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Antipsychotic (AP)-naive first-episode psychosis (FEP) patients display early dysglycemia, including insulin resistance and prediabetes. Metabolic dysregulation may therefore be intrinsic to psychosis spectrum disorders (PSDs), independent of the metabolic effects of APs. However, the potential biological pathways that overlap between PSDs and dysglycemic states remain to be identified. Using meta-analytic approaches of transcriptomic datasets, we investigated whether AP-naive FEP patients share overlapping gene expression signatures with non-psychiatrically ill early dysglycemia individuals. We meta-analyzed peripheral transcriptomic datasets of AP-naive FEP patients and non-psychiatrically ill early dysglycemia subjects to identify common gene expression signatures. Common signatures underwent pathway enrichment analysis and were then used to identify potential new pharmacological compounds via Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our search results yielded 5 AP-naive FEP studies and 4 early dysglycemia studies which met inclusion criteria. We discovered that AP-naive FEP and non-psychiatrically ill subjects exhibiting early dysglycemia shared 221 common signatures, which were enriched for pathways related to endoplasmic reticulum stress and abnormal brain energetics. Nine FDA-approved drugs were identified as potential drug treatments, of which the antidiabetic metformin, the first-line treatment for type 2 diabetes, has evidence to attenuate metabolic dysfunction in PSDs. Taken together, our findings support shared gene expression changes and biological pathways associating PSDs with dysglycemic disorders. These data suggest that the pathobiology of PSDs overlaps and potentially contributes to dysglycemia. Finally, we find that metformin may be a potential treatment for early metabolic dysfunction intrinsic to PSDs.

Transplantation of Neural Stem/Progenitor Cells (NPCs) is a promising regenerative strategy to promote neural repair following injury and degeneration because of the ability of these cells to proliferate, migrate, and integrate with the host tissue. Precise in vitro control of NPC proliferation without compromising multipotency and differentiation ability is critical in stem cell maintenance. This idea was highlighted in recent clinical trials, where discrepancies in NPC culturing protocols produced inconsistent therapeutic benefits. Of note, cell density plays an important role in regulating the survival, proliferation, differentiation, and fate choice of stem cells. To determine the extent of variability produced by inconsistent culturing densities, the present study cultured human-induced pluripotent NPCs (hiPSC-NPCs) at either a low or high plating density. hiPSC-NPCs were then isolated for transcriptomic analysis or differentiation in vitro. Following sequencing analysis, genes involved in cell–cell contact-mediated pathways, including Hippo-signaling, NOTCH, and WNT were differentially expressed. Modulation of these pathways was highly associated with the regulation of pro-neuronal transcription factors, which were also upregulated in response to higher-density hiPSC-NPC culture. Moreover, higher plating density translated into a greater neuronal and less astrocytic differentiation in vitro. This study highlights the importance of precisely controlling culture conditions during the development of NPC transplantation therapies.

PurposeThe aim of this Intensive Care Medicine Rapid Practice Guideline (ICM‑RPG) was to formulate evidence‑based guidance for the use of dexmedetomidine for sedation in invasively mechanically ventilated adults in the intensive care unit (ICU).MethodsWe adhered to the methodology for trustworthy clinical practice guidelines, including use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and the Evidence-to-Decision framework to generate recommendations. The guideline panel comprised 28 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. Through teleconferences and web‑based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients’ values and preferences, costs and resources, feasibility, acceptability, and research priorities.ResultsThe ICM‑RPG panel issued one weak recommendation (suggestion) based on overall moderate certainty of evidence: \"In invasively mechanically ventilated adult ICU patients, we suggest using dexmedetomidine over other sedative agents, if the desirable effects including a reduction in delirium are valued over the undesirable effects including an increase in hypotension and bradycardia\".ConclusionThis ICM-RPG provides updated evidence-based guidance on the use of dexmedetomidine for sedation in mechanically ventilated adults, and outlines uncertainties and research priorities.

In a randomized trial involving patients with subclinical (typically asymptomatic) atrial fibrillation, apixaban led to a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding.

