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Abstract Background Neuroblastoma (NB) is a heterogeneous embryonal malignancy and the deadliest tumor of infancy. It is a complex disease that can result in diverse clinical outcomes. In some children, tumors regress spontaneously. Others respond well to existing treatments. But for the high-risk group, which constitutes approximately 40% of all patients, the prognosis remains dire despite collaborative efforts in basic and clinical research. While its exact cellular origin is still under debate, NB is assumed to arise from the neural crest cell lineage including multipotent Schwann cell precursors (SCPs), which differentiate into sympatho-adrenal cell states eventually producing chromaffin cells and sympathoblasts. Methods To investigate clonal development of neuroblastoma cell states, we performed haplotype-specific analysis of human tumor samples using single-cell multi-omics, including joint DNA/RNA sequencing of sorted single cells (DNTR-seq). Samples were also assessed using immunofluorescence stainings and fluorescence in-situ hybridization (FISH). Results Beyond adrenergic tumor cells, we identify subpopulations of aneuploid SCP-like cells, characterized by clonal expansion, whole-chromosome 17 gains, as well as expression programs of proliferation, apoptosis, and a non-immunomodulatory phenotype. Conclusion Aneuploid pre-malignant SCP-like cells represent a novel feature of NB. Genetic evidence and tumor phylogeny suggest that these clones and malignant adrenergic populations originate from aneuploidy-prone cells of migrating neural crest or SCP origin, before lineage commitment to sympatho-adrenal cell states. Our findings expand the phenotypic spectrum of NB cell states. Considering the multipotency of SCPs in development, we suggest that the transformation of fetal SCPs may represent one possible mechanism of tumor initiation in NB with chromosome 17 aberrations as a characteristic element.

IntroductionRecognition memory, an essential component of cognitive health, can suffer from biological limitations of stress, aging, or neurodegenerative disease. Vagus nerve stimulation (VNS) is a neuromodulation therapy with the potential to improve cognitive function. This study investigated the effectiveness of multiple sessions of VNS to enhance recognition memory in healthy rodents and the underlying cognitive benefits of VNS by proteomic analysis of the synaptosome.MethodsRats demonstrated VNS-induced recognition memory improvements using a novel object recognition (NOR) task. Using the LC–MS/MS method, roughly 3,000 proteins in the synaptosome of the hippocampus were analyzed.ResultsProtein–protein interaction (PPI) enrichment analysis found differentially expressed proteins related to synaptic signaling and neurotransmitter pathways. PPI network analysis identified six unique protein clusters, including a cluster of synaptic signaling related pathways. Using ingenuity pathway analysis (IPA), rapamycin-insensitive companion of mTOR was identified as an upstream regulator of synaptosome changes due to VNS-paired training.DiscussionBased on these results, it is proposed that VNS may mediate cognitive enhancement via increases in glutamatergic signaling and early LTP during the consolidation period, followed by sustained synaptic plasticity via modified post-synaptic receptor expression and dendritic outgrowth. Further investigation is required to determine if VNS is a good candidate to ameliorate cognitive impairment.

Educational technologies are often developed such that students work on specific social levels (e.g., individual, small group, whole class) at specific times. However, in the reality of the classroom, learning activities are not so cleanly divided, with transitions occurring between social levels for students at different times. To support these social transitions in a way that can promote student learning, we need to lower the teacher's orchestration load around managing fluid social transitions. Co-orchestration, in which the orchestration decisions are shared between different parties, can help to lower the orchestration load when it is designed according to the teacher's values and classroom culture. In this paper, we present a taxonomy of social transitions and investigate how the responsibilities of orchestration can be divided between primary school teachers and a co-orchestration system in order to support the extension from rigid social transitions to fluid transitions in technology-enhanced classrooms. We used a design process involving teachers and thematic analysis to uncover co-orchestration design desiderata that balance teachers' orchestration loads while providing them with a sense of control. We present six design desires for maintaining a balance between teacher and system responsibilities regarding the orchestration of social transitions that can be implemented, such as in our mid-fidelity prototype, to support the range of social transitions. The list of desires contribute to co-orchestration research and more broadly technology design for classrooms by highlighting the changing balance of teacher control depending on what is the focus of the orchestration support.

