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Remdesivir (RDV) is the first drug approved by the FDA for clinical treatment of hospitalized patients infected with COVID-19 because it has been shown to have good antiviral activity against a variety of viruses, including Arenaviridae and Coronaviridae viral families. However, it has been reported that its clinical treatment leads to the symptoms of sick sinus syndrome such as sinus bradycardia, conduction block, and sinus arrest, but the electrophysiological mechanism of its specific cardiac adverse events is still unclear. We report complementary, experimental, studies of its electrophysiological effects. In wireless cardiac telemetry experiments in vivo and electrocardiographic studies in ex vivo cardiac preparations, RDV significantly caused sinus bradycardia, sinus atrial block, and prolongation of the QT interval in guinea pigs. Dose-dependent effects of RDV on the electrical activities of sinoatrial node (SA node) preparations of guinea pigs were characterised by multielectrode, optical RH237 voltage mapping. These revealed reversibly reduced sinoatrial conduction time (SACT), increased AP durations (APDs), and decreased the pacemaking rate of the SA node. Patch-clamp experiments showed that RDV significantly inhibited the If current of HCN4 channels, resulting in a significant decrease in the spontaneous firing rate of SA node cells, which may underlie the development of sick sinus node syndrome. In addition, RDV significantly inhibits IKr currents in hERG channels, leading to prolongation of the QT interval and playing a role in bradycardia. Therefore, these findings provide insights into the understanding the bradycardia effect of RDV, which may be used as basic theoretical guidance for the intervention of its adverse events, and prompt safety investigations of RDV’s cardiac safety in the future.

Abstract Objective To conduct a systematic review and meta-analysis to investigate the clinical efficacy of acupuncture combined with active exercise training in improving pain and function of knee osteoarthritis (KOA) individuals. Data sources PubMed, EMBASE, The Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wan Fang Data, Technology Periodical Database and China Biology Medicine were searched from their inceptions to April 5, 2023. Review methods We analyzed trials of acupuncture combined with active exercise training for KOA. The included studies were of high quality (Jadad ≥ 4) and RCTs. Study selection, data extraction, risk of bias and quality assessment were independently performed by two reviewers. We performed systematic analyses based on different outcome measures, including total efficiency rate, visual analogue scale (VAS), the Western Ontario and Mcmaster Universities Osteoarthritis Index (WOMAC), the Lysholm Knee Scale (LKS) and range of motion (ROM). We used Review Manager 5.3 and Stata/MP 14.0 to analyze the data. And it was verified by trial sequence analysis (TSA). If I 2 > 50% and p

Ageing is an inevitable process that affects various tissues and organs of the human body, leading to a series of physiological and pathological changes. Mechanisms such as telomere depletion, stem cell depletion, macrophage dysfunction, and cellular senescence gradually manifest in the body, significantly increasing the incidence of diseases in elderly individuals. These mechanisms interact with each other, profoundly impacting the quality of life of older adults. As the ageing population continues to grow, the burden on the public health system is expected to intensify. Globally, the prevalence of musculoskeletal system diseases in elderly individuals is increasing, resulting in reduced limb mobility and prolonged suffering. This review aims to elucidate the mechanisms of ageing and their interplay while exploring their impact on diseases such as osteoarthritis, osteoporosis, and sarcopenia. By delving into the mechanisms of ageing, further research can be conducted to prevent and mitigate its effects, with the ultimate goal of alleviating the suffering of elderly patients in the future.

The direct-drive actuator of permanent magnet synchronous motor is an innovative application of servo technology in the field of high-voltage circuit breaker, which can drive the movable contact of high-voltage switch to complete the breaking and closing operation according to the optimal path. At present, the travel curve of motor direct-drive actuator cannot match the mechanism and system characteristics effectively, and there is no systematic planning method. To address the travel curve planning of motor direct-drive actuator, a travel curve planning method based on polynomial model and multi-objective optimization is proposed. Firstly, the kinematic and kinetic models of motor direct-drive actuator loads are established, then the polynomial model is used to generate the travel curve clusters, and finally, a multi-objective optimization algorithm is constructed based on the motor direct-drive actuator and circuit breaker operation indexes, and the multi-objective optimization algorithm weights are optimized by combining with particle swarm algorithm, and the best travel curve is selected. Simulation and experimental studies show that the method can achieve stable and reliable operation of the motor direct-drive operating mechanism, and can achieve 11.2% energy consumption optimization compared with existing methods, improve the overall power density of the system, and further reduce the overall running time and extend the service life of the dynamic contacts during continuous operation.

