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Mutations in the lever arm of β-cardiac myosin are a frequent cause of hypertrophic cardiomyopathy, a disease characterized by hypercontractility and eventual hypertrophy of the left ventricle. Here, we studied five such mutations: three in the pliant region of the lever arm (D778V, L781P, and S782N) and two in the light chain-binding region (A797T and F834L). We investigated their effects on both motor function and myosin subfragment 2 (S2) tail-based autoinhibition. The pliant region mutations had varying effects on the motor function of a myosin construct lacking the S2 tail: overall, D778V increased power output, L781P reduced power output, and S782N had little effect on power output, while all three reduced the external force sensitivity of the actin detachment rate. With a myosin containing the motor domain and the proximal S2 tail, the pliant region mutations also attenuated autoinhibition in the presence of filamentous actin but had no impact in the absence of actin. By contrast, the light chain-binding region mutations had little effect on motor activity but produced marked reductions in autoinhibition in both the presence and absence of actin. Thus, mutations in the lever arm of β-cardiac myosin have divergent allosteric effects on myosin function, depending on whether they are in the pliant or light chain-binding regions.

To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an ‘off’ state that can be converted to an ‘on’ state when exertion is increased. The ‘off’ state is equated with a folded-back structure known as the interacting-heads motif (IHM), which is a regulatory feature of all class-2 muscle and non-muscle myosins. We report here the human β-cardiac myosin IHM structure determined by cryo-electron microscopy to 3.6 Å resolution, providing details of all the interfaces stabilizing the ‘off’ state. The structure shows that these interfaces are hot spots of hypertrophic cardiomyopathy mutations that are thought to cause hypercontractility by destabilizing the ‘off’ state. Importantly, the cardiac and smooth muscle myosin IHM structures dramatically differ, providing structural evidence for the divergent physiological regulation of these muscle types. The cardiac IHM structure will facilitate development of clinically useful new molecules that modulate IHM stability. The authors report the high-resolution structure of human β-cardiac myosin in its sequestered state. The results provide insights into the cardiac regulation and represent a tool to investigate the development of inherited cardiomyopathies.

The Coronavirus disease 2019 (COVID-19) global pandemic has transformed almost every facet of human society throughout the world. Against an emerging, highly transmissible disease, governments worldwide have implemented non-pharmaceutical interventions (NPIs) to slow the spread of the virus. Examples of such interventions include community actions, such as school closures or restrictions on mass gatherings, individual actions including mask wearing and self-quarantine, and environmental actions such as cleaning public facilities. We present the Worldwide Non-pharmaceutical Interventions Tracker for COVID-19 (WNTRAC), a comprehensive dataset consisting of over 6,000 NPIs implemented worldwide since the start of the pandemic. WNTRAC covers NPIs implemented across 261 countries and territories, and classifies NPIs into a taxonomy of 16 NPI types. NPIs are automatically extracted daily from Wikipedia articles using natural language processing techniques and then manually validated to ensure accuracy and veracity. We hope that the dataset will prove valuable for policymakers, public health leaders, and researchers in modeling and analysis efforts to control the spread of COVID-19. Measurement(s) Preventive Intervention • Public Health Technology Type(s) natural language processing objective • Artificial Intelligence Sample Characteristic - Environment anthropogenic environment Sample Characteristic - Location Global Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.13999484