Abstract Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determine crystal structures of VHL/753b/BCL-xL and VHL/753b/BCL-2 ternary complexes. The two ternary complexes exhibit markedly different architectures that are accompanied by distinct networks of interactions at the VHL/753b-linker/target interfaces. The importance of these interfacial contacts is validated via functional analysis and informed subsequent rational and structure-guided design focused on the 753b linker and BCL-2/BCL-xL warhead. This results in the design of a degrader, WH244, with enhanced potency to degrade BCL-xL/BCL-2 in cells. Using biophysical assays followed by in cell activities, we are able to explain the enhanced target degradation of BCL-xL/BCL-2 in cells. Most PROTACs are empirically designed and lack structural studies, making it challenging to understand their modes of action and specificity. Our work presents a streamlined approach that combines rational design and structure-based insights backed with cell-based studies to develop effective PROTAC-based cancer therapeutics.

IntroductionClinician implicit racial bias (IB) may lead to lower quality care and adverse health outcomes for Black patients. Educational efforts to train clinicians to mitigate IB vary widely and have insufficient evidence of impact. We developed and pilot-tested an evidence-based clinician IB curriculum, “REACHing Equity.”MethodsTo assess acceptability and feasibility, we conducted an uncontrolled one-arm pilot trial with post-intervention assessments. REACHing Equity is designed for clinicians to: (1) acquire knowledge about IB and its impact on healthcare, (2) increase awareness of one's own capacity for IB, and (3) develop skills to mitigate IB in the clinical encounter. We delivered REACHing Equity virtually in three facilitated, interactive sessions over 7–9 weeks. Participants were health care providers who completed baseline and end-of-study evaluation surveys.ResultsOf approximately 1,592 clinicians invited, 37 participated, of whom 29 self-identified as women and 24 as non-Hispanic White. Attendance averaged 90% per session; 78% attended all 3 sessions. Response rate for evaluation surveys was 67%. Most respondents agreed or strongly agreed that the curriculum objectives were met, and that REACHing Equity equipped them to mitigate the impact of implicit bias in clinical care. Participants consistently reported higher self-efficacy for mitigating IB after compared to before completing the curriculum.ConclusionsDespite apparent barriers to clinician participation, we demonstrated feasibility and acceptability of the REACHing Equity intervention. Further research is needed to develop objective measures of uptake and clinician skill, test the impact of REACHing Equity on clinically relevant outcomes, and refine the curriculum for uptake and dissemination.ClinicalTrials.gov ID: NCT03415308.

Abstract Shotgun proteomics is essential for protein identification and quantification in biomedical research, but protein isoform characterization is challenging due to the extensive number of peptides shared across proteins, hindering our understanding of protein isoform regulation and their roles in normal and disease biology. We systematically assess the challenge and opportunities of shotgun proteomics-based protein isoform characterization using in silico and experimental data, and then present SEPepQuant, a graph theory-based approach to maximize isoform characterization. Using published data from one induced pluripotent stem cell study and two human hepatocellular carcinoma studies, we demonstrate the ability of SEPepQuant in addressing the key limitations of existing methods, providing more comprehensive isoform-level characterization, identifying hundreds of isoform-level regulation events, and facilitating streamlined cross-study comparisons. Our analysis provides solid evidence to support a widespread role of protein isoform regulation in normal and disease processes, and SEPepQuant has broad applications to biological and translational research.

