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Background Therapies to prevent recurrence of Clostridioides difficile infection (CDI) in pediatric patients are needed. Bezlotoxumab is a fully human monoclonal antibody approved for prevention of recurrent CDI in adults. We assessed the pharmacokinetics, safety, tolerability, and efficacy of bezlotoxumab in pediatric patients. Methods MODIFY III was a multicenter, double-blind, placebo-controlled study of bezlotoxumab in children (1 to <18 years) receiving antibacterial treatment for CDI. Participants were randomized 3:1 to receive a single infusion of bezlotoxumab (10 mg/kg) or placebo and were stratified by age at randomization (cohort 1: 12 to <18 years, cohort 2: 1 to <12 years). The primary objective was to characterize bezlotoxumab pharmacokinetics to support dose selection for pediatric patients; the primary endpoint was the area under the bezlotoxumab serum concentration–time curve (AUC0-inf). Safety, tolerability, and efficacy were monitored for 12 weeks post-infusion. Results A total of 148 participants were randomized and 143 were treated: 107 with bezlotoxumab and 36 with placebo (cohort 1 n = 60, cohort 2 n = 83; median age 9.0 years); 52.4% of participants were male and 80.4% were white. Geometric mean ratios (90% CI) for bezlotoxumab AUC0-inf were 1.06 (0.95, 1.18) and 0.82 (0.75, 0.89) h * μg/mL for cohorts 1 and 2, respectively. Bezlotoxumab 10 mg/kg was generally well-tolerated with an adverse event profile similar to placebo, including no treatment discontinuations due to adverse events. CDI recurrence was low and comparable for bezlotoxumab (11.2%) and placebo (14.7%). Conclusions The results of this study support the bezlotoxumab dose of 10 mg/kg for pediatric patients. Trial registration NCT03182907 at ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

MXenes are one of the key materials for micro-supercapacitors (MSCs), integrating miniaturized energy-storage components with microelectronics. However, the energy densities of MSCs are greatly hampered by MXenes' narrow working potential window (typically ≤0.6 V) in aqueous electrolytes. Here, we report the fabrication of high-voltage MXene-MSCs through the efficient regulation of reaction kinetics in 2D Ti3C2T x MXene microelectrodes using a water-in-LiCl (WIL, 20 m LiCl) salt gel electrolyte. Importantly, the intrinsic energy-storage mechanism of MXene microelectrodes in WIL, which is totally different from traditional electrolytes (1 m LiCl), was revealed through in situ and ex situ characterizations. We validated that the suppression of MXene oxidation at high anodic potential occurred due to the high content of WIL regulating anion intercalation in MXene electrodes, which effectively broadened the voltage window of MXene-MSCs. Remarkably, the symmetric planar MXene-MSCs presented a record operating voltage of 1.6 V, resulting in an exceptionally high volumetric energy density of 31.7 mWh cm−3. With the ultra-high ionic conductivity (69.5 mS cm−1) and ultralow freezing point (−57°C) of the WIL gel electrolyte, our MSCs could be operated in a wide temperature range of −40 to 60°C, and worked for a long duration even at −40°C, demonstrative of its practicality in extreme environments. [ABSTRACT FROM AUTHOR]

Many people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients. [ABSTRACT FROM AUTHOR]

