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Objective: The aim of the study was to elucidate the cellular mechanism underlying the suppression of glucose-induced insulin secretion in mice fed a high-fat diet (HFD) for 15 weeks.Research Design and Methods: C57BL6J mice were fed a HFD or a normal diet (ND) for 3 or 15 weeks. Plasma insulin and glucose levels in vivo were assessed by intraperitoneal glucose tolerance test. Insulin secretion in vitro was studied using static incubations and a perfused pancreas preparation. Membrane currents, electrical activity, and exocytosis were examined by patch-clamp technique measurements. Intracellular calcium concentration ([Ca(2+)](i)) was measured by microfluorimetry. Total internal reflection fluorescence microscope (TIRFM) was used for optical imaging of exocytosis and submembrane depolarization-evoked [Ca(2+)](i). The functional data were complemented by analyses of histology and gene transcription.Results: After 15 weeks, but not 3 weeks, mice on HFD exhibited hyperglycemia and hypoinsulinemia. Pancreatic islet content and beta-cell area increased 2- and 1.5-fold, respectively. These changes correlated with a 20-50% reduction of glucose-induced insulin secretion (normalized to insulin content). The latter effect was not associated with impaired electrical activity or [Ca(2+)](i) signaling. Single-cell capacitance and TIRFM measurements of exocytosis revealed a selective suppression (>70%) of exocytosis elicited by short (50 ms) depolarization, whereas the responses to longer depolarizations were (500 ms) less affected. The loss of rapid exocytosis correlated with dispersion of Ca(2+) entry in HFD beta-cells. No changes in gene transcription of key exocytotic protein were observed.Conclusions: HFD results in reduced insulin secretion by causing the functional dissociation of voltage-gated Ca(2+) entry from exocytosis. These observations suggest a novel explanation to the well-established link between obesity and diabetes. [ABSTRACT FROM AUTHOR]

Objectives: Home health care (HHC) serves more than 5 million older adults annually in the United States, aiming to prevent unnecessary hospitalizations and emergency department (ED) visits. Despite efforts, up to 25% of patients in HHC experience these adverse events. The underutilization of clinical notes, aggregated data approaches, and potential demographic biases have limited previous HHC risk prediction models. This study aimed to develop a time-series risk model to predict hospitalizations and ED visits in patients in HHC, examine model performance over various prediction windows, identify top predictive variables and map them to data standards, and assess model fairness across demographic subgroups., Setting and Participants: A total of 27,222 HHC episodes between 2015 and 2017., Methods: The study used health care process modeling of electronic health records, including clinical notes processed with natural language processing techniques and Medicare claims data. A Light Gradient Boosting Machine algorithm was used to develop the risk prediction model, with performance evaluated using 5-fold cross-validation. Model fairness was assessed across gender, race/ethnicity, and socioeconomic subgroups., Results: The model achieved high predictive performance, with an F1 score of 0.84 for a 5-day prediction window. Twenty top predictive variables were identified, including novel indicators such as the length of nurse-patient visits and visit frequency. Eighty-five percent of these variables mapped completely to the US Core Data for Interoperability standard. Fairness assessment revealed performance disparities across demographic and socioeconomic groups, with lower model effectiveness for more historically underserved populations., Conclusions and Implications: This study developed a robust time-series risk model for predicting adverse events in patients in HHC, incorporating diverse data types and demonstrating high predictive accuracy. The findings highlight the importance of considering established and novel risk factors in HHC. Importantly, the observed performance disparities across subgroups emphasize the need for fairness adjustments to ensure equitable risk prediction across all patient populations., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Trauma-informed care has been posited as a framework for creating ideal and safe environments for patients to participate in treatment. However, there are limited studies that demonstrate the impact of a focused trauma-informed care training on ED staff. We implemented a 4-hour trauma-informed care training in a general emergency department. We aimed to measure changes in knowledge, opinions, self-rated competency, barriers, and recent practices before and after implementing trauma-informed care training. We hypothesized that the training would result in significant self-reported improvement in all domains., Methods: We performed a pre/post interventional study with the intervention being a trauma-informed care training adapted for ED clinical care staff. A validated, publicly available survey tool (Center for Pediatric Stress Trauma-Informed Care [TIC] Provider Survey) was used to assess knowledge, opinions, competency, and utilization of and perceived barriers to trauma-informed care. Pre- and post-training surveys were collected. Responses were stratified by role. Continuous variables were compared using analysis of variance; categorical variables compared using Pearson's chi-square., Results: Participants demonstrated a high level of perceived knowledge and opinions of trauma-informed care before and after training. We observed significant increases in self-reported competence for all ED staff, some increase in utilization of trauma-informed care in recent practice, and significant decreases in perceived barriers to providing trauma-informed care., Discussion: Trauma-informed care training is an effective means to improving ED staff self-perceived competence and practice of trauma-informed care even among those with high self-perceived knowledge and opinions of trauma-informed care before the training. Future study should explore the patient-level impact of trauma-informed care training, as well as how to continue to reduce barriers to system-wide implementation of trauma-informed care practices., (Copyright © 2025 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Brain development requires the coordinated growth of structures and cues that are essential for forming neural circuits and cognitive functions. The corpus callosum, the largest interhemispheric connection, is formed by the axons of callosal projection neurons through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps can lead to a range of disorders known as syndromic corpus callosum dysgenesis (CCD). We report five unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly and enlarged ventricles. Using in vitro and in vivo mouse models and complementation assays, we show that WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further propose that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