Abstract ISG15 plays a crucial role in the innate immune response and has been well-studied due to its antiviral activity and regulation of signal transduction, apoptosis, and autophagy. ISG15 is a ubiquitin-like protein that is activated by an E1 enzyme (Uba7) and transferred to a cognate E2 enzyme (UBE2L6) to form a UBE2L6-ISG15 intermediate that functions with E3 ligases that catalyze conjugation of ISG15 to target proteins. Despite its biological importance, the molecular basis by which Uba7 catalyzes ISG15 activation and transfer to UBE2L6 is unknown as there is no available structure of Uba7. Here, we present cryo-EM structures of human Uba7 in complex with UBE2L6, ISG15 adenylate, and ISG15 thioester intermediate that are poised for catalysis of Uba7-UBE2L6-ISG15 thioester transfer. Our structures reveal a unique overall architecture of the complex compared to structures from the ubiquitin conjugation pathway, particularly with respect to the location of ISG15 thioester intermediate. Our structures also illuminate the molecular basis for Uba7 activities and for its exquisite specificity for ISG15 and UBE2L6. Altogether, our structural, biochemical, and human cell-based data provide significant insights into the functions of Uba7, UBE2L6, and ISG15 in cells.

Abstract Introduction Obtaining body weights remotely could improve feasibility of pragmatic trials. This investigation examined whether weights collected via cellular scale or electronic health record (EHR) correspond to gold standard in‐person study weights. Methods The agreement of paired weight measurements from cellular scales were compared to study scales from a weight loss intervention and EHR‐collected weights were compared to study scales from a weight loss maintenance intervention. Differential weight change estimates between intervention and control groups using both pragmatic methods were compared to study collected weight. In the Log2Lose feasibility weight loss trial, in‐person weights were collected bi‐weekly and compared to weights collected via cellular scales throughout the study period. In the MAINTAIN weight loss maintenance trial, in‐person weights were collected at baseline, 14, 26, 42 and 56 weeks. All available weights from the EHR during the study period were obtained. Results On average, in Log2Lose cellular scale weights were 0.6 kg (95% CI: −2.9, 2.2) lower than in‐person weights; in MAINTAIN, EHR weights were 2.8 kg (SE: −0.5, 6.0) higher than in‐person weights. Estimated weight change using pragmatic methods and study scales in both studies were in the same direction and of similar magnitude. Conclusion Both methods can be used as cost‐effective and real‐world surrogates within a tolerable variability for the gold‐standard. Trial registration NCT02691260; NCT01357551.

Abstract Proteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage—a process crucial for viral survival and replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2H)-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is a potent, covalent inhibitor of both the proteases and its potency was evaluated in enzymatic and antiviral assays. In this study, we screened a collection of 34 ebselen and ebselen diselenide derivatives for SARS-CoV-2 PLpro and Mpro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four Mpro inhibitors superior to ebselen. Independently, ebselen was shown to inhibit the N7-methyltransferase activity of SARS-CoV-2 nsp14 protein involved in viral RNA cap modification. Hence, selected compounds were also evaluated as nsp14 inhibitors. In the second part of our work, we employed 11 ebselen analogues—bis(2-carbamoylaryl)phenyl diselenides—in biological assays to evaluate their anti-SARS-CoV-2 activity in Vero E6 cells. We present their antiviral and cytoprotective activity and also low cytotoxicity. Our work shows that ebselen, its derivatives, and diselenide analogues constitute a promising platform for development of new antivirals targeting the SARS-CoV-2 virus.

This article applies object detection to CCTV video material to investigate the potential of using machine learning to automate behavior tracking. This study includes video tapings of two captive Bornean orangutans and their behavior. From a 2 min training video containing the selected behaviors, 334 images were extracted and labeled using Rectlabel. The labeled training material was used to construct an object detection model using Create ML. The use of object detection was shown to have potential for automating tracking, especially of locomotion, whilst filtering out false positives. Potential improvements regarding this tool are addressed, and future implementation should take these into consideration. These improvements include using adequately diverse training material and limiting iterations to avoid overfitting the model.