Cleaning and disinfecting tasks and product use are associated with elevated prevalence of asthma and respiratory symptoms among healthcare workers; however, the levels of exposure that pose a health risk remain unclear. The objective of this study was to estimate the peak, average, and determinants of real-time total volatile organic compound (TVOC) exposure associated with cleaning tasks and product-use. TVOC exposures were measured using monitors equipped with a photoionization detector (PID). A simple correction factor was applied to the real-time measurements, calculated as a ratio of the full-shift average TVOC concentrations from a time-integrated canister and the PID sample, for each sample pair. During sampling, auxiliary information, e.g. tasks, products used, engineering controls, was recorded on standardized data collection forms at 5-min intervals. Five-minute averaged air measurements (n = 10 276) from 129 time-series comprising 92 workers and four hospitals were used to model the determinants of exposures. The statistical model simultaneously accounted for censored data and non-stationary autocorrelation and was fit using Markov-Chain Monte Carlo within a Bayesian context. Log-transformed corrected concentrations (cTVOC) were modeled, with the fixed-effects of tasks and covariates, that were systematically gathered during sampling, and random effect of person-day. The model-predicted geometric mean (GM) cTVOC concentrations ranged from 387 parts per billion (ppb) for the task of using a product containing formaldehyde in laboratories to 2091 ppb for the task of using skin wipes containing quaternary ammonium compounds, with a GM of 925 ppb when no products were used. Peak exposures quantified as the 95th percentile of 15-min averages for these tasks ranged from 3172 to 17 360 ppb. Peak and GM task exposures varied by occupation and hospital unit. In the multiple regression model, use of sprays was associated with increasing exposures, while presence of local exhaust ventilation, large room volume, and automatic sterilizer use were associated with decreasing exposures. A detailed understanding of factors affecting TVOC exposure can inform targeted interventions to reduce exposures and can be used in epidemiologic studies as metrics of short-duration peak exposures. [ABSTRACT FROM AUTHOR]

Objectives Use of cleaning and disinfecting products is associated with work-related asthma among healthcare workers, but the specific levels and factors that affect exposures remain unclear. The objective of this study was to evaluate the determinants of selected volatile organic compound (VOC) exposures in healthcare settings. Methods Personal and mobile-area air measurements (n = 143) from 100 healthcare workers at four hospitals were used to model the determinants of ethanol, acetone, 2-propanol, d -limonene, α-pinene, and chloroform exposures. Hierarchical cluster analysis was conducted to partition workers into groups with similar cleaning task/product-use profiles. Linear mixed-effect regression models using log-transformed VOC measurements were applied to evaluate the association of individual VOCs with clusters of task/product use, industrial hygienists’ grouping (IH) of tasks, grouping of product application, chemical ingredients of the cleaning products used, amount of product use, and ventilation. Results Cluster analysis identified eight task/product-use clusters that were distributed across multiple occupations and hospital units, with the exception of clusters consisting of housekeepers and floor strippers/waxers. Results of the mixed-effect models showed significant associations between selected VOC exposures and several clusters, combinations of IH-generated task groups and chemical ingredients, and product application groups. The patient/personal cleaning task using products containing chlorine was associated with elevated levels of personal chloroform and α-pinene exposures. Tasks associated with instrument sterilizing and disinfecting were significantly associated with personal d -limonene and 2-propanol exposures. Surface and floor cleaning and stripping tasks were predominated by housekeepers and floor strippers/waxers, and use of chlorine-, alcohol-, ethanolamine-, and quaternary ammonium compounds-based products was associated with exposures to chloroform, α-pinene, acetone, 2-propanol, or d -limonene. Conclusions Healthcare workers are exposed to a variety of chemicals that vary with tasks and ingredients of products used during cleaning and disinfecting. The combination of product ingredients with cleaning and disinfecting tasks were associated with specific VOCs. Exposure modules for questionnaires used in epidemiologic studies might benefit from seeking information on products used within a task context. [ABSTRACT FROM AUTHOR]

Clinical therapies of pluripotent stem cells (PSCs)-based transplantation have been hindered by frequent development of teratomas or tumors in animal models and clinical patients. Therefore, clarifying the mechanism of carcinogenesis in stem cell therapy is of great importance for reducing the risk of tumorigenicity. Here we differentiate Oct4-GFP mouse embryonic stem cells (mESCs) into neural progenitor cells (NPCs) and find that a minority of Oct4+ cells are continuously sustained at Oct4+ state. These cells can be enriched and proliferated in a standard ESC medium. Interestingly, the differentiation potential of these enriched cells is tightly restricted with much higher tumorigenic activity, which are thus defined as differentiation-resistant ESCs (DR-ESCs). Transcriptomic and epigenomic analyses show that DR-ESCs are characterized by primordial germ cell-like gene signatures (Dazl, Rec8, Stra8, Blimp1, etc.) and specific epigenetic patterns distinct from mESCs. Moreover, the DR-ESCs possess germ cell potential to generate Sycp3+ haploid cells and are able to reside in sperm-free spermaduct induced by busulfan. Finally, we find that TGFβ signaling is overactivated in DR-ESCs, and inhibition of TGFβ signaling eliminates the tumorigenicity of mESC-derived NPCs by inducing the full differentiation of DR-ESCs. These data demonstrate that these TGFβ-hyperactivated germ cell-like DR-ESCs are the main contributor for the tumorigenicity of ESCs-derived target cell therapy and that inhibition of TGFβ signaling in ESC-derived NPC transplantation could drastically reduce the risk of tumor development. [ABSTRACT FROM AUTHOR]