Telemedicine has been adopted in the inpatient setting to facilitate clinical interactions between on-site clinicians and isolated hospitalized patients. Such remote interactions have the potential to reduce pathogen exposure and use of personal protective equipment but may also pose new safety concerns given prior evidence that isolated patients can receive suboptimal care. Formal evaluations of the use and practical acceptance of inpatient telemedicine among hospitalized patients are lacking. We aimed to evaluate the experience of patients hospitalized for COVID-19 with inpatient telemedicine introduced as an infection control measure during the pandemic. We conducted a qualitative evaluation in a COVID-19 designated non-intensive care hospital unit at a large academic health center (Stanford Health Care) from October 2020 through January 2021. Semistructured qualitative interviews focused on patient experience, impact on quality of care, communication, and mental health. Purposive sampling was used to recruit participants representing diversity across varying demographics until thematic saturation was reached. Interview transcripts were qualitatively analyzed using an inductive-deductive approach. Interviews with 20 hospitalized patients suggested that nonemergency clinical care and bridging to in-person care comprised the majority of inpatient telemedicine use. Nurses were reported to enter the room and call on the tablet far more frequently than physicians, who typically entered the room at least daily. Patients reported broad acceptance of the technology, citing improved convenience and reduced anxiety, but preferred in-person care where possible. Quality of care was believed to be similar to in-person care with the exception of a few patients who wanted more frequent in-person examinations. Ongoing challenges included low audio volume, shifting tablet location, and inconsistent verbal introductions from the clinical team. Patient experiences with inpatient telemedicine were largely favorable. Although most patients expressed a preference for in-person care, telemedicine was acceptable given the circumstances associated with the COVID-19 pandemic. Improvements in technical and care team use may enhance acceptability. Further evaluation is needed to understand the impact of inpatient telemedicine and the optimal balance between in-person and virtual care in the hospital setting.

Background MYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies. Methods INSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti–host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2). Results Total enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 ( P  > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P  = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P  > 0.999). Conclusions In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively. Trial registration ClinicalTrials.gov, INSTRIDE 1 ( NCT02227862 ; date of registration, August 28, 2014); INSTRIDE 2 ( NCT02227875 ; date of registration, August 28, 2014).

Macrodontia is a dental anomaly pertaining to the increased size of a tooth or multiple teeth. Double teeth are dental abnormalities concerning tooth morphology and the term traditionally refers to geminated or fused teeth. These anomalies may manifest in both primary and permanent dentitions and usually become apparent in childhood. They may cause a variety of clinical sequelae, including orthodontic complications, such as crowding, ectopic eruption of adjacent teeth and periodontal concerns. Double teeth are also at a higher risk of developing caries. The aesthetic implications of these dental anomalies can affect the psychosocial development of a patient. This, together with the range of functional repercussions, can often need dental treatment to improve quality of life. The functional and aesthetic complexities that may arise in the affected patients can require endodontic, restorative, surgical and/or orthodontic input as part of the management strategy and execution. We present four clinical cases of paediatric patients where a range of management approaches were employed for both macrodontia and double teeth.Key pointsThis paper provides a review of the literature regarding macrodontia and double teeth and the treatment options available.We present a number of cases managed in our department employing a range of treatment approaches.We advocate multidisciplinary input in the planning and management of macrodontia and double teeth in the permanent dentition.

Purpose of Review \"How do various nutrients influence the pathophysiology of rosacea, and what are the specific biochemical markers and genetic factors involved in the dietary modulation of this inflammatory skin condition?\". Explanation The goal of this review is to examine the complex relationship between diet and rosacea, particularly focusing on how various nutrients may influence the pathophysiology of this common inflammatory skin condition. We seek to answer questions regarding the specific biochemical markers and genetic factors involved, as well as the potential pathways through which diet can exacerbate or mitigate rosacea symptoms. Recent Findings Recent research has highlighted the significance of genetic and environmental factors in the pathogenesis of rosacea, with a particular emphasis on neurovascular dysregulation, innate immune responses, and skin microbiota imbalances. Studies have identified the roles of various biochemical markers, such as IGFBPs, SHBG, mTORC-1, and FOXO1, and their interactions with dietary elements like glycemic load, glycemic index, and vitamin D. The activation of transient receptor potential (TRP) cation channels and their impact on neurogenic vasodilation has also been explored, providing new insights into potential pathogenic pathways. Review Summary This review concludes that the pathophysiology of rosacea is multifaceted, involving intricate interactions between diet, genetic predispositions, and environmental factors. Key findings include the identification of specific biochemical markers and genetic pathways that are influenced by dietary intake, which in turn affect the severity of rosacea symptoms. Understanding these connections opens avenues for future research focused on targeted dietary interventions as potential therapeutic strategies for managing rosacea. The major takeaway is the significant impact of diet on rosacea, which may guide future studies and clinical practices aimed at improving patient outcomes through nutritional modifications. Graphical Abstract