Background: Continuity of care (COC) for older adults has been associated with lower use of healthcare services, decreased risk of hospitalisation, and lower mortality. However, research on COC in older adults is limited by short time periods and small sample sizes. Long-term COC can only develop if the patient stays with the general practice for ≥10 years. Therefore, research that focuses on long duration and broader populations is needed. Aim: To measure the extent of longitudinal site-level COC in general practice and listing duration of the patient–general practice relation for all older Danish citizens. Design & setting: Retrospective cohort study of all patients aged ≥65 years on 31 December 2021 listed with a Danish general practice (N = 1 144 941 persons). Method: Individual-level register data were used on start and end dates for listing with a general practice to analyse site-level COC by number of changes and listing duration of the patient–general practice relation from January 2007–December 2021. Results: During the 15 years, 39.3% of older adults did not change general practice. Among the remaining 60.7%, who experienced discontinuity of care, 34.0% changed once, 16.3% changed twice, and 6.3% changed three times. Overall, 3 times. The duration of the patient–general practice relations were on average 9.5 years. Overall, 27.5% lasted 0–4 years, 33.7% lasted 5–9 years, and 38.8% lasted ≥10 years. Conclusion: Danish general practice provides high levels of site-level COC for their older patients. On average, patients aged ≥65 years changed general practice once and had a patient–general practice relation length of 9.5 years.

IntroductionWomen with early ovarian removal (

Abstract Background The purpose of this manuscript is to introduce reserve and resilience as novel concepts in chronic kidney disease (CKD) research and present baseline data from a unique prospective cohort study designed to characterize recovery from functional decline after a health event. Methods The Physical REsilience Prediction in Advanced REnal Disease (PREPARED) study recruited a national, prospective cohort of Veterans ≥70 years old with an estimated glomerular filtration rate (eGFR)

Introduction Out-of-hours primary care services cannot provide the same continuity and coordination of care as general practice. Thus, patients with high risk of complex care trajectories should, when possible, be treated by the general practitioner during daytime opening hours. This study aims to analyse the variation among general practices in the frequencies of daytime services for persons aged ≥75 years and how it relates to the patients’ use of out-of-hours services.Methods and analysis Register-based cohort study of all Danish citizens aged ≥75 years, of whom >98% are listed with a general practice. Using Poisson regression, we will estimate each practice’s excess variation in delivered daytime services compared with the expected based on the characteristics of its listed patients. Delivered daytime services will be analysed overall and separately for face-to-face, phone, email, home visit and preventive services. The association with the use of out-of-hours services will be analysed by Poisson regression.Ethics and dissemination Complying with European data protection rules, the legal services at University of Southern Denmark (Research & Innovation Organisation) approved the data processing activities regarding this project (journal number 11.593). According to section 14.2 of the Act on Research Ethics Review of Health Research Projects, because the study is based solely on register data, approval from the ethics committee and informed consent are not required. Results from the study will be disseminated as publications in peer-reviewed scientific journals and at international conferences.

Background: Vagus nerve stimulation (VNS) improves cognition in humans and rodents, but the effects of a single session of VNS on performance and plasticity are not well understood. Objective: Behavioral performance and hippocampal (HC) electrophysiology/neurotrophin expression were measured in healthy adult rats after VNS paired training to investigate changes in cognition and synaptic plasticity. Methods: Platinum/iridium electrodes were surgically implanted around the left cervical branch of the VN of anesthetized male Sprague-Dawley rats (N = 47). VNS (100 μs biphasic pulses, 30 Hz, 0.8 mA) paired Novel Object Recognition (NOR)/Passive Avoidance Task (PAT) were assessed 24 h after training and post-mortem tissue was collected 48 h after VNS (N = 28). Electrophysiology recordings were collected using a microelectrode array system to assess functional effects on HC slices 90 min after VNS (N = 19). Sham received the same treatment without VNS and experimenters were blinded. Results: Stimulated rats exhibited improved performance in NOR (p

Abstract Essential oils and aromatic extracts (oleoresins, absolutes, concretes, resinoids) are often used as food flavorings and constituents of fragrance compositions. The flavor and fragrance industry observed significant growth in the sales of some natural materials during the COVID-19 outbreak. Some companies worldwide are making false claims regarding the effectiveness of their essential oils or blends (or indirectly point toward this conclusion) against coronaviruses, even though the available data on the activity of plant materials against highly pathogenic human coronaviruses are very scarce. Our exploratory study aimed to develop pioneering knowledge and provide the first experimental results on the inhibitory properties of hundreds of flavor and fragrance materials against SARS-CoV-2 main and papain-like proteases and the antiviral potential of the most active protease inhibitors. As essential oils are volatile products, they could provide an interesting therapeutic strategy for subsidiary inhalation in the long term.

