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Qing Zhan,1 Yanlei Xu,1 Lingling Zhan,2 Bingjie Wang,3 Yinjuan Guo,3,4 Xiaocui Wu,3,4 Wenxiu Ai,5 Zengqiang Song,6 Fangyou Yu3,4 1Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, 330006, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 3Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200082, People’s Republic of China; 4Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200082, People’s Republic of China; 5Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 6School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of ChinaCorrespondence: Fangyou Yu; Zengqiang Song Tel +86-021-65115006; +86-577-86699396Email wzjxyfy@163.com; songzengqiang09@163.comIntroduction: The ability of Staphylococcus aureus to form biofilms is associated with high mortality and treatment costs. Established biofilms cannot be eradicated by many conventional antibiotics due to the development of antibiotic tolerance by S. aureus. Here we report the synthesis and biological characterization of novel small-molecule compounds with antibiofilm activity. Chromone 5-maleimide substitution compounds (CM3a) showed favorable antibacterial activity against S. aureus.Methods: CM3A with antibacterial activity was synthesized and screened. The minimum inhibitory concentration (MIC) of CM3a were determined by the broth microdilution method. Biofilm eradication assay and colony count methods were used to investigate the effect of CM3a on S. aureus biofilm disruption and killing. Changes in biofilm architecture when subjected to CM3a, were visualized using confocal laser scanning microscopy (CLSM). CCK-8 assay and survival rate of Galleria mellonella larvae were used to test the toxicity of CM3a.Results: The minimum inhibitory concentration (MIC) of CM3a against S. aureus was about 26.4 μM. Biofilm staining and laser scanning confocal microscopy analysis showed that CM3a eradicated S. aureus biofilms by reducing the viability of the constituent bacterial cells. On the other hand, CM3a showed negligible toxicity against mouse alveolar epithelial cells and Galleria mellonella larvae.Conclusion: Chromone derivatives CM3a has therapeutic potential as a safe and effective compound for the treatment of S. aureus infection.Keywords: chromone derivative, maleimide, Staphylococcus aureus, biofilm, eradicate

This paper reports on the results of a series of co-design workshops devised to generate new messaging ideas for a novel hand sanitizer unit that features a video screen and feedback system. Students of different nationalities, ages and genders were involved in the process either to prime design sessions, or devise/evaluate new ideas for the screen to display in a university setting. The project aimed not only to produce animated designs for subsequent testing but also to elicit key preferences for hand hygiene message tone, content and visual appearance. Research findings revealed a clear preference in the student community for positive, caring and playful approaches to hand hygiene messaging in contrast to many messaging approaches featured in previous studies. In terms of visual approach, students expressed a preference for colourful illustrations rather than photographs or word-based messages. The paper highlights some particularly rich ideas developed to exploit the novelty of the device, such as specific animated sequences or immediate visual rewards of internet memes as ways to engage the student audience. Co-design proved valuable in devising new insights for the hygiene communication community.

Xiaofei Shen, 1 Li Liu, 2 Jingyi Yu, 2 Wenxiu Ai, 1 Xingwei Cao, 3 Qing Zhan, 4 Yinjuan Guo, 5, 6 Liangxing Wang, 1 Fangyou Yu 5, 6 1Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People’s Republic of China; 3Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China; 4Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang 330006, People’s Republic of China; 5Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200082, People’s Republic of China; 6Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200082, People’s Republic of ChinaCorrespondence: Liangxing Wang; Fangyou Yu Email 38805@163.com; wzjxyfy@163.comObjective: The 16S rRNA methylase-mediated high-level resistance to aminoglycosides has become a great concern. The purpose of the study was to investigate the occurrence of 16S rRNA methyltransferase (RMTase) genes in carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates associated with bloodstream infections (BSIs) in China.Methods: From July 2015 to December 2018, a total of 137 unique CRKP clinical isolates associated with BSIs were collected from 11 Chinese teaching hospitals. PCR and DNA sequencing were used to identify 16S RMTase genes. Whole-genome sequencing (WGS) was performed on all CRKP clinical isolates. Relevant information was extracted from WGS data (antibiotic resistance determinants, K-type and wzi allelic types). All 16S RMTase-producing CRKP clinical isolates were characterized by antimicrobial susceptibility testing, multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE).Results: In this study, 137 CRKPs were found to harbor at least one carbapenemase gene. Among 137 CRKPs, 78 (56.9%, 78/137) were positive for 16S RMTase genes (5 for armA, 70 for rmtB, 3 for both armA and rmtB) and highly resistant to gentamicin and amikacin (MICs ≥ 256 mg/L). Seventy-five isolates harboring 16S RMTase genes also produced ESBLs. In this study, 5 sequence types (STs) and 6 capsule serotypes were found among 78 isolates positive for 16S RMTases genes, while 14 STs and 6 capsule serotypes were found among 59 isolates negative for 16S RMTases genes. Compared with the isolates negative for 16S RMTases genes, the STs and capsular serotypes of 16S RMTases-positive strains are more concentrated. Among 78 16S RMTases-positive strains, the most prevalent clone type is ST11-PFGE-B-KL64-wzi64 (62.8%, 49/78), which mainly carries the rmtB and blaKPC genes and is distributed in 7 provinces in China.Conclusion: A high prevalence of 16S RMTase genes was found among CRKP clinical isolates associated with BSIs from Chinese teaching hospitals, which was attributed to the dissemination of the ST11-PFGE-B-KL64-wzi64 clone.Keywords: CRKP, BSIs, 16S RMTase genes, aminoglycosides, molecular characteristics