Interferon-alpha has activity against multiple myeloma. Modakafusp alfa is an immunocytokine comprising two attenuated interferon-alpha2b molecules and an anti-CD38 IgG4 antibody, targeting delivery of interferon-alpha to CD38+ immune and myeloma cells. This phase I/II trial (NCT03215030) enrolled patients with relapsed/refractory multiple myeloma with ≥3 prior lines of treatment and refractory to or intolerant of ≥1 proteasome inhibitor and ≥1 immunomodulatory drug. During dose escalation, modakafusp alfa was administered at ten doses in four schedules across 13 cohorts. The primary endpoint was safety for dose escalation, and overall response rate for dose expansion. We enrolled 106 patients who had received a median of 6.5 lines of prior therapy; 84% of patients had myeloma previously refractory to an anti-CD38 antibody. The most feasible dosing schedule was every 4 weeks (Q4W), at which the maximum tolerated dose was 3 mg/kg. Among 30 patients treated at 1.5 mg/kg Q4W, the overall response rate was 43.3%, with a median duration of response of 15.1 months (95% CI, 7.1-26.1); median progression-free survival was 5.7 months (95% CI, 1.2-14.0). Grade ≥3 adverse events occurred in 28 (93.3%) patients, the most common were neutropenia (66.7%) and thrombocytopenia (46.7%); infections were reported in 8 (26.7%) patients (including grade 3 in 4 [16.7%]). Modakafusp alfa therapy induced upregulation of the type I interferon gene signature score, increased CD38 receptor density in CD38+ cells, and innate and adaptive immune cell activation. Modakafusp alfa resulted in anti-tumor activity and immune activation in patients with multiple myeloma. Adverse events were primarily hematologic., (Copyright © 2024 American Society of Hematology.)

The primary objective of nutrition research is to make discoveries that will improve human health, and this is more likely to happen when researchers collaborate and share research findings with clinicians, program and policy makers, and the public. Nutrition research directly informs evidence-based care provided by registered dietitian nutritionists. However, the current academic model often lacks sufficient incentives and preparation for researchers to effectively disseminate their work. Consequently, research findings can be misrepresented, misinterpreted, distorted from their original context, or fail to reach the intended audience altogether. The aim of this article was to describe the importance and value of communication and disseminating nutrition research with various audiences and discuss what material should be disseminated. The information presented can serve as a guide for nutrition researchers to effectively disseminate their research for maximal impact and relevance., (Copyright © 2024 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Objective: To determine if the results of the OXYGEN trial changed using an "as-treated" approach instead of the original "intention-to-treat" approach. The multi-center randomized controlled OXYGEN trial aimed to determine the effectiveness of high FiO2 in decreasing infection rates for high-risk tibial plateau, tibial pilon, and calcaneus fractures., Methods: A secondary analysis of a multi-center randomized controlled trial conducted at 29 US trauma centers was performed. A total of 1231 patients aged 18-80 years with tibial plateau, tibial pilon, or calcaneus fractures thought to be at elevated risk of infection were enrolled. Patients were randomly assigned to receive inspired oxygen at a concentration of 80 % FiO2 (treatment) or 30 % FiO2 (control). Adherence was defined using two different criteria. Criterion 1 required at least 80 % of the surgery time ≤40 % FiO2 for the control group or ≥70 % FiO2 for the treatment group. Criterion 2 required at least 80 % of surgery time within 20-40 % (control) or 70-90 % FiO2 (treatment). The primary outcome was surgical site infection (SSI) within 182 days of definitive fracture fixation. Secondary outcomes were deep and superficial surgical site infections within 90, 182, and 365 days of definitive fixation., Results: Under Criterion 1, the primary outcome occurred in 7 % (38/523) and 10 % (49/471) of patients in the treatment and control groups, respectively (p = 0.10). Deep infection occurred in 30 (6 %) treatment and 30 (6 %) control patients (p = 0.75). Superficial infection occurred in 9 (2 %) treatment and 20 (4 %) control patients (RR, 0.41; p = 0.03). Using Criterion 2, the primary outcome occurred in 7 % (36/498) of treatment and 10 % (48/468) of control patients (p = 0.12). Deep infection occurred in 28 (6 %) treatment and 29 (6 %) control patients (p = 0.81). Superficial infection occurred in 9 (2 %) treatment and 20 (4.3 %) control patients (RR = 0.43; p = 0.03)., Conclusions: When re-analyzing based on which patients actually received high or control levels of perioperative oxygen fraction, the results are somewhat consistent with the original "intent-to-treat" analysis. Specifically, high perioperative oxygen lowered the risk of superficial SSI but did not affect deep infections., Competing Interests: Declaration of competing interest No conflicts specific to this manuscript were declared., (Copyright © 2024. Published by Elsevier Ltd.)