Uba6 is an E1 enzyme that regulates numerous cellular processes by activating ubiquitin and FAT10 pathways. Here, the authors present crystal structures that illuminate Uba6 catalytic mechanisms and reveal inositol hexakisphosphate as a cofactor that modulates Uba6 activity.

Vagus nerve stimulation (VNS) has been recognized as a useful neuromodulation tool to target the central nervous system by electrical stimulation of peripheral nerves. Activation of the nucleus of the solitary tract (NTS) in the brainstem by vagal afferent nerve fibers allows for modulation of various higher order brain regions, including limbic and cerebral cortex structures. Along with neurological and psychiatric indications, clinical and preclinical studies suggest that VNS can improve memory. While the underlying mechanisms to improve memory with VNS involve brain areas, such as the prefrontal cortex and processes including alertness and arousal, here we focus on VNS-induced memory improvements related to the hippocampus, the main area implicated in memory acquisition. In addition, we detail research demonstrating that a targeted approach to VNS can modify memory outcomes and delve into the molecular mechanisms associated with these changes. These findings indicate that a greater understanding of VNS mechanisms while also considering stimulation parameters, administration site, timing in relation to training, and sex-specific factors, may allow for optimal VNS application to enhance memory.

It is well established that episodic memory declines with age and one of the primary explanations for this decline is an age-related impairment in the ability to form new associations. At a neural level, both the medial temporal lobe (MTL) and lateral prefrontal cortex (PFC) are thought to be critical for associative memory, and grey matter volume loss in these regions has been associated with age-related declines in episodic memory. While some recent work has compared the relative contributions of grey matter volume in MTL and PFC regions to item and associative memory, studies investigating the unique and shared contributions of age-related differences in the MTL and PFC to memory differences are still rare. In this study, we use a lifespan approach to examine the relationship between grey matter volume within substructures of the MTL and PFC on the one hand and item and associative memory on the other. To this end, we used data from over 300 healthy individuals uniformly spread across the adult lifespan from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) and tested the multivariate relationship between grey matter volumes and item/associative memory scores using canonical correlation analysis. We show that structures of the PFC alone predict memory performance better than either structures of the MTL alone or PFC and MTL combined. Moreover, our results also indicate that grey matter volume in the inferior frontal gyrus - pars opercularis, superior frontal gyrus, and middle frontal gyrus relates most strongly to memory (particularly associative memory, which loaded higher than item memory) and this effect persists when controlling for age and education. Finally, we also show that the relationship between frontal grey matter volume and memory is not moderated by age or sex. Taken together, these findings emphasize the critical role of the frontal lobes, and the control processes they subserve, in determining the effects of age on associative memory.

Simultaneous targeting of BCL-xL and BCL-2 is an attractive approach for cancer treatment. Based on information gained by computational structure modelling, the authors develop a PROTAC that induces degradation of both BCL-xL and BCL-2 and effectively targets BCL-xL/2-dependent leukaemia cells.

Task-specific training constitutes a core element for evidence-based rehabilitation strategies targeted at improving upper extremity activity after stroke. Its combination with additional treatment strategies and neurotechnology-based solutions could further improve patients' outcomes. Here, we studied the effect of gamified robot-assisted upper limb motor training on motor performance, skill learning, and transfer with respect to a non-gamified control condition with a group of chronic stroke survivors. The results suggest that a gamified training strategy results in more controlled motor performance during the training phase, which is characterized by a higher accuracy (lower deviance), higher smoothness (lower jerk), but slower speed. The responder analyses indicated that mildly impaired patients benefited most from the gamification approach. In conclusion, gamified robot-assisted motor training, which is personalized to the individual capabilities of a patient, constitutes a promising investigational strategy for further improving motor performance after a stroke.