Background Intranasal dexmedetomidine provides noninvasive, effective procedural sedation for pediatric patients, and has been widely used in clinical practice. However, the dosage applied has varied fourfold in pediatric clinical studies. To validate an appropriate dosing regimen, this study investigated the pharmacokinetics of intranasal dexmedetomidine in Chinese children under 3 yr old. Methods Intranasal dexmedetomidine 2 µg · kg−1 was administered to children with simple vascular malformations undergoing interventional radiological procedures. A population pharmacokinetic analysis with data from an optimized sparse-sampling design was performed using nonlinear mixed-effects modeling. Clearance was modeled using allometric scaling and a sigmoid postmenstrual age maturation model. Monte Carlo simulations were performed to assess the different dosing regimens. Results A total of 586 samples from 137 children aged 3 to 36 months were included in the trial. The data were adequately described by a two-compartment model with first-order elimination. Body weight with allometric scaling and maturation function were significant covariates of dexmedetomidine clearance. The pharmacokinetic parameters for the median subjects (weight 10 kg and postmenstrual age 101 weeks) in the authors’ study were apparent central volume of distribution 7.55 l, apparent clearance of central compartment 9.92 l · h−1, apparent peripheral volume of distribution 7.80 l, and apparent intercompartmental clearance 61.7 l · h−1. The simulation indicated that at the dose of 2 µg · kg−1, 95% of simulated individuals could achieve a target therapeutic concentration of 0.3 ng · ml−1 within 20 min, and the average peak concentration of 0.563 ng · ml−1 could be attained at 61 min. Conclusions The pharmacokinetic characteristics of intranasal dexmedetomidine were evaluated in Chinese pediatric patients aged between 3 and 36 months. An evidence-based dosing regimen at 2 µg · kg−1 could achieve a preset therapeutic threshold of mild to moderate sedation that lasted for up to 2 h. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Online communities offer many potential sources of value to individuals and organisations. However, the effectiveness of online communities in delivering benefits such as knowledge sharing depends on the network of social relations within a community. Research in this area aims to understand and optimize such networks. Researchers in this area employ diverse network creation methods, with little focus on the selection process, the fit of the selected method, or its relative accuracy. In this study we evaluate and compare the performance of four network creation methods. First we review the literature to identify four network creation methods (algorithms) and their underlying assumptions. Using several data sets from an online community we test and compare the accuracy of each method against a baseline ('actual') network determined by content analysis. We use visual inspection, network correlation analysis and sensitivity analysis to highlight similarities and differences between the methods, and find some differences significant enough to impact study results. Based on our observations we argue for more careful selection of network creation methods. We propose two key guidelines for research into social networks that uses unstructured data from online communities. The study contributes to the rigour of methodological decisions underpinning research in this area.

According to recent studies, gas sensors based on MoSe2 have better detection performance than graphene-based sensors, especially for N-based gas molecules, but the reason for that is not fully understood at the microscopic level. Here, we investigate the adsorption of CO, CO2, NH3, NO and NO2 gas molecules on MoSe2 monolayer by the density functional theory calculations. Our results reveal that indeed MoSe2 monolayer is more sensitive to adsorption of N-containing gas molecules than C-containing, which can be attributed to the distinct charge transfer between the gas molecules and MoSe2. The conductance was further calculated using the nonequilibrium Green's function (NEGF) formalism. The reduced conductance was found for NH3 and NO2 adsorbed MoSe2, consistent with the high sensitivity of MoSe2 for NH3 and NO2 molecules in the recent experiments. In addition, the adsorption sensitivity can significantly be improved by an external electric field, which implies the controllable gas detection by MoSe2. The magnetic moments of adsorbed NO and NO2 molecules can also be effectively modulated by the field-sensitive charge transfer. Our results not only give microscopic explanations to the recent experiments, but also suggest using MoSe2 as a promising material for controlled gas sensing.