Some insects, such as the painted lady butterfly Vanessa cardui , exhibit complex annual migratory cycles spanning multiple generations. Traversing extensive seas or deserts is often a required segment of these migratory journeys. We develop a bioavailable strontium isoscape for Europe and Africa and then use isotope geolocation combining hydrogen and strontium isotopes to estimate the natal origins of painted ladies captured north and south of the Sahara during spring and autumn, respectively. Our findings reveal moderate migratory connectivity across the Sahara characterized by a broad-front, parallel migration. We also report evidence of a leapfrog migration, wherein early autumn migrants from higher latitudes cover greater distances southward than their late autumn counterparts. This work represents a major advancement in understanding insect migratory patterns and connectivity, particularly across extensive barriers, which is essential for understanding population dynamics and predicting the impacts of global change on insect-mediated ecosystem services., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Introduction: Trauma-informed care has been posited as a framework to optimize patient care and engagement, but there is a paucity of data on patient-level outcomes after trauma-informed care training in health care settings. We sought to measure patient-level outcomes after a painful procedure after implementation of trauma-informed care training for ED staff., Methods: As part of a quality improvement initiative, we trained 110 ED providers in trauma-informed care. Next, we prospectively recruited patients who had undergone a painful procedure to complete a survey to assess several patient-level outcomes, such as anxiety reduction and overall experience of care. We compared differences in patient outcomes for those who were treated by providers in the trauma-informed care intervention group with those who were treated by providers who did not complete the training (usual care)., Results: One-hundred forty-seven adult patients completed survey measures (n = 76 trauma-informed care intervention group; n = 71 usual care group) over a 1-month period. Most patients offered the highest rating for all ED staff-related questions. We found no significant differences in assessment of patient-reported outcomes based on intervention versus usual care., Discussion: Our trauma-informed care training did not seem to have a significant effect on our selected patient outcomes. This may be caused by the training itself or the challenges in measurement of the patient-level impact of trauma-informed care training owing to the study design, setting, and lack of standardized tools. Recommendations for future study of trauma-informed care training and measuring its direct impact on patients in the ED setting are discussed., (Copyright © 2024 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Objective: Addressing the acute mental healthcare needs of children is a national crisis. Despite the ongoing crisis, there are limited prior studies that capture caregiver perspectives on acute pediatric mental healthcare, notably in a general emergency department (ED) in a rural state. Based on these knowledge gaps, our objective was to assess caregiver opinions and perspectives of acute management for children boarding with mental health conditions., Methods: Semistructured interviews were conducted with caregivers of patients (under 18 years old) with a primary mental health condition boarding in a general ED (length of stay ≥24 hours) within a qualitative grounded theory approach. An interview guide was developed a priori and reviewed among key stakeholders. A trained study team performed the interviews. A coding tree was developed through an iterative process that included double-coding transcripts and monitoring of interrater reliability to perform thematic analysis., Results: Fourteen interviews were conducted to reach thematic saturation. Key themes elicited from caregivers included mental healthcare delivery, access to mental healthcare services, care setting, and level of support for families and caregivers. Most caregivers focused on the following challenges and suggestions: access to appropriate, evidence-based mental healthcare, improved communication between all stakeholders involved, and staff education on mental healthcare for children., Conclusions: Caregivers face considerable challenges in attaining timely and appropriate acute mental health care for their children. Immediate and innovative resource allocation is needed across the healthcare continuum to bolster the acute mental healthcare services currently offered to children and families, especially in the general ED setting., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The Short Musculoskeletal Function Assessment (SMFA) is a well validated, widely used patient-reported outcome (PRO) measure for orthopaedic patients. Despite its widespread use and acceptance, this measure does not have an agreed upon minimal clinically important difference (MCID). The purpose of the present study was to create distributional MCIDs with use of a large cohort of research participants with severe lower extremity fractures., Methods: Three distributional approaches were used to calculate MCIDs for the Dysfunction and Bother Indices of the SMFA as well as all its domains: (1) half of the standard deviation (one-half SD), (2) twice the standard error of measurement (2SEM), and (3) minimal detectable change (MDC). In addition to evaluating by patient characteristics and the timing of assessment, we reviewed these calculations across several injury groups likely to affect functional outcomes., Results: A total of 4,298 SMFA assessments were collected from 3,185 patients who had undergone surgical treatment of traumatic injuries of the lower extremity at 60 Level-I trauma centers across 7 multicenter, prospective clinical studies. Depending on the statistical approach used, the MCID associated with the overall sample ranged from 7.7 to 10.7 for the SMFA Dysfunction Index and from 11.0 to 16.8 for the SMFA Bother Index. For the Dysfunction Index, the variability across the scores was small (<5%) within the sex and age subgroups but was modest (12% to 18%) across subgroups related to assessment timing., Conclusions: A defensible MCID can be found between 7 and 11 points for the Dysfunction Index and between 11 and 17 points for the Bother Index. The precise choice of MCID may depend on the preferred statistical approach and the population under study. While differences exist between MCID values based on the calculation method, values were consistent across the categories of the various subgroups presented., Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: This work was funded by the Department of Defense (Peer-Reviewed Orthopaedic Research Program award numbers W81XWH-09-2-0108, W8XWH-10-2-0090, W81XWH-10-2-0134, and W81XWH-12-1-0588), National Institutes of Health award number R01AR064066-01, and the Orthopaedic Trauma Association. The sponsors had no role in the design or conduct of the trial; the collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript for submission. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/I93 )., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Background:  Over the past 30 years, the American Medical Informatics Association (AMIA) has played a pivotal role in fostering a collaborative community for professionals in biomedical and health informatics. As an interdisciplinary association, AMIA brings together individuals with clinical, research, and computer expertise and emphasizes the use of data to enhance biomedical research and clinical work. The need for a recognition program within AMIA, acknowledging applied informatics skills by members, led to the establishment of the Fellows of AMIA (FAMIA) Recognition Program in 2018., Objectives:  To outline the evolution of the FAMIA program and shed light on its origins, development, and impact. This report explores factors that led to the establishment of FAMIA, considerations affecting its development, and the objectives FAMIA seeks to achieve within the broader context of AMIA., Methods:  The development of FAMIA is examined through a historical lens, encompassing key milestones, discussions, and decisions that shaped the program. Insights into the formation of FAMIA were gathered through discussions within AMIA membership and leadership, including proposals, board-level discussions, and the involvement of key stakeholders. Additionally, the report outlines criteria for FAMIA eligibility and the pathways available for recognition, namely the Certification Pathway and the Long-Term Experience Pathway., Results:  The FAMIA program has inducted five classes, totaling 602 fellows. An overview of disciplines, roles, and application pathways for FAMIA members is provided. A comparative analysis with other fellow recognition programs in related fields showcases the unique features and contributions of FAMIA in acknowledging applied informatics., Conclusion:  Now in its sixth year, FAMIA acknowledges the growing influence of applied informatics within health information professionals, recognizing individuals with experience, training, and a commitment to the highest level of applied informatics and the science associated with it., Competing Interests: The authors have no conflict of interests to disclose regarding this study., (Thieme. All rights reserved.)