Abstract Background Erenumab, a monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor, is registered for migraine prevention. Compared to other conventional migraine prevention medicines (i.e. topiramate, betablockers and amitriptyline) erenumab has better tolerability. Impaired hemostasis has not been reported previously. Here, we report the first case of an increased tendency to bruise in a migraine patient treated with erenumab. Case presentation A 41-year old female migraine patient was treated with erenumab for 12 months, which led to a significant reduction of headache and migraine days. Three months after treatment start, she experienced increased tendency to bruise leading to extreme ecchymosis after 4 months treatment. Platelet counts and aggregation, thromboelastography, activated partial thromboplastin time (APTT) and international normalized ratio (INR) were all normal. Thorough interview revealed intake of fish oil supplements for many years prior to treatment. The increased tendency to bruise subsided after discontinuation of fish oil supplements. Conclusion The combination of fish oil supplements and erenumab may cause increased tendency to bruise. Erenumab has no effect on the platelets per se but may cause impaired wound healing by suppression of CGRP. Thus, small and unnoticeable bruises may be aggravated instead in patients with tendency to bruise caused by for instance fish oil supplements.

Objective: Pharmacological strategies that engage multiple mechanisms-of-action have demonstrated synergistic benefits for metabolic disease in preclinical models. One approach, concurrent activation of the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptors (i.e. triagonism), combines the anorectic and insulinotropic activities of GLP-1 and GIP with the energy expenditure effect of glucagon. While the efficacy of triagonism in preclinical models is known, the relative contribution of GcgR activation remains unassessed. This work aims to addresses that central question. Methods: Herein, we detail the design of unimolecular peptide triagonists with an empirically optimized receptor potency ratio. These optimized peptide triagonists employ a protraction strategy permitting once-weekly human dosing. Additionally, we assess the effects of these peptides on weight-reduction, food intake, glucose control, and energy expenditure in an established DIO mouse model compared to clinically relevant GLP-1R agonists (e.g. semaglutide) and dual GLP-1R/GIPR agonists (e.g. tirzepatide). Results: Optimized triagonists normalize body weight in DIO mice and enhance energy expenditure in a manner superior to that of GLP-1R mono-agonists and GLP-1R/GIPR co-agonists. Conclusions: These pre-clinical data suggest unimolecular poly-pharmacology as an effective means to target multiple mechanisms contributing to obesity and further implicate GcgR activation as the differentiating factor between incretin receptor mono- or dual-agonists and triagonists.

Whereas previous research has focused on the link between (mental and physical) workload and task performance, less is known about the intervening mechanisms influencing this relationship. In the present study, we test the moderating roles of daily recovery and total sleep time in the relationship between work pressure and daily task performance. Using performance and recovery theories, we hypothesized that (a) work pressure relates positively to daily task performance, and that both (b) daily recovery in the form of psychological detachment and relaxation, and (c) total sleep time independently enhance this relationship. Our hypotheses were tested in a 30-day diary study with 110 officer cadets on a cross-Atlantic voyage on a Naval sail ship. The results of multilevel modeling lend support to all three hypotheses. Taken together, our findings suggest that recovery and sleep duration between shifts play a key role in the relationship between daily work pressure and task performance. We discuss the implications of these findings for the stressor-detachment model.

Healthy aging is associated with episodic memory decline, particularly in the ability to encode and retrieve object-context associations (context memory). Neuropsychological and neuroimaging studies have highlighted the importance of the medial temporal lobes (MTL) in supporting episodic memory across the lifespan. However, given the functional heterogeneity of the MTL, volumetric declines in distinct regions may impact performance on specific episodic memory tasks, and affect the function of the large-scale neurocognitive networks supporting episodic memory encoding and retrieval. In the current study, we investigated how MTL structure may mediate age-related differences in performance on spatial and temporal context memory tasks, in a sample of 125 healthy adults aged 19–76 years old. Standard T1-weighted MRIs were segmented into the perirhinal, entorhinal and parahippocampal cortices, as well as the anterior and posterior hippocampal subregions. We observed negative linear and quadratic associations between age and volume of the parahippocampal cortex, and anterior and posterior hippocampal subregions. We also found that volume of the posterior hippocampus fully mediated the association between age and spatial, but not temporal context memory performance. Further, we employed a multivariate behavior partial-least-squares analysis to assess how age and regional MTL volumes correlated with brain activity during the encoding and retrieval of spatial context memories. We found that greater activity within lateral prefrontal, parietal, and occipital regions, as well as within the anterior MTL was related to older age and smaller volume of the posterior hippocampus. Our results highlight the heterogeneity of MTL contributions to episodic memory across the lifespan and provide support for the posterior-anterior shift in aging, and scaffolding theory of aging and cognition.