Excessive nitrogen (N) and phosphorus (P) loading is one of the greatest threats to aquatic ecosystems in the Anthropocene, causing eutrophication of rivers, lakes, and marine coastlines worldwide. For lakes across the United States, eutrophication is driven largely by nonpoint nutrient sources from tributaries that drain surrounding watersheds. Decades of monitoring and regulatory efforts have paid little attention to small tributaries of large water bodies, despite their ubiquity and potential local importance. We used a snapshot of nutrient inputs from nearly all tributaries of Lake Michigan—the world’s fifth largest freshwater lake by volume—to determine how land cover and dams alter nutrient inputs across watershed sizes. Loads, concentrations, stoichiometry (N:P), and bioavailability (percentage dissolved inorganic nutrients) varied by orders of magnitude among tributaries, creating a mosaic of coastal nutrient inputs. The 6 largest of 235 tributaries accounted for ∼70% of the daily N and P delivered to Lake Michigan. However, small tributaries exhibited nutrient loads that were high for their size and biased toward dissolved inorganic forms. Higher bioavailability of nutrients from small watersheds suggests greater potential to fuel algal blooms in coastal areas, especially given the likelihood that their plumes become trapped and then overlap in the nearshore zone. Our findings reveal an underappreciated role that small streams may play in driving coastal eutrophication in large water bodies. Although they represent only a modest proportion of lake-wide loads, expanding nutrient management efforts to address smaller watersheds could reduce the ecological impacts of nutrient loading on valuable nearshore ecosystems.

People with subclinical atrial fibrillation are at increased risk of stroke, albeit to a lesser extent than those with clinical atrial fibrillation, leading to an ongoing debate regarding the benefit of anticoagulation in these individuals. In the ARTESiA trial, the direct-acting oral anticoagulant apixaban reduced stroke or systemic embolism compared with aspirin in people with subclinical atrial fibrillation, but the risk of major bleeding was increased with apixaban. In a prespecified subgroup analysis of ARTESiA, we tested the hypothesis that people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack, who are known to have an increased risk of recurrent stroke, would show a greater benefit from oral anticoagulation for secondary stroke prevention compared with those without a history of stroke or transient ischaemic attack. ARTESiA is a double-blind, double-dummy, randomised controlled trial conducted at 247 sites in 16 countries across Europe and North America. Adults aged 55 years or older with device-detected subclinical atrial fibrillation lasting from 6 min to 24 h and a CHA2DS2-VASc score of 3 or higher were randomly assigned using an interactive web-based system to oral apixaban 5 mg twice per day or oral aspirin 81 mg once per day. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding, assessed as absolute risk differences. Analyses were by intention to treat. ARTESiA is registered with ClinicalTrials.gov (NCT01938248) and is completed; this report presents a prespecified subgroup analysis in people with a history of stroke or transient ischaemic attack. Between May 7, 2015, and July 30, 2021, 4012 people with subclinical atrial fibrillation were randomly allocated either apixaban (n=2015) or aspirin (n=1997). A history of stroke or transient ischaemic attack was present in 346 (8·6%) participants (172 assigned to apixaban and 174 to aspirin), among whom the annual rate of stroke or systemic embolism was 1·20% (n=7; 95% CI 0·48 to 2·48) with apixaban versus 3·14% (n=18; 1·86 to 4·96) with aspirin; (hazard ratio [HR] 0·40, 95% CI 0·17 to 0·95). In participants without a history of stroke or transient ischaemic attack (n=3666; 1843 assigned to apixaban and 1823 to aspirin), the annual rate of stroke or systemic embolism was 0·74% (n=48; 95% CI 0·55 to 0·98) with apixaban versus 1·07% (n=68; 95% CI 0·83 to 1·36) with aspirin (HR 0·69, 95% CI 0·48 to 1·00). The absolute risk difference in incidence of stroke or systemic embolism at 3·5 years of follow-up was 7% (95% CI 2 to 12) in participants with versus 1% (0 to 3) in participants without a history of stroke or transient ischaemic attack. The annual rate of major bleeding in participants with a history of stroke or transient ischaemic attack was 2·26% with apixaban (n=13; 95% CI 1·21 to 3·87) versus 1·16% with aspirin (n=7; 0·47 to 2·39; HR 1·94, 95% CI 0·77 to 4·87). The absolute risk difference in major bleeding events at 3·5 years was 3% (–1 to 8) in individuals with a versus 1% (–1 to 2) in those without a history of stroke or transient ischaemic attack. Treatment with the direct-acting oral anticoagulant apixaban in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack led to a 7% absolute risk reduction in stroke or systemic embolism over 3·5 years, compared with a 1% absolute risk reduction for individuals without a previous history of stroke or transient ischaemic attack. The corresponding absolute increase in major bleeding was 3% and 1%, respectively. Apixaban could be considered for secondary stroke prevention in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack. The Canadian Institutes of Health Research, Bristol-Myers Squibb–Pfizer Alliance, Heart and Stroke Foundation of Canada, Canadian Stroke Prevention and Intervention Network, Hamilton Health Sciences, Accelerating Clinical Trials Network, Population Health Research Institute, and Medtronic.