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations; however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESCs), including a knockout and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-sequencing analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Across temperate forests, many tree species produce flowers before their leaves emerge. This flower-leaf phenological sequence, known as hysteranthy, is generally described as an adaptation for wind pollination. However, this explanation does not address why hysteranthy is also common in biotically pollinated taxa. We quantified flower-leaf sequence variation in the American plums (Prunus, subg. Prunus sect. Prunocerasus), a clade of insect-pollinated trees, using herbaria specimens and Bayesian hierarchical modeling. We tested two common, but rarely interrogated hypotheses - that hysteranthy confers aridity tolerance and/or pollinator visibility - by modeling the associations between hysteranthy and related traits. To understand how these phenology-trait associations were sensitive to taxonomic scale and flower-leaf sequence classification, we then extended these analyses to all Prunus species in North America. Our findings across two taxonomic levels support the hypotheses that hysteranthy may help temporally partition hydraulic demand to reduce water stress and increase pollinator visibility - thereby reducing selective pressure on inflorescence size. Our results provide foundational insights into the evolution of flower-leaf sequences in the genus Prunus, with implications for understanding these patterns in biotically pollinated plants in general. Our approach suggests a path to advance these hypotheses to other clades, but teasing out drivers fully will require new experiments., (© 2024 The Authors. New Phytologist © 2024 New Phytologist Foundation.)

Objective: To determine whether intrawound vancomycin changes the bacteriology of surgical site infection pathogens and investigate the emergence of antibiotic-resistant pathogens., Design: Secondary analysis of phase III, prospective, randomized clinical trial., Setting: Thirty-six US trauma centers., Patient Selection Criteria: Patients who became infected after fixation of tibial plateau or pilon fracture., Outcome Measures and Comparisons: Pathogen types and bacterial susceptibilities as determined from routine clinical culture in the operating room., Results: Seventy-four patients were studied who were 67.5% male with a mean age of 48.6 years. A lower proportion of gram-positive cocci was observed in the vancomycin powder compared with the standard-of-care group (3.7% vs. 8.0%, P = 0.01). Methicillin-resistant Staphylococcus aureus infection incidence was comparable in both the vancomycin powder and the standard-of-care groups, but rates of methicillin-susceptible S. aureus infections were lower in the treatment group (1.4% vs. 4.8%, P = 0.01). The incidence of coagulase-negative Staphylococci and gram-negative rod infections were similar in both groups. There was no significant difference in susceptibilities between groups in rates of vancomycin-resistant enterococcus., Conclusions: Topical vancomycin powder decreases the likelihood of gram-positive infections consistent with the biologic activity of vancomycin. Fewer methicillin-susceptible S. aureus and coagulase-negative Staphylococci infections were observed in the group treated with vancomycin powder. An effect of vancomycin powder on methicillin-resistant S. aureus infection risk was not detected given the low incidence in both the intrawound vancomycin and the standard-of-care groups. There was no emergence of gram-negative rod infections or increased resistance patterns observed. Use of topical vancomycin powder does not seem to produce infections in these patients with greater antibiotic resistance than would have occurred without its use., Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Family-professional partnerships are important for youth learning to use aided augmentative and alternative communication (AAC). This study examined the family-oriented beliefs and practices of speech-language pathologists (SLPs) working with preschool and school-aged children learning to use aided AAC (aged 3-21 years), specifically during the COVID-19 pandemic., Method: Participants were 25 SLPs who participated in an individual semistructured interview. Qualitative analysis was used to identify and describe groups of SLPs based on commonalities and differences in their beliefs and practices working with families. The characteristics of SLPs in each group was also explored descriptively (e.g., race/ethnicity, work setting, caseload)., Results: SLPs clustered into three groups based on their beliefs and practices: (a) professionally centered, (b) family-allied, and (c) family-focused. SLPs varied across these groups in how they planned services, offered training/coaching, communicated, shared resources, offered emotional support, and adapted to and with different families., Conclusions: Findings indicate the need to support greater family-centeredness in AAC services by building on the strengths of SLPs in the field. Promoting strong family-professional partnerships could in turn improve outcomes for students who use AAC., Supplemental Material: https://doi.org/10.23641/asha.25044125.