Abstract Introduction Long‐term effects of behavioral weight loss maintenance interventions need to be assessed in order to understand their durability of effects. This can be evaluated with the use of weights recorded in the electronic medical record. The goal of this study was to use electronic health record (EHR)‐recorded weight to examine outcomes 2 years beyond the completion of a trial in which participants were randomized to receive a weight maintenance intervention or usual care after required initial weight loss. Methods Weights collected in the Veteran's Affairs national EHR were obtained for 2 years following trial completion. Outliers and implausible weights were identified and removed prior to analysis. Mixed‐effects models with quadratic time were fit to estimate between‐arm differences in weight change. Results Model‐estimated weight at trial completion was 109.7 kg for usual care and 106.8 kg for intervention, estimated difference of −2.9 kg (95% confidence interval [CI]: −8.8, 3.0; p = 0.34). Two years later, estimated mean weight collected from (n = 211) participants with available EMR weights was 111.5 kg for usual care and 108.0 kg for intervention, estimated difference −3.4 kg (95% CI: −9.3, 2.4 kg; p = 0.35). Conclusions While not statistically significant, weights from the EHR suggest the possibility of a clinically meaningful difference that should be confirmed by future adequately powered studies.

Arginine methylation has been reported to regulate AKT-associated signalling. Here, the authors show that PRMT5-mediated arginine methylation promotes AKT activity and induces tumourigenesis.

The molecular mechanism of ubiquitin transfer from E1 to E2 enzymes is still unclear. By solving the crystal structure of a covalently trapped E1–E2–ubiquitin thioester mimetic, the authors identify two conformations of this complex which suggest an affinity switch mechanism for thioester transfer.

Strong, trusted partnerships within a social capital framework are core to Peace Corps’ successful international, national, and community interactions and outcomes. The Peace Corps’ integrated three level model has thrived since its beginning in 1961. During this time, about 250 000 two-year Volunteers have lived and worked in 142 countries. In March 2020, the Peace Corps had to evacuate all 7 000 currently serving Volunteers because of the world-wide Covid-19 pandemic, a task organized and completed in nine days. The evacuation’s success depended on the resiliency of these honored long-term partnerships, and specifically: a partnership model with three intertwining layers of collaboration between national and host country staff and Volunteers; years of respectful integration of Volunteers in local communities building mutual trust; in-country and cross-nation preparedness for health, safety, and security emergencies; transparent communication during the evacuation among all involved parties in every nation with Volunteers; and in-country and host country staff support across countries during the evacuation. This case study illustrates elements of effective and sustainable partnerships that ensure their effectiveness during a crisis and survival beyond the crisis. I write this at the anniversary of one year from my stepping down as the twentieth Director of the Peace Corps. During my tenure, I brought home all 7 000 currently serving Volunteers in nine days as the Covid-19 pandemic spread across countries. This massive – and successful – undertaking was possible because of long-standing and trusted partnerships between the Peace Corps and the communities and countries hosting Peace Corps Volunteers. This is my personal reflection and a reminder to build, honor, and tend relationships with international partners who are collaborators in learning, service, and research in good times and our friends, protectors, and allies in times of crisis.