Background: The provision of reliable patient education is essential for shared decision-making. However, many clinicians are reluctant to use commonly available resources, as they are generic and may contain information of insufficient quality. Clinician-created educational materials, accessed during the waiting time prior to consultation, can potentially benefit clinical practice if developed in a time- and resource-efficient manner. Objective: The aim of this study is to evaluate the utility of educational videos in improving patient decision-making, as well as consultation satisfaction and anxiety, within the outpatient management of chronic disease (represented by atrial fibrillation). The approach involves clinicians creating audiovisual patient education in a time- and resource-efficient manner for opportunistic delivery, using mobile smart devices with internet access, during waiting time before consultation. Methods: We implemented this educational approach in outpatient clinics and collected patient responses through an electronic survey. The educational module was a web-based combination of 4 short videos viewed sequentially, followed by a patient experience survey using 5-point Likert scales and 0-100 visual analogue scales. The clinician developed the audiovisual module over a 2-day span while performing usual clinical tasks, using existing hardware and software resources (laptop and tablet). Patients presenting for the outpatient management of atrial fibrillation accessed the module during waiting time before their consultation using either a URL or Quick Response (QR) code on a provided tablet or their own mobile smart devices. The primary outcome of the study was the module’s utility in improving patient decision-making ability, as measured on a 0-100 visual analogue scale. Secondary outcomes were the level of patient satisfaction with the videos, measured with 5-point Likert scales, in addition to the patient’s value for clinician narration and the module’s utility in improving anxiety and long-term treatment adherence, as represented on 0-100 visual analogue scales. Results: This study enrolled 116 patients presenting for the outpatient management of atrial fibrillation. The proportion of responses that were “very satisfied” with the educational video content across the 4 videos ranged from 93% (86/92) to 96.3% (104/108) and this was between 98% (90/92) and 99.1% (107/108) for “satisfied” or “very satisfied.” There were no reports of dissatisfaction for the first 3 videos, and only 1% (1/92) of responders reported dissatisfaction for the fourth video. The median reported scores (on 0-100 visual analogue scales) were 90 (IQR 82.5-97) for improving patient decision-making, 89 (IQR 81-95) for reducing consultation anxiety, 90 (IQR 81-97) for improving treatment adherence, and 82 (IQR 70-90) for the clinician’s narration adding benefit to the patient experience. Conclusions: Clinician-created educational videos for chronic disease management resulted in improvements in patient-reported informed decision-making ability and expected long-term treatment adherence, as well as anxiety reduction. This form of patient education was also time efficient as it used the sunk time cost of waiting time to provide education without requiring additional clinician input.