ObjectiveTo investigate the effects of vestibular rehabilitation training (VRT) combined with anti-vertigo drugs on vertigo and balance function in patients with vestibular neuronitis (VN).Data sourcesPubMed, EMBASE, The Cochrane Library, Web of Science, CNKI, Wan Fang Data, VIP, and CBM were searched until July 13, 2023.ParticipantsPatients with vestibular neuronitis participated in the study.ResultsTwenty one studies including 1,415 patients were included in this review for meta-analysis. According to the Physiotherapy Evidence Database (PEDro) quality assessment, four studies received high quality (≥seven scores) and 17 studies received moderate quality (six scores). The meta-analysis showed that VRT combined with anti-vertigo drugs significantly reduced the Dizziness Handicap Inventory (DHI) score, the Vestibular Disorders Activities of Daily Living Scale (VADL) score and the Canal Paresis (CP) score, and improved the overall efficiency and the Berg Balance Scale (BBS) score, promoting vestibular evoked myogenic potentials (VEMPs) returned to normal in VN compared to simple anti-vertigo drugs or VRT alone.ConclusionThe results of this meta-analysis demonstrate the efficacy and safety of VRT combined with anti-vertigo drugs in patients with VN. Combined therapy can alleviate vestibular dysfunction such as vertigo and vomiting in patients, improve daily activity ability and balance ability, in addition to VRT has fewer adverse reactions, so it is extremely safe. However, there are shortcomings such as lack of long-term follow-up and different frequency and duration of treatment. Therefore, future randomized controlled trials (RCTs) with larger sample sizes and longer-term observations are needed to verify the effectiveness of VRT in combination with anti-vertigo drugs for VN.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/

Abstract T‐wave alternans (TWA) has been used for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death (SCD) in multiple clinical settings; however, possible mechanism(s) underlying the spontaneous transition from cellular alternans reflected by TWA to arrhythmias in impaired repolarization remains unclear. The healthy guinea pig ventricular myocytes under E‐4031 blocking IKr (0.1 μM, N = 12; 0.3 μM, N = 10; 1 μM, N = 10) were evaluated using whole‐cell patch‐clamp. The electrophysiological properties of isolated perfused guinea pig hearts under E‐4031 (0.1 μM, N = 5; 0.3 μM, N = 5; 1 μM, N = 5) were evaluated using dual‐ optical mapping. The amplitude/threshold/restitution curves of action potential duration (APD) alternans and potential mechanism(s) underlying the spontaneous transition of cellular alternans to ventricular fibrillation (VF) were examined. There were longer APD80 and increased amplitude and threshold of APD alternans in E‐4031 group compared with baseline group, which was reflected by more pronounced arrhythmogenesis at the tissue level, and were associated with steep restitution curves of the APD and the conduction velocity (CV). Conduction of AP alternans augmented tissue's functional spatiotemporal heterogeneity of regional AP/Ca alternans, as well as the AP/Ca dispersion, leading to localized uni‐directional conduction block that spontaneous facilitated the formation of reentrant excitation waves without the need for additional premature stimulus. Our results provide a possible mechanism for the spontaneous transition from cardiac electrical alternans in cellular action potentials and intercellular conduction without the involvement of premature excitations, and explain the increased susceptibility to ventricular arrhythmias in impaired repolarization. In this study, we implemented voltage‐clamp and dual‐optical mapping approaches to investigate the underlying mechanism(s) for the arrhythmogenesis of cardiac alternans in the guinea pig heart at cellular and tissue levels. Our results demonstrated a spontaneous development of reentry from cellular alternans, arising from a combined actions of restitution properties of action potential duration, conduction velocity of excitation wave and interplay between alternants of action potential and the intracellular Ca handling. We believe this study provides new insights into underlying the mechanism, by which cellular cardiac alternans spontaneously evolves into cardiac arrhythmias.

Building energy codes are essential tools for achieving energy efficiency in buildings. However, the full energy savings potential of these codes can only be realized if buildings are constructed in compliance with them. Therefore, evaluating building energy code compliance is crucial in bridging the gap between the energy efficiency requirements set by energy codes and the actualized energy savings achieved. An energy code compliance evaluation serves as a mechanism to assess construction practices, evaluate the effectiveness of code enforcement, identify gaps in compliance, and guide strategies for improvement through training and education. Conducting code compliance evaluation activities involves field studies that require careful design and significant resources. Historically, more emphasis has been placed on developing and adopting building energy codes, while efforts to evaluate compliance have been relatively limited and lacking consistent approaches. The passage of the 2009 American Recovery and Reinvestment Act (ARRA), which mandated that states create plans for achieving 90% compliance within eight years, stimulated the need for an energy code compliance evaluation. As a result, federal, state, and local governments, and utilities have invested in the development of methodologies and tools for code compliance evaluation studies. This paper reviews the code compliance evaluation studies conducted in the United States over the past three decades. It describes and compares the methodologies and metrics used to assess building energy code compliance, summarizes the general elements and steps involved in the evaluation process, and discusses common issues in these studies. Over time, code compliance evaluation methodologies have evolved from isolated development within individual states, regions, and utilities, to widely accepted protocols applicable across different states and local jurisdictions. There has been a transition in compliance metrics, shifting from historical compliance rates to energy-consumption-oriented approaches.

Building energy code compliance is the crucial link between the actual energy savings and the efficiency prescribed in energy codes. A research project aiming to identify opportunities to reduce energy consumption in new single-family residential construction by increasing compliance with the building energy code was conducted in several states of the United States. The study was comprised of three phases: (1) a baseline study to document typical practice and identify opportunities for improvement based on empirical data gathered from the field; (2) an education and training phase targeting the opportunities identified; and (3) a post-study to assess whether a reduction in average state-wide energy use could be achieved following the education and training phase. We proposed a novel methodology based on large-scale building energy simulation inferred by limited field data to assess the performance of a large population of homes. This paper presents the methodology, findings, and results of this study. The state-wide average energy consumption decreased at Phase III from Phase I for five of the seven states involved in the analysis. The measure-level savings potential analysis shows an overall reduction. Overall, the training and education phase plays a recognizable role in improving compliance with building energy codes.