Abstract Background Acute otitis media (AOM) is a common and most often self-limiting infection in childhood, usually managed in general practice. Even though antibiotics are only recommended when certain diagnostic and clinical criteria are met a high antibiotic prescription rate is observed. The study’s objective was to analyse associations between patient- and general practitioner (GP) characteristics and antibiotic prescribing for children with AOM in an effort to explain the high antibiotic prescribing rates. Methods All general practices in the Northern, Southern and Central regions of Denmark were invited to record symptoms, examinations, findings and antibiotic treatment for all children ≤7 years of age diagnosed with AOM during a four-week winter period in 2017/2018. Associations were analysed by means of multivariate logistic regressions. The study design was cross-sectional. Results GPs from 60 general practices diagnosed 278 children with AOM of whom 207 (74%) were prescribed antibiotics, most often penicillin V (60%). About half of the children had tympanometry performed. Antibiotic prescribing rates varied considerably between practices (0–100%). Antibiotic prescribing was associated with fever (odds ratio (OR) 3.69 95% confidence interval (CI) 1.93–7.05), purulent ear secretion (OR 2.35 95% CI 1.01–5.50) and poor general condition (OR 3.12 95% CI 1.31–7.46), and the practice’s antibiotic prescribing rate to other patients with symptoms of an acute respiratory tract infection (OR 2.85 CI 95% 1.07–7.60) and specifically to other children with AOM (OR 4.15 CI 95% 1.82–9.47). Conclusion GPs’ antibiotic prescribing rates for children with AOM vary considerably even considering the of signs, symptoms, request for antibiotics, and use of tympanometry. Interventions to reduce overprescribing should be targeted high-prescribing practices.

Objectives:. We sought to evaluate whether weight change up to 5 years after bariatric surgery differed by antidepressant class taken before surgery. Background:. Bariatric surgery induces significant weight loss, but outcomes are highly variable. The specific type of antidepressant used prior to surgery may be an important factor in long-term weight loss. Methods:. This retrospective cohort study from 2000 to 2016 compared the 5-year weight loss of 556 Veterans who were taking antidepressant monotherapy (bupropion, selective serotonin reuptake inhibitors [SSRIs], or serotonin-norepinephrine reuptake inhibitors [SNRIs]) before bariatric surgery (229 sleeve gastrectomy and 327 Roux-en-Y gastric bypass) versus 556 matched nonsurgical controls. Results:. Patients taking bupropion before sleeve gastrectomy had greater differential weight loss between surgical patients and matched controls than those taking SSRIs at 1 (8.9 pounds; 95% confidence interval [CI], 1.6–16.3; P = 0.02) and 2 years (17.6 pounds; 95% CI, 5.9–29.3; P = 0.003), but there was no difference at 5 years (11.9 pounds; 95% CI, –8.9 to 32.8; P = 0.26). Findings were similar for gastric bypass patients taking bupropion compared to SSRIs at 1 (9.7 pounds; 95% CI, 2.0–17.4; P = 0.014), 2 (12.0 pounds; 95% CI, –0.5 to 24.5; P = 0.06), and 5 years (4.8 pounds; 95% CI, –16.7 to 26.3; P = 0.66). No significant differences were observed comparing patients taking SNRI versus SSRI medications. Conclusions:. Sleeve gastrectomy and gastric bypass patients taking bupropion had greater weight loss than those taking SSRIs, although these differences may wane over time. Bupropion may be the first-line antidepressant of choice among patients with severe obesity considering bariatric surgery.

The emergence of severe acute respiratory syndrome (SARS-CoV-2) in 2019 marked the third occurrence of a highly pathogenic coronavirus in the human population since 2003. As the death toll surpasses 5 million globally and economic losses continue, designing drugs that could curtail infection and disease progression is critical. In the US, three highly effective Food and Drug Administration (FDA)–authorized vaccines are currently available, and Remdesivir is approved for the treatment of hospitalized patients. However, moderate vaccination rates and the sustained evolution of new viral variants necessitate the ongoing search for new antivirals. Several viral proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them the papain-like protease (PLpro) and the main protease (Mpro). Inhibition of these proteases would target viral replication, viral maturation, and suppression of host innate immune responses. Knowledge of inhibitors and assays for viruses were quickly adopted for SARS-CoV-2 protease research. Potential candidates have been identified to show inhibitory effects against PLpro and Mpro, both in biochemical assays and viral replication in cells. These results encourage further optimizations to improve prophylactic and therapeutic efficacy. In this review, we examine the latest developments of potential small-molecule inhibitors and peptide inhibitors for PLpro and Mpro, and how structural biology greatly facilitates this process.