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AimsLoss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis.Methods and resultsThis was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides >150 mg/dL (>1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild.ConclusionVupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.

Social interaction can be seen as a dynamic feedback loop that couples action, reaction, and internal cognitive processes across individual agents. A fuller understanding of the social brain requires a description of how the neural dynamics across coupled brains are linked and how they coevolve over time. We elaborate a multi-brain framework that considers social interaction as an integrated network of neural systems that dynamically shape behavior, shared cognitive states, and social relationships. We describe key findings from multi-brain experiments in humans and animal models that shed new light on the function of social circuits in health and disease. Finally, we discuss recent progress in elucidating the cellular-level mechanisms underlying inter-brain neural dynamics and outline key areas for future research.

A central question related to virtually all social decisions is how animals integrate sex-specific cues from conspecifics. Using microendoscopic calcium imaging in mice, we find that sex information is represented in the dorsal medial prefrontal cortex (dmPFC) across excitatory and inhibitory neurons. These cells form a distributed code that differentiates the sex of conspecifics and is strengthened with social experience. While males and females both represent sex in the dmPFC, male mice show stronger encoding of female cues, and the relative strength of these sex representations predicts sex preference behavior. Using activity-dependent optogenetic manipulations of natively active ensembles, we further show that these specific representations modulate preference behavior toward males and females. Together, these results define a functional role for native representations of sex in shaping social behavior and reveal a neural mechanism underlying male- versus female-directed sociality.

Background22q11.2 deletions and duplications are copy number variations (CNVs) that predispose to developmental neuropsychiatric disorders. Both CNVs are associated with autism spectrum disorder (ASD), while the deletion confers disproportionate risk for schizophrenia. Neurobehavioral profiles associated with these reciprocal CNVs in conjunction with brain imaging measures have not been reported.MethodsWe profiled the impact of 22q11.2 CNVs on neurobehavioral measures relevant to ASD and psychosis in 106 22q11.2 deletion carriers, 38 22q11.2 duplication carriers, and 82 demographically matched healthy control subjects. To determine whether brain-behavior relationships were altered in CNV carriers, we further tested for interactions between group and regional brain structure on neurobehavioral domains.ResultsCognitive deficits were observed in both CNV groups, with the lowest IQs in deletion carriers. ASD and dimensionally measured ASD traits were elevated in both CNV groups; however, duplication carriers exhibited increased stereotypies compared to deletion carriers. Moreover, discriminant analysis using ASD subdomains distinguished between CNV cases with 76% accuracy. Both psychotic disorder diagnosis and dimensionally measured positive and negative symptoms were elevated in deletion carriers. Finally, healthy control subjects showed an inverse relationship between processing speed and cortical thickness in heteromodal association areas, which was absent in both CNV groups.Conclusions22q11.2 CNVs differentially modulate intellectual functioning and psychosis-related symptomatology but converge on broad ASD-related symptomatology. However, subtle differences in ASD profiles distinguish CNV groups. Processing speed impairments, coupled with the lack of normative relationship between processing speed and cortical thickness in CNV carriers, implicate aberrant development of the cortical mantle in the pathology underlying impaired processing speed ability.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Aims: To review the evidence and reach consensus on recommendations for follow-up after total hip and knee arthroplasty. Methods: A programme of work was conducted, including: a systematic review of the clinical and cost-effectiveness literature; analysis of routine national datasets to identify pre-, peri-, and postoperative predictors of mid-to-late term revision; prospective data analyses from 560 patients to understand how patients present for revision surgery; qualitative interviews with NHS managers and orthopaedic surgeons; and health economic modelling. Finally, a consensus meeting considered all the work and agreed the final recommendations and research areas. Results: The UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE) recommendations apply to post-primary hip and knee arthroplasty follow-up. The ten-year time point is based on a lack of robust evidence beyond ten years. The term 'complex cases' refers to individual patient and surgical factors that may increase the risk for arthroplasty failure. For Orthopaedic Data Evaluation Panel (ODEP) 10A* minimum implants, it is safe to disinvest in routine follow-up from one to years post-non-complex hip and knee arthroplasty provided there is rapid access to orthopaedic review. For ODEP 10A* minimum implants in complex cases, or non-ODEP 10A* minimum implants, periodic follow-up post-hip and knee arthroplasty may be required from one to ten years. At ten years post-hip and knee arthroplasty, clinical and radiological evaluation is recommended. After ten years post-hip and knee arthroplasty, frequency of further follow-up should be based on the ten-year assessment; ongoing rapid access to orthopaedic review is still required. Conclusion: Complex cases, implants not meeting the ODEP 10A* criteria, and follow-up after revision surgery are not covered by this recommendation. Cite this article: Bone Jt Open 2023;4(2):72–78.