Motivation Functional imaging at single-neuron resolution offers a highly efficient tool for studying the functional connectomics in the brain. However, mainstream neuron-detection methods focus on either the morphologies or activities of neurons, which may lead to the extraction of incomplete information and which may heavily rely on the experience of the experimenters. Results We developed a convolutional neural networks and fluctuation method-based toolbox (ImageCN) to increase the processing power of calcium imaging data. To evaluate the performance of ImageCN, nine different imaging datasets were recorded from awake mouse brains. ImageCN demonstrated superior neuron-detection performance when compared with other algorithms. Furthermore, ImageCN does not require sophisticated training for users. Availability and implementation ImageCN is implemented in MATLAB. The source code and documentation are available at https://github.com/ZhangChenLab/ImageCN. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Artificial neural networks (ANNs) are powerful computational tools that are designed to replicate the human brain and adopted to solve a variety of problems in many different fields. Fault tolerance (FT), an important property of ANNs, ensures their reliability when significant portions of a network are lost. In this paper, a fault/noise injection-based (FIB) genetic algorithm (GA) is proposed to construct fault-tolerant ANNs. The FT performance of an FIB-GA was compared with that of a common genetic algorithm, the back-propagation algorithm, and the modification of weights algorithm. The FIB-GA showed a slower fitting speed when solving the exclusive OR (XOR) problem and the overlapping classification problem, but it significantly reduced the errors in cases of single or multiple faults in ANN weights or nodes. Further analysis revealed that the fit weights showed no correlation with the fitting errors in the ANNs constructed with the FIB-GA, suggesting a relatively even distribution of the various fitting parameters. In contrast, the output weights in the training of ANNs implemented with the use the other three algorithms demonstrated a positive correlation with the errors. Our findings therefore indicate that a combination of the fault/noise injection-based method and a GA is capable of introducing FT to ANNs and imply that the distributed ANNs demonstrate superior FT performance. [ABSTRACT FROM AUTHOR]

Background Peptic ulcer disease (PUD) has been linked to immunological dysfunctions and malnutrition—both are predictors of herpes zoster (HZ). We hypothesized that PUD patients might have a greater risk for developing HZ.Methods Using the longitudinal National Health Insurance Research Database, we conducted a retrospective population-based cohort study to evaluate the incidence of HZ in adult PUD patients and controls matched by age and gender. Kaplan-Meier analysis and Cox regression were conducted to compare differences in the development of HZ. The effects of comorbidities on the risk of HZ and the associations between different risk factors of PUD and HZ were assessed by subgroup analyses.Results We identified 41 229 adults PUD patients and 41 229 controls. Over an 8-year follow-up, the cumulative incidence of HZ in PUD patients (11.76/1000 person-years) was significantly higher than controls (6.56/1000 person-years) (P < 0.001, by log-rank test). After adjusting for potential confounders, PUD was an independent predictor for HZ (adjusted hazard ratio: 1.77, 95% confidence interval 1.64–1.91, P < 0.001). Major risk factors of PUD were non-selective nonsteroidal anti-inflammatory drugs (nsNSAID) usage and Helicobacter pylori infection. Subgroup analyses revealed that PUD is an independent predictor of HZ after excluding the potential confounding effects of the comorbidities; PUD associated with the combination of nsNSAID usage and Helicobacter pylori infection leads to greatest risk of HZ.Conclusions Adults with PUD are at increased risk of HZ independently compared with the general population. Further studies are required to clarify the nature of the associations between HZ and PUD. [ABSTRACT FROM PUBLISHER]

The article discusses a study which examines the volatile components of three indigenous citrus species in Taiwan including Citrus (C.) taiwanica, C. tachibana and C. depressa. Findings reveal that eight volatile components were identified including linalool, geranial and limonene. It also indicates that C. taiwanica was associated with sour orange while either C. depressa or C. tachibana belonged to the mandarin group as revealed in the qualitative and quantitative patterns of the volatiles.