Temperature is thought to be a key factor influencing global species richness patterns. We investigate the link between temperature and diversification in the butterfly family Pieridae by combining next generation DNA sequences and published molecular data with fine-grained distribution data. We sampled nearly 600 pierid butterfly species to infer the most comprehensive molecular phylogeny of the family and curated a distribution dataset of more than 800,000 occurrences. We found strong evidence that species in environments with more stable daily temperatures or cooler maximum temperatures in the warm seasons have higher speciation rates. Furthermore, speciation and extinction rates decreased in tandem with global temperatures through geological time, resulting in a constant net diversification., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Rationale: Many insect species undertake multigenerational migrations in the Afro-tropical and Palearctic ranges, and understanding their migratory connectivity remains challenging due to their small size, short life span and large population sizes. Hydrogen isotopes (δ 2 H) can be used to reconstruct the movement of dispersing or migrating insects, but applying δ 2 H for provenance requires a robust isotope baseline map (i.e. isoscape) for the Afro-Palearctic., Methods: We analyzed the δ 2 H in the wings (δ 2 H wing ) of 142 resident butterflies from 56 sites across the Afro-Palearctic. The δ 2 H wing values were compared to the predicted local growing-season precipitation δ 2 H values (δ 2 H GSP ) using a linear regression model to develop an insect wing δ 2 H isoscape. We used multivariate linear mixed models and high-resolution and time-specific remote sensing climate and environmental data to explore the controls of the residual δ 2 H wing variability., Results: A strong linear relationship was found between δ 2 H wing and δ 2 H GSP values (r 2  = 0.53). The resulting isoscape showed strong patterns across the Palearctic but limited variation and high uncertainty for the Afro-tropics. Positive residuals of this relationship were correlated with dry conditions for the month preceding sampling whereas negative residuals were correlated with more wet days for the month preceding sampling. High intra-site δ 2 H wing variance was associated with lower relative humidity for the month preceding sampling and higher elevation., Conclusion: The δ 2 H wing isoscape is applicable for tracing herbivorous lepidopteran insects that migrate across the Afro-Palearctic range but has limited geolocation potential in the Afro-tropics. The spatial analysis of uncertainty using high-resolution climatic data demonstrated that many African regions with highly variable evaporation rates and relative humidity have δ 2 H wing values that are less related to δ 2 H GSP values. Increasing geolocation precision will require new modeling approaches using more time-specific environmental data and/or independent geolocation tools., (© 2023 The Authors. Rapid Communications in Mass Spectrometry published by John Wiley & Sons Ltd.)

Schizophrenia (SZ) is a heterogeneous and debilitating psychiatric disorder with a strong genetic component. To elucidate functional networks perturbed in schizophrenia, we analysed a large dataset of whole-genome studies that identified SNVs, CNVs, and a multi-stage schizophrenia genome-wide association study. Our analysis identified three subclusters that are interrelated and with small overlaps: GO:0007017~Microtubule-Based Process, GO:00015629~Actin Cytoskeleton, and GO:0007268~SynapticTransmission. We next analysed three distinct trio cohorts of 75 SZ Algerian, 45 SZ French, and 61 SZ Japanese patients. We performed Illumina HiSeq whole-exome sequencing and identified de novo mutations using a Bayesian approach. We validated 88 de novo mutations by Sanger sequencing: 35 in French, 21 in Algerian, and 32 in Japanese SZ patients. These 88 de novo mutations exhibited an enrichment in genes encoding proteins related to GO:0051015~actin filament binding ( p = 0.0011) using David, and enrichments in GO: 0003774~transport ( p = 0.019) and GO:0003729~mRNA binding ( p = 0.010) using Amigo. One of these de novo variant was found in CORO1C coding sequence. We studied Coro1c haploinsufficiency in a Coro1c +/- mouse and found defects in the corpus callosum. These results could motivate future studies of the mechanisms surrounding genes encoding proteins involved in transport and the cytoskeleton, with the goal of developing therapeutic intervention strategies for a subset of SZ cases.

Background: Using mouse genetic studies and systematic assessments of brain neuroanatomical phenotypes, we set out to identify which of the 30 genes causes brain defects at the autism-associated 16p11.2 locus., Results: We show that multiple genes mapping to this region interact to regulate brain anatomy, with female mice exhibiting far fewer brain neuroanatomical phenotypes. In male mice, among the 13 genes associated with neuroanatomical defects (Mvp, Ppp4c, Zg16, Taok2, Slx1b, Maz, Fam57b, Bola2, Tbx6, Qprt, Spn, Hirip3, and Doc2a), Mvp is the top driver implicated in phenotypes pertaining to brain, cortex, hippocampus, ventricles, and corpus callosum sizes. The major vault protein (MVP), the main component of the vault organelle, is a conserved protein found in eukaryotic cells, yet its function is not understood. Here, we find MVP expression highly specific to the limbic system and show that Mvp regulates neuronal morphology, postnatally and specifically in males. We also recapitulate a previously reported genetic interaction and show that Mvp +/- ;Mapk3 +/- mice exhibit behavioral deficits, notably decreased anxiety-like traits detected in the elevated plus maze and open field paradigms., Conclusions: Our study highlights multiple gene drivers in neuroanatomical phenotypes, interacting with each other through complex relationships. It also provides the first evidence for the involvement of the major vault protein in the regulation of brain size and neuroanatomy, specifically in male mice., (© 2023. The Author(s).)

Purpose: The COVID-19 pandemic caused significant changes for family-professional interactions. Many services shifted to telepractice, with new opportunities for parents and speech-language pathologists (SLPs) to partner for service delivery. Parent-coached models of augmentative and alternative communication (AAC) intervention provide positive outcomes for children; however, SLPs have reported difficulty building strong partnerships with families. The shift to telepractice during the COVID-19 pandemic provided a unique context to examine factors influencing parent-SLP partnerships, particularly for parents with children who use aided AAC., Method: Twenty-five parents and 25 SLPs who engaged in services with children and youth from 3 to 21 years of age who used aided AAC during the initial stages of the COVID-19 pandemic in June 2020 participated. Semistructured interviews were conducted individually with parents and SLPs to understand perspectives on whether the change in service delivery facilitated or hindered family-oriented practice. Inductive qualitative analysis was used to analyze information about the factors impacting parent-SLP partnerships., Results: The parent-SLP partnership was influenced by setting and systemic determinants, and intrinsic determinants to the parent and the SLP that included their history and rapport, beliefs about partnering, and knowledge and skills. These determinants served as barriers or facilitators to their partnership., Conclusions: It is essential to consider the relationship, expectations, and knowledge and skills that SLPs and parents bring to the partnership, along with extrinsic structural factors that can impact this partnership. Positive rapport, valued partnership, and an openness to sharing knowledge through teaming and collaboration provided for positive parent-SLP partnerships.