Older adults admitted for falls and its complications, including traumatic brain injury (TBI), is increasing. Recent studies have shown that those with falls who presented to the emergency department (ED) had an increased frequency of ED revisits, especially those with head trauma.To determine the characteristics and predictors of fall-related traumatic brain injury (FRTBI) in older adults.Retrospective medical chart review of 339 patients aged 65 years and older admitted for TBI in 2014 due to a fall. Characteristics analysed include demographics, fall circumstances, prior ED visits, polypharmacy, readmission, functional status and specialist outpatient clinic utilisation before and after FRTBI.A total of 339 (37.4%) patients admitted due to FRTBI was 65 years old and older; 112 (33.0%) for subdural haemorrhage (SDH); 227 (67.0%) for head injury (HI), with a mean age of 80 years. A total of 46 (41.1%) patients with SDH and 107 (47.1%) with HI had a previous ED visit within the last year, while 22 (19.6%) of SDH and 49 (21.6%) of HI had hospitalisation 3 months prior to FRTBI. FRTBI was associated with significant decline in activities of daily living, polypharmacy and increased specialist outpatient clinic appointments (P0.001). Mortality was 11 (3.2%). Mild cognitive impairment or dementia was significantly associated with admissions for FRTBI, 3.31 (95% confidence interval 1.68-6.51, P = 0.001) using adjusted logistic regression.FRTBI is associated with significant functional decline and increased resource utilisation with almost half of the patients having had prior ED visits or hospitalisation. Future studies should focus on falls risk assessment and interventions for high-risk older adults prior to discharge from ED and hospital, and its impact on readmissions due to FRTBI.

Computational modelling of fracture has been attempted in the past with a range of numerical approaches including finite element, extended finite element and meshless methods. The cracking particle method (CPM) of Rabczuk is a pragmatic alternative to explicit modelling of crack surfaces in which a crack is represented by a set of cracking particles that can be easily updated when the crack propagates. The change of cracking angle is recorded in discrete segments of broken lines, which makes this methodology suitable to model discontinuous cracks. In this paper, a new CPM is presented that improves on two counts: firstly, crack path curvature modelling is improved by the use of bilinear segments centred at each particle and secondly, efficiency for larger problems is improved via an adaptive process of both refinement and recovery. The system stiffness is calculated and stored in local matrices, so only a small influenced domain should be recalculated for each step while the remainder can be read directly from storage, which greatly reduces the computational expense. The methodology is applied to several 2D crack problems, and good agreement to analytical solutions and previous work is obtained.

Multiple crack simulation is of great importance in failure analysis since fracture in brittle materials in practice usually comprises multiple cracks. Traditional numerical methods like the extended finite element and the element free Galerkin methods meet dilemmas when solving this kind of problem, as the computational expense increases with the number of level set functions used for crack descriptions. The cracking particle method (CPM) developed by Rabczuk, by which crack patterns are simplified and discretized through a set of cracking segments, has shown to be a promising alternative. The branched crack problem, as a representative of multiple crack problems, is studied here to demonstrate the advantages of the CPM. Cracking particles can be split multiply due to the use of bilinear cracking lines and then the discontinuity at the intersection is fulfilled easily. An adaptivity strategy is adopted to control the size of cracking segments and the number of degrees of freedom. Stress intensity factors at the crack tips are calculated and show good agreement with previous results.

Summary Background Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not respond to or who have progressive disease after salvage therapies have a poor prognosis. Loncastuximab tesirine is a CD19-directed antibody–drug conjugate with encouraging phase 1 single-agent antitumour activity and acceptable safety in non-Hodgkin lymphoma. We aimed to evaluate the antitumour activity and safety of loncastuximab tesirine in patients with relapsed or refractory DLBCL. Methods We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with relapsed or refractory DLBCL after two or more multiagent systemic treatments, who had measurable disease and Eastern Cooperative Oncology Group performance status 0–2. Eligible patients received loncastuximab tesirine intravenously on day 1 of each 21-day cycle, at 150 μg/kg for two cycles, then 75 μg/kg thereafter, for up to 1 year or until disease relapse or progression, unacceptable toxicity, death, major protocol deviation, pregnancy, or patient, investigator, or sponsor decision. The primary endpoint was overall response rate assessed by central review. Primary antitumour activity and safety analyses were done in the as-treated population (patients who received at least one dose of loncastuximab tesirine), when all responding patients had at least 6 months of follow-up after initial documented response. Enrolment is complete. This trial is registered with ClinicalTrials.gov , NCT03589469 . Findings Between Aug 1, 2018, and Sept 24, 2019, 184 patients were assessed for eligibility and 145 (79%) were enrolled and received at least one dose of loncastuximab tesirine, including patients with high-risk characteristics for poor prognosis, such as double-hit, triple-hit, transformed, or primary refractory DLBCL. 70 of 145 patients had complete or partial response (overall response rate 48·3% [95% CI 39·9–56·7]); 35 had complete response and 35 had partial response. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). Serious adverse events were reported in 57 (39%) of 145 patients. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine. Interpretation Loncastuximab tesirine has substantial single-agent antitumour activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL. Funding ADC Therapeutics.