The Medaka is an excellent genetic system for studies of vertebrate development and disease and environmental and evolutionary biology studies. To facilitate the mapping of markers or the cloning of affected genes in Medaka mutants identified by forward-genetic screens, we have established a panel of whole-genome radiation hybrids (RHs) and RH maps for three Medaka chromosomes. RH mapping is useful, since markers to be mapped need not be polymorphic and one can establish the order of markers that are difficult to resolve by genetic mapping owing to low genetic recombination rates. RHs were generated by fusing the irradiated donor, OLF-136 Medaka cell line, with the host B78 mouse melanoma cells. Of 290 initial RH clones, we selected 93 on the basis of high retention of fragments of the Medaka genome to establish a panel that allows genotyping in the 96-well format. RH maps for linkage groups 12, 17, and 22 were generated using 159 markers. The average retention for the three chromosomes was 19% and the average break point frequency was ∼33 kb/cR. We estimate the potential resolution of the RH panel to be ∼186 kb, which is high enough for integrating RH data with bacterial artificial chromosome clones. Thus, this first RH panel will be a useful tool for mapping mutated genes in Medaka. [ABSTRACT FROM PUBLISHER]

The effects of 24‐epibrassinolide (EBR) spray application on gas‐exchange, chlorophyll fluorescence characteristics, Rubisco activity, and carbohydrate metabolism were investigated in cucumber (Cucumis sativus L. cv. Jinchun No. 3) plants grown in a greenhouse. EBR significantly increased the light‐saturated net CO2 assimilation rate (Asat) from 3 h to 7d after spraying, with 0.1 mg l–1 EBR proving most effective. Increased Asat in EBR‐treated leaves was accompanied by increases in the maximum carboxylation rate of Rubisco (Vc,max) and in the maximum rate of RuBP regeneration (Jmax). EBR‐treated leaves also had a higher quantum yield of PSII electron transport (ɸPSII) than the controls, which was mainly due to a significant increase in the photochemical quenching (qP), with no change in the efficiency of energy capture by open PSII reaction centres (F′v/F′m). EBR did not influence photorespiration. In addition, significant increases in the initial activity of Rubisco and in the sucrose, soluble sugars, and starch contents were observed followed by substantial increases in sucrose phosphate synthase (SPS), sucrose synthase (SS), and acid invertase (AI) activities after EBR treatment. It was concluded that EBR increases the capacity of CO2 assimilation in the Calvin cycle, which was mainly attributed to an increase in the initial activity of Rubisco. [ABSTRACT FROM PUBLISHER]

A correction is presented to the article "Peaks, Means, and Determinants of Real-Time TVOC Exposures Associated with Cleaning and Disinfecting Tasks in Healthcare Settings" which appeared in the previous issue of the periodical.

Citrate synthase (CS) is an important enzyme in energy conversion and material circulation, participating in many important biochemical processes. In the present study, CS from Microcystis aeruginosa PCC7806 (MaCS) was cloned and expressed in Escherichia coli Rosetta (DE3). The recombinant MaCS was purified and its enzymological properties were characterized. The results showed that MaCS formed dimers in native status. The optimum temperature and pH of MaCS was 30°C and 8.2, respectively. MaCS displayed relative high thermal stability. Treatment at 50°C for 20 min only decreased 11.30% activity of MaCS and the half-life of MaCS was approximately 35 min at 55°C. The k cat and K m of acetyl-CoA and oxaloacetic acid were 17.133 s−1 (k cat) and 11.62 μM (K m), 24.502 s−1 and 103.00 μM, respectively. MaCS activity was not drastically inhibited by monovalent ions and NADH but depressed by divalent ions and some small molecular compounds, especially Mg2+, Zn2+, Co2+ and DTT. Overall, these data contributed to further understanding of energy metabolism in cyanobacteria and also provided basic information for industrial application of CS. [ABSTRACT FROM AUTHOR]