Abstract Aims We aimed to summarize existing evidence from published randomized trials that assessed atrial fibrillation (AF) screening for stroke prevention. Methods and results We searched MEDLINE for randomized trials that enrolled patients without known AF, screened for AF using electrocardiogram-based methods, and reported stroke outcomes. For this analysis, we excluded studies that focused on post-stroke populations. We combined data using a random-effects model and performed trial sequential meta-analysis using an O’Brien-Fleming alpha-spending function. We identified four randomized clinical trials with a total of 35 836 participants. The populations, screening intervention, and definition of stroke varied markedly. As compared with no screening, AF screening was associated with a reduction in stroke (relative risk 0.91; 95% confidence interval: 0.84–0.99]. Trial sequential meta-analysis found that the cumulative z-score did not cross the stopping boundary. After polling members of the AF-SCREEN and AFFECT-EU consortia, we identified a further 12 trials that are complete but have not yet reported stroke outcomes or are ongoing and expected to collect stroke outcomes. These consortia are planning an individual participant data meta-analysis which will permit the exploration of methodological heterogeneity. Conclusions If and how to screen for AF is an important public health concern. The body of evidence published to date suggests that AF could be effective to prevent strokes in some settings. The AF-SCREEN/AFFECT-EU individual patient data meta-analysis aims to comprehensively assess the benefits and risks of AF screening, and determine how population, screening method, and health-system factors influence stroke prevention. Graphical Abstract Graphical Abstract

Background/Objectives: Homeless populations have higher rates of chronic illness and mortality than more advantaged peers but have low primary care engagement. Nurse-managed clinics emerged as a possible solution to increase healthcare access for marginalized populations. This paper presents a comprehensive evaluation of feasibility (conceptualized as patient recruitment and retention) and acceptability (conceptualized as patient satisfaction) of a nurse-managed primary care clinic tailored to people experiencing homelessness and poverty. Methods: This is a three-year retrospective chart review study of the clinic’s services, patient characteristics, and patient satisfaction. All adult patients for the three-year period were included (N = 514). Feasibility was measured by the number of unique patients seen and visits completed, ratio of completed to scheduled visits, and number of returning patients. Acceptability was measured by a 19-item Likert format (1–5) patient satisfaction survey. Patient characteristics were captured from intake forms. Results: Most patients were male, African American or White, and non-Hispanic. Regarding social determinants of health (SDOH), most patients did not have college education, were unemployed or unable to work, experienced homelessness, had no primary care provider, and no health insurance. Over three years, 1972 visits were scheduled and 1372 (69.6%) completed. A total of 514 patients were seen (37.5% of all visits), with 858 follow-up visits (62.5%). Returning patients (≥2 visits) totaled 59.1%. Yearly data shows steady growth in recruitment and retention. Patient satisfaction with facets of care (access, communication, interpersonal relations) was very high (Mrange = 4.63–4.69), including with Nurse Practitioner care, as was global satisfaction (M = 4.71; SD = 0.61; 76.3% very satisfied). Conclusions: Results indicate that a homeless-tailored nurse-managed clinic can recruit and retain homeless and working poor patients (feasibility), with high patient satisfaction with its services and staff (acceptability), independently of patient demographics or SDOH. Challenges related to retention deserve further study as well as the impact of services on the continuity of care, health, and well-being.

Natural selection arising from resource competition and environmental heterogeneity can drive adaptive radiation. Ecological opportunity facilitates this process, resulting in rapid divergence of ecological traits in many celebrated radiations. In other cases, sexual selection is thought to fuel divergence in mating signals ahead of ecological divergence. Comparing divergence rates between naturally and sexually selected traits can offer insights into processes underlying species radiations, but to date such comparisons have been largely qualitative. Here, we quantitatively compare divergence rates for four traits in African mormyrid fishes, which use an electrical communication system with few extrinsic constraints on divergence. We demonstrate rapid signal evolution in theParamormyropsspecies flock compared to divergence in morphology, size, and trophic ecology. This disparity in the tempo of trait evolution suggests that sexual selection is an important early driver of species radiation in these mormyrids. We also found slight divergence in ecological traits among closely related species, consistent with a supporting role for natural selection inParamormyropsdiversification. Our results highlight the potential for sexual selection to drive explosive signal divergence when innovations in communication open new opportunities in signal space, suggesting that opportunity can catalyze species radiations through sexual selection, as well as natural selection.