanation of observations of high-Froude-number ship wakes that are narrower than the classical Kelvin 3 9 ∘ angle was recently offered by Rabaud and Moisy. The explanation relies on the assumption that a ship hull does not create waves longer than its length. A validation of this theoretical model has also been given. The validation is based on the approximation of the flow created by a ship hull by means of a Gaussian distribution of pressure at the free surface. These two flow models predict a wake angle ψ m a x that decreases like 1 / F as the Froude number F increases beyond F ≈ 0.5 . A third theoretical explanation was recently proposed by the authors. This theoretical explanation assumes that the wave pattern of a ship mostly consists of dominant waves that are created by the ship bow and stern, and is mostly determined by interference effects between these dominant waves. The analysis of interference effects on the Kelvin wake of a ship predicts a wake angle ψ m a x ≈ 0.14 / F 2 for a monohull ship, or ψ m a x ≈ 0.2 b / F for a catamaran with beam/length ratio b . The ‘flow models’ underlying these three alternative theoretical explanations of narrow ship wakes are examined, and the corresponding theoretical predictions are compared to the 37 observations of ship wakes reported by Rabaud and Moisy for Froude numbers F within the wide range 0.1 < F < 1.7 . The wake observations are found to be consistent with the predictions given by an analysis of interference between the bow and stern waves of a monohull ship, or a catamaran with beam/length ratio b within the range 0.4 ≤ b ≤ 0.8 . Indeed, agreement is consistently strong for the 35 wake observations within the range 0.1 < F < 1.4 . This range of Froude numbers includes the range F < 0.6 , where interference between transverse bow and stern waves is important, and corresponds to the vast majority of ships. The predictions given by the Rabaud–Moisy ‘cutoff-wavelength model’ and the ‘Gaussian pressure distribution model’ are in close agreement with two wake observations for 1.6 < F < 1.7 and may also be consistent with several wake observations for 0.6 < F < 1.4 , but are not consistent with most observations. This finding and a critical examination of the assumptions underlying the Rabaud–Moisy model and the Gaussian pressure distribution model suggest that these theoretical models may not be realistic for most ships. This conclusion is further validated by numerical computations of wave patterns for F = 1 . The computed waves are largest along a ray angle that agrees with the prediction of the bow and stern waves interference model, but is noticeably smaller than predicted by the Gaussian pressure distribution model. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacology: The main components of HuangKui capsules’ are the total flavonoids extracted from the flowers of Abelmoschus manihot L medic. They have been widely used to treat chronic glomerulonephritis, diabetic nephropathy and nephrotic syndrome. The combination of HuangKui capsules and glibenclamide is a possible therapy for patients with diabetes mellitus and diabetic nephropathy. However, there is no report about effects of HuangKui capsules on the glibenclamide pharmacokinetics till now. Aim of the study: This study was aimed investigating the effect of HuangKui capsules on pharmacokinetics of glibenclamide in rats. Material and methods: Eight rats were administered with an oral dose of HuangKui capsules (0.75gkg−1) once daily for 10 consecutive days. All the rats were administered orally with the glibenclamide (1mgkg−1) before the first time and after the last time given HuangKui capsules. LC–MS/MS was utilized to determine the concentration of glibenclamide in rat plasma and to calculate the corresponding pharmacokinetic parameters. The statistical differences of the two cycles were evaluated by paired-samples t-test. Results: In the rats treated with HuangKui capsules and glibenclamide, the t 1/2, the time point of maximum plasma concentration (T max) of glibenclamide increased obviously (p <0.05) compared with the glibenclamide alone, while maximum plasma concentrations (C max), area under the plasma concentration-time curve (AUC(0−t)) decreased significantly (p <0.05). There was no significant difference between other parameters. Conclusion: HuangKui capsules can reduce the absorption of glibenclamide and accelerate the metabolism of glibenclamide. [Copyright &y& Elsevier]