IntroductionThe paediatric dentistry department at St Thomas’ Hospital transformed its walk-in emergency service to an urgent dental centre during the COVID-19 pandemic, accepting referrals via the NHS 111 service. There are conflicting ethical duties for tertiary care clinicians managing paediatric dental patients. This study measured the current activity levels of the dental emergency service at St Thomas’ Hospital, the appropriateness of NHS 111 referrals, the proportion of referrals accepted for care and the outcomes of those accepted referrals.MethodsA retrospective service evaluation was undertaken including 125 patients referred by the NHS 111 service to the dental emergency clinic at St Thomas’ Hospital between 1 September and 29 October 2021.ResultsHalf (50%) of the patients seen were aged between 0 and 5 years. A quarter (24%) of referrals were true dental emergencies. Patients were referred for isolated dental pain (58%), facial swelling (25%), trauma (13%), broken fillings (3%) and other conditions (2%). Three-quarters (74%) were accepted for treatment. Most accepted patients were added to waiting lists for treatment under general anaesthesia (66%), local anaesthesia (5%) or inhalation sedation (4%). Two-thirds of accepted patients (67%) were not registered with a dentist while over three-quarters of rejected patients (79%) had their own dentist in primary care.ConclusionsFollowing the pandemic, paediatric dental emergency services continue to be overwhelmed by children requiring non-urgent dental care. Solutions to deteriorating patient access are crucial, ensuring that provision of care remains ethical and that those who require urgent dental care are prioritised.

Long-distance transport of many organelles inside eukaryotic cells is driven by the dynein and kinesin motors on microtubule filaments. More than 30 years since the discovery of these motors, unanswered questions include motor–organelle selectivity, structural determinants of processivity, collective behaviour of motors and track selection within the complex cytoskeletal architecture, to name a few. Fluorescence microscopy has been invaluable in addressing some of these questions. Here we present a review of some efforts to understand these sub-microscopic machines using fluorescence.

Scaling petaflop supercomputers to exascale requires a 500x increase in FLOPS, but at the cost of only a 3x increase in the total power consumption. In addition, computing systems implemented with nanometer scale multi-gate field effect transistors are increasingly integrating heterogeneous cores, GPUs, and accelerators. The power delivery and energy management of such complex chip multi-processors (CMP) is, therefore, a challenging research task spanning across the system, architecture, circuits, and device stack. A set of on-chip energy management techniques that are similar to supply side and demand side management in a SMART grid is developed. The techniques span the circuit and system layers. Intelligence is introduced in the operation of the on-chip power distribution network (PDN) to sense variations in the computational activity across cores and reconfigure the PDN to optimize the energy efficiency. A circuit level technique that improves the energy efficiency through the implementation of under-provisioned on-chip voltage regulators (OCVRs) interconnected through a switch network is developed. An operating system level task scheduling heuristic distributes the workloads on the cores such that the required reconfiguration of the PDN is minimized. SPICE simulations indicate up to a 44% reduction in the energy consumption of the CMP. An evolving on-chip power delivery methodology where reference voltages of the OCVRs are controlled through a particle swarm optimizer (PSO) is developed. The PSO negates the effects of transistor aging and process, temperature, and power supply noise induced variation in the load circuit, OCVRs, and on-chip timing sensors. The simulation results indicate an average reduction of 35% and 5% in, respectively, the power consumption and operating temperature of the voltage domains. In addition, the end of life of the voltage domain is prolonged due to a mean reduction in the aging induced Vth shift of 40%. Novel circuit techniques to detect and set the power supply voltages and suppress power supply noise are developed. The run-time circuit techniques for power supply voltage detection and clamping are demonstrated for a heterogeneous 3-D integrated circuit through SPICE simulation of a device plane in a 22 nm technology and a power plane in a 45 nm technology. The power supply voltages of less than 1 V are successfully set and provided as a reference to an OCVR within 500 ns of initiating an active state and with variation of less than 1% in the reference voltage. Noise on the power supply is suppressed through the use of hyperabrupt p-n junction varactors as on-chip decoupling capacitors. The voltage droops and overshoots on the on chip power distribution network are suppressed by up to 60% as compared to metal insulator metal (MIM) or deep trench decoupling capacitors of the same capacitance. With approximately 42% and 15% of the data center power consumed by, respectively, the processors and the cooling system, the run-time energy management techniques developed in this thesis have significant potential to reduce the running cost of exascale data centers.