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: Little is known about proactive risk assessment concerning emergency department (ED) visits and hospitalizations in patients with heart failure (HF) who receive home healthcare (HHC) services. This study developed a time series risk model for predicting ED visits and hospitalizations in patients with HF using longitudinal electronic health record data. We also explored which data sources yield the best-performing models over various time windows., Materials and Methods: We used data collected from 9362 patients from a large HHC agency. We iteratively developed risk models using both structured (eg, standard assessment tools, vital signs, visit characteristics) and unstructured data (eg, clinical notes). Seven specific sets of variables included: (1) the Outcome and Assessment Information Set, (2) vital signs, (3) visit characteristics, (4) rule-based natural language processing-derived variables, (5) term frequency-inverse document frequency variables, (6) Bio-Clinical Bidirectional Encoder Representations from Transformers variables, and (7) topic modeling. Risk models were developed for 18 time windows (1-15, 30, 45, and 60 days) before an ED visit or hospitalization. Risk prediction performances were compared using recall, precision, accuracy, F1, and area under the receiver operating curve (AUC)., Results: The best-performing model was built using a combination of all 7 sets of variables and the time window of 4 days before an ED visit or hospitalization (AUC = 0.89 and F1 = 0.69)., Discussion and Conclusion: This prediction model suggests that HHC clinicians can identify patients with HF at risk for visiting the ED or hospitalization within 4 days before the event, allowing for earlier targeted interventions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The vacuolar protein sorting-associated protein 13B (VPS13B) is a large and highly conserved protein. Disruption of VPS13B causes the autosomal recessive Cohen syndrome, a rare disorder characterized by microcephaly and intellectual disability among other features, including developmental delay, hypotonia, and friendly-personality. However, the underlying mechanisms by which VPS13B disruption leads to brain dysfunction still remain unexplained. To gain insights into the neuropathogenesis of Cohen syndrome, we systematically characterized brain changes in Vps13b-mutant mice and compared murine findings to 235 previously published and 17 new patients diagnosed with VPS13B-related Cohen syndrome. We showed that Vps13b is differentially expressed across brain regions with the highest expression in the cerebellum, the hippocampus and the cortex with postnatal peak. Half of the Vps13b -/- mice die during the first week of life. The remaining mice have a normal lifespan and display the core phenotypes of the human disease, including microcephaly, growth delay, hypotonia, altered memory, and enhanced sociability. Systematic 2D and 3D brain histo-morphological analyses reveal specific structural changes in the brain starting after birth. The dentate gyrus is the brain region with the most prominent reduction in size, while the motor cortex is specifically thinner in layer VI. The fornix, the fasciculus retroflexus, and the cingulate cortex remain unaffected. Interestingly, these neuroanatomical changes implicate an increase of neuronal death during infantile stages with no progression in adulthood suggesting that VPS13B promotes neuronal survival early in life. Importantly, whilst both sexes were affected, some neuroanatomical and behavioral phenotypes were less pronounced or even absent in females. We evaluate sex differences in Cohen patients and conclude that females are less affected both in mice and patients. Our findings provide new insights about the neurobiology of VPS13B and highlight previously unreported brain phenotypes while defining Cohen syndrome as a likely new entity of non-progressive infantile neurodegeneration., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests. The following are the supplementary data related to this article. Supplementary data to this article can be found online at https://doi.org/10.1016/j.nbd.2023.106259., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder., Methods: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae., Results: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae -/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans., Conclusion: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Butterflies are a diverse and charismatic insect group that are thought to have evolved with plants and dispersed throughout the world in response to key geological events. However, these hypotheses have not been extensively tested because a comprehensive phylogenetic framework and datasets for butterfly larval hosts and global distributions are lacking. We sequenced 391 genes from nearly 2,300 butterfly species, sampled from 90 countries and 28 specimen collections, to reconstruct a new phylogenomic tree of butterflies representing 92% of all genera. Our phylogeny has strong support for nearly all nodes and demonstrates that at least 36 butterfly tribes require reclassification. Divergence time analyses imply an origin ~100 million years ago for butterflies and indicate that all but one family were present before the K/Pg extinction event. We aggregated larval host datasets and global distribution records and found that butterflies are likely to have first fed on Fabaceae and originated in what is now the Americas. Soon after the Cretaceous Thermal Maximum, butterflies crossed Beringia and diversified in the Palaeotropics. Our results also reveal that most butterfly species are specialists that feed on only one larval host plant family. However, generalist butterflies that consume two or more plant families usually feed on closely related plants., (© 2023. The Author(s).)

Migratory insects are key players in ecosystem functioning and services, but their spatiotemporal distributions are typically poorly known. Ecological niche modeling (ENM) may be used to predict species seasonal distributions, but the resulting hypotheses should eventually be validated by field data. The painted lady butterfly ( Vanessa cardui ) performs multigenerational migrations between Europe and Africa and has become a model species for insect movement ecology. While the annual migration cycle of this species is well understood for Europe and northernmost Africa, it is still unknown where most individuals spend the winter. Through ENM, we previously predicted suitable breeding grounds in the subhumid regions near the tropics between November and February. In this work, we assess the suitability of these predictions through i) extensive field surveys and ii) two-year monitoring in six countries: a large-scale monitoring scheme to study butterfly migration in Africa. We document new breeding locations, year-round phenological information, and hostplant use. Field observations were nearly always predicted with high probability by the previous ENM, and monitoring demonstrated the influence of the precipitation seasonality regime on migratory phenology. Using the updated dataset, we built a refined ENM for the Palearctic-African range of V. cardui . We confirm the relevance of the Afrotropical region and document the missing natural history pieces of the longest migratory cycle described in butterflies.

Aims: To identify clusters of risk factors in home health care and determine if the clusters are associated with hospitalizations or emergency department visits., Design: A retrospective cohort study., Methods: This study included 61,454 patients pertaining to 79,079 episodes receiving home health care between 2015 and 2017 from one of the largest home health care organizations in the United States. Potential risk factors were extracted from structured data and unstructured clinical notes analysed by natural language processing. A K-means cluster analysis was conducted. Kaplan-Meier analysis was conducted to identify the association between clusters and hospitalizations or emergency department visits during home health care., Results: A total of 11.6% of home health episodes resulted in hospitalizations or emergency department visits. Risk factors formed three clusters. Cluster 1 is characterized by a combination of risk factors related to "impaired physical comfort with pain," defined as situations where patients may experience increased pain. Cluster 2 is characterized by "high comorbidity burden" defined as multiple comorbidities or other risks for hospitalization (e.g., prior falls). Cluster 3 is characterized by "impaired cognitive/psychological and skin integrity" including dementia or skin ulcer. Compared to Cluster 1, the risk of hospitalizations or emergency department visits increased by 1.95 times for Cluster 2 and by 2.12 times for Cluster 3 (all p < .001)., Conclusion: Risk factors were clustered into three types describing distinct characteristics for hospitalizations or emergency department visits. Different combinations of risk factors affected the likelihood of these negative outcomes., Impact: Cluster-based risk prediction models could be integrated into early warning systems to identify patients at risk for hospitalizations or emergency department visits leading to more timely, patient-centred care, ultimately preventing these events., Patient or Public Contribution: There was no involvement of patients in developing the research question, determining the outcome measures, or implementing the study., (© 2022 John Wiley & Sons Ltd.)

The closure of schools and healthcare facilities across the United States due to COVID-19 has dramatically changed the way that services are provided to children with disabilities. Little is known about how children who use augmentative and alternative communication (AAC), their families and their service providers have been impacted by these changes. This qualitative study sought to understand the perspectives of parents and speech-language pathologists (SLPs) on how COVID-19 has affected children, families, services providers and the delivery of AAC-related communication services. For the study, 25 parents and 25 SLPs of children who used aided AAC participated in semi-structured interviews, with data analyzed using qualitative thematic analysis. Parents and SLPs highlighted wide disparities in how children have been impacted, ranging from views of children making more progress with communication and language than before the pandemic to worries about regression. A complex system of factors and processes may explain these differences. COVID-19 will have lasting impacts on the lives of children with complex communication needs. This research highlights the crucial role of family-service provider partnerships and access to quality AAC services for children during the pandemic and into the future.

Similarities in male and female genitalic structure isolate a small group of taxa in the genus Iolaus Hübner, [1819], subgenus Philiolaus Stempffer & Bennett, 1958, related to Iolaus aequatorialis Stempffer & Bennett, 1958. They are assigned to the newly proposed I. aequatorialis species group with two new species recognised and described. This action also clarifies previous taxonomic misunderstandings involving a few other species with similar facies because of a lack of information on male and female genital morphology.

Ethnopharmacological Significance: Medicinal plants from the Terminalia genus are widely used as remedies against many infectious diseases, including malaria. As such, Terminalia ivorensis A. Chev. and Terminalia brownii Fresen. are famous due to their usefulness in traditional medicines to treat malaria and yellow fever. However, further information is needed on the extent of anti-Plasmodium potency of extracts and fractions from these plants and their phytochemical profile., Aim of the Study: This study was designed to investigate the in vitro antiplasmodial activity and to determine the chemical profile of promising extracts and fractions from T. ivorensis and T. brownii stem bark., Materials and Methods: Crude aqueous, ethanolic, methanolic, hydroethanolic and ethyl acetate extracts were prepared by maceration from the stem barks of T. brownii and T. ivorensis. They were subsequently tested against chloroquine-sensitive (Pf3D7) and multidrug-resistant (PfDd2) strains of P. falciparum using the parasite lactate dehydrogenase (PfLDH) assay. Extracts showing very good activity on both plasmodial strains were further fractionated using column chromatography guided by evidence of antiplasmodial activity. All bioactive extracts and fractions were screened for their cytotoxicity on Vero and Raw cell lines using the resazurin-based assay and on erythrocytes using the hemolysis assay. The phytochemical profiles of selected potent extracts and fractions were determined by UPLC-QTOF-MS analysis., Results: Of the ten extracts obtained from both plant species, nine showed inhibitory activity against both P. falciparum strains (Pf3D7 and PfDd2), with median inhibitory concentration (IC 50 ) values ranging from 0.13 μg/ml to 10.59 μg/ml. Interestingly, the aqueous extract of T. ivorensis (Ti W ) and methanolic extract of T. brownii (Tb M ) displayed higher antiplasmodial activities against both strains (IC 50 0.13-1.43 μg/ml) and high selectivity indices (SI > 100). Their fractionation led to two fractions from T. ivorensis and two from T. brownii that showed very promising antiplasmodial activity (IC 50 0.15-1.73 μg/mL) and SI greater than 100. The hemolytic assay confirmed the safety of crude extracts and fractions on erythrocytes. UPLC-MS-based phytochemical analysis of the crude aqueous extract of T. ivorensis showed the presence of ellagic acid (1) and leucodelphidin (2), while analysis of the crude methanol extract of T. brownii showed the presence of ellagic acid (1), leucodelphinidin (2), papyriogenin D (3), dihydroactinidiolide (4) and miltiodiol (5)., Conclusions: The extracts and fractions from T. ivorensis and T. brownii showed very good antiplasmodial activity, thus supporting the traditional use of the two plants in the treatment of malaria. Chemical profiling of the extracts and fractions led to the identification of chemical markers and the known antimalarial compound ellagic acid. Further isolation and testing of other pure compounds from the active fractions could lead to the identification of potent antiplasmodial compounds., (Copyright © 2022 Elsevier B.V. All rights reserved.)

CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 CHD7 . Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the Chd7 gene engineered on inbred and outbred genetic backgrounds. We found that both models showed consistent phenotypes with the core clinical manifestations seen in CHARGE syndrome, but the phenotypes in the inbred Chd7 model were more severe, sometimes having reduced penetrance and included dysgenesis of the corpus callosum, hypoplasia of the hippocampus, abnormal retrosplenial granular cortex, ventriculomegaly, hyperactivity, growth delays, impaired grip strength and repetitive behaviors. Interestingly, we also identified previously unreported features including reduced levels of basal insulin and reduced blood lipids. We suggest that the phenotypic variation reported in individuals diagnosed with CHARGE syndrome is likely due to the genetic background and modifiers. Finally, our study provides a valuable resource, making it possible for mouse biologists interested in Chd7 to make informed choices on which mouse model they should use to study phenotypes of interest and investigate in more depth the underlying cellular and molecular mechanisms.

Objective: There is a lack of research on adverse event (AE) detection in oncology patients, despite the propensity for iatrogenic harm. Two common methods include voluntary safety reporting (VSR) and chart review tools, such as the Institute for Healthcare Improvement's Global Trigger Tool (GTT). Our objective was to compare frequency and type of AEs detected by a modified GTT compared with VSR for identifying AEs in oncology patients in a larger clinical trial., Methods: Patients across 6 oncology units (from July 1, 2013, through May 29, 2015) were randomly selected. Retrospective chart reviews were conducted by a team of nurses and physicians to identify AEs using the GTT. The VSR system was queried by the department of quality and safety of the hospital. Adverse event frequencies, type, and harm code for both methods were compared., Results: The modified GTT detected 0.90 AEs per patient (79 AEs in 88 patients; 95% [0.71-1.12] AEs per patient) that were predominantly medication AEs (53/79); more than half of the AEs caused harm to the patients (41/79, 52%), but only one quarter were preventable (21/79; 27%). The VSR detected 0.24 AEs per patient (21 AEs in 88 patients; 95% [0.15-0.37] AEs per patient), a large plurality of which were medication/intravenous related (8/21); more than half did not cause harm (70%). Only 2% of the AEs (2/100) were detected by both methods., Conclusions: Neither the modified GTT nor the VSR system alone is sufficient for detecting AEs in oncology patient populations. Further studies exploring methods such as automated AE detection from electronic health records and leveraging patient-reported AEs are needed., Competing Interests: F.C. received funding from the National Institutes of Health. L.S. received funding from the National Institutes of Health under R01DK116898. R.R. disclosed that he is a cofounder of Hospitech Respiration and disclosed work for hire. A.M. received additional funding from Risk Management Foundation Insurance Company. M.C.’s institution received funding from research grants funded by the Agency for Healthcare Research and Quality and research contracts funded by the Food and Drug Administration and Office of the Assistant Secretary of Preparedness and Response. K.O.S. received support for article research from the Gordon and Betty Moore Foundation. D.W.B. received funding from SEA Medical, Intensix, EarlySense, QPID, Zynx, CDI (Negev), Enelgy, ValeraHealth, and MDClone; and he disclosed that he is a coinventor on patent no. 6029138 held by the Brigham and Women’s Hospital on the use of decision support software for medical management, licensed to the Medicalis Corporation, where he holds a minority equity position. The remaining authors disclose no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: About one in five patients receiving home healthcare (HHC) services are hospitalized or visit an emergency department (ED) during a home care episode. Early identification of at-risk patients can prevent these negative outcomes. However, risk indicators, including language in clinical notes that indicate a concern about a patient, are often hidden in narrative documentation throughout their HHC episode., Objective: The aim of the study was to develop an automated natural language processing (NLP) algorithm to identify concerning language indicative of HHC patients' risk of hospitalizations or ED visits., Methods: This study used the Omaha System-a standardized nursing terminology that describes problems/signs/symptoms that can occur in the community setting. First, five HHC experts iteratively reviewed the Omaha System and identified concerning concepts indicative of HHC patients' risk of hospitalizations or ED visits. Next, we developed and tested an NLP algorithm to identify these concerning concepts in HHC clinical notes automatically. The resulting NLP algorithm was applied on a large subset of narrative notes (2.3 million notes) documented for 66,317 unique patients ( n = 87,966 HHC episodes) admitted to one large HHC agency in the Northeast United States between 2015 and 2017., Results: A total of 160 Omaha System signs/symptoms were identified as concerning concepts for hospitalizations or ED visits in HHC. These signs/symptoms belong to 31 of the 42 available Omaha System problems. Overall, the NLP algorithm showed good performance in identifying concerning concepts in clinical notes. More than 18% of clinical notes were detected as having at least one concerning concept, and more than 90% of HHC episodes included at least one Omaha System problem. The most frequently documented concerning concepts were pain, followed by issues related to neuromusculoskeletal function, circulation, mental health, and communicable/infectious conditions., Conclusion: Our findings suggest that concerning problems or symptoms that could increase the risk of hospitalization or ED visit were frequently documented in narrative clinical notes. NLP can automatically extract information from narrative clinical notes to improve our understanding of care needs in HHC. Next steps are to evaluate which concerning concepts identified in clinical notes predict hospitalization or ED visit., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