Abstract Background Follow-up visits 5 or 7 years after surgery were recommended for people having primary hip or knee replacement. The benefits of this practice to patients and the healthcare system, however, have not yet been specifically examined. The aim of this study was to investigate the association between long-term follow-up outpatient hospital visits and revision rates for patients who undergo primary knee or hip replacement surgery. Methods Cohorts were identified for patients undergoing knee or hip replacement surgery using medical records from primary care practices within the UK Clinical Practice Research Datalink (CPRD) GOLD dataset linked to hospital records from the English Hospital Episodes Statistics (HES) data. Two groups of patients were compared in terms of revision and mortality rates: those with at least one long-term (between five and 10 years since primary surgery) follow-up visit at the orthopaedic department (‘Follow-up’ group), and those without (‘No follow-up’ group). Results A total of 9856 (4349 in the Follow-up group) patients with knee replacement and 10,837 (4870 in the Follow-up group) with hip replacement were included in the analysis. For knee replacement, the incidence of revision was 3.6% for those followed-up and 0.6% for those not followed-up. An adjusted regression model confirmed the difference in the hazard ratio (HR) for revision was statistically significant (HR: 5.65 [95% CI 3.62 to 8.81]). Mortality at 4 years was lower for the Follow-up (17%) compared to the No follow-up group (21%), but this difference was not statistically significant (HR: 0.95 [0.84 to 1.07]). For hip replacement, the incidence of revision rates were 3.2 and 1.4% for the follow-up and not follow-up groups, respectively, the difference being statistically significant (HR: 2.34 [1.71 to 3.20]). Mortality was lower for the Follow-up (15%) compared to the No follow-up group (21%), but the difference was not statistically significant (HR: 0.91 [0.81 to 1.02]). Conclusion Patients attending follow-up orthopaedic consultations show a higher risk of revision surgery compared to those who are not followed-up. A cause for this difference could not be identified in this study but a likely explanation is that surgeons play an effective role as ultimate arbitrators when identifying patients to be included in long-term follow-up lists.

Introduction: Follow-up of the mothers and their offspring recruited to a randomized controlled trial comparing neonatal outcomes in women with gestational diabetes treated with metformin or glibenclamide was conducted 9 years ago. A significant decrease in neonatal hypoglycemia in the group treated with metformin was seen in the original study. Methodology: Results of clinical examination, blood sample collection, and dual-energy X-ray absorptiometry (DEXA) scan not published in a brief communication are described in this study. The nutritional status was assessed using a 3-day recall method using the Indian Food Composition Table 2017. The physical activity of offspring was assessed using the Global Physical Activity Questionnaire. Results: The overall follow-up rate of the cohort was 49% and similar in both the groups. The anthropometric details, blood tests, and DEXA in the women and their offspring were similar except that the offspring of the group on metformin had higher triglyceride values than the offspring of the women treated with glibenclamide. The average body mass index of the offspring was similar and was 18. Currently, women who were treated with glibenclamide 9 years ago had higher fasting plasma glucose levels (9.2 [7.3, 12.6]) than the metformin group (7.2 [6.1, 8.4] median [interquartile range]), P = 0.02. They also had significantly higher diastolic blood pressure readings 77.1mmHg (8.9) and 72.1mmHg (11.7) mean (SD), P = 0.035. (Information from the previously published brief communication). Conclusion: No significant adverse outcome was seen in women treated with metformin and the offspring 9 years later.

The COVID-19 pandemic forced many American schools to hastily transition to online learning. I assess how the online learning experience of students enrolled in brick and mortar schools that transitioned to online learning in Spring 2020 compared to the experience of students who were already enrolled in virtual schools when the pandemic began. Absent formal assessments to quantify learning loss, such comparison can help contextualize the performance of brick and mortar schools in their transition to online learning, and perhaps inform how policy can promote higher-quality online schooling, a burgeoning policy concern amidst widespread school closures forecasted for the 2020-2021 academic year. I hypothesize that, owing to experience and expertise, virtual schools provided a higher quality education than did brick and mortar schools operating online. I test this hypothesize by administering surveys to parents of students enrolled in online schools. When applicable, parents also complete a survey about the online learning experience of siblings enrolled in brick and mortar schools that switched to online learning in Spring 2020. I compare survey outcomes across four constructs: active learning, communication, pedagogical efficacy, and classroom management. Overall, I observe that virtual schools earned substantially higher marks across the four constructs.

Land management is vital for agricultural production and ecosystem service maintenance to mitigate the effects of climate change. This is particularly important in regions with higher proportions of sloping land, where degradation is more prevalent. The mountainous northwest of Vietnam provides a salient example of an area with sloping and highly degraded soils. This article employed data envelopment analysis to investigate the effect of sustainable land management practices on efficiency and yield in the cultivation of oranges. Determinants of production efficiency and the interaction between efficiency and yield were also analyzed. Results indicate that 130 out of the studied 174 groves are not operating at optimal efficiency levels and that most producers would benefit by increasing their scale of production. Furthermore, the adoption of sustainable land management was found to improve production efficiency and yield both positively and significantly. Finally, the production efficiency of orange groves is positively affected by the ethnicity of the head of the farming household, access to extension services, and the degree of sustainable land management adoption. Farming households headed by members with higher levels of education and more farming experience were also found to significantly contribute to scale efficiency.

Abstract Background COVID-19 posed many challenges to medical education in the United Kingdom (UK). This includes implementing assessments during 4 months of national lockdowns within a 2-year period, where in-person education was prohibited. This study aimed to identify medical school assessment formats emerging during COVID-19 restrictions, investigate medical students’ perspectives on these and identify influencing factors. Methods The study consisted of two phases: a questionnaire asking medical students about assessment changes they experienced, satisfaction with these changes and preference regarding different assessments that emerged. The second phase involved semi-structured interviews with medical students across the UK to provide a deeper contextualized understanding of the complex factors influencing their perspectives. Results In the questionnaire responses, open-book assessments had the highest satisfaction, and were the preferred option indicated. Furthermore, in the case of assessment cancellation, an increase in weighting of future assessments was preferred over increase in weighting of past assessments. Students were also satisfied with formative or pass-fail assessments. Interview analyses indicate that although cancellation or replacement of summative assessments with formative assessments reduced heightened anxiety from additional COVID-19 stressors, students worried about possible future knowledge gaps resulting from reduced motivation for assessment-related study. Students’ satisfaction level was also affected by timeliness of communication from universities regarding changes, and student involvement in the decision-making processes. Perceived fairness and standardisation of test-taking conditions were ranked as the most important factors influencing student satisfaction, followed closely by familiarity with the format. In contrast, technical issues, lack of transparency about changes, perceived unfairness around invigilation, and uncertainty around changes in assessment format and weighting contributed to dissatisfaction. Conclusions Online open-book assessments were seen as the most ideal amongst all participants, and students who experienced these were the most satisfied with their assessment change. They were perceived as most fair and authentic compared to real-life medical training. We seek to inform educators about student perceptions of successful assessment strategies under COVID-19 restrictions and provide evidence to allow debate on ongoing assessment reform and innovation. While this work looks specifically at assessment changes during COVID-19, understanding factors affecting student perception of assessment is applicable to examinations beyond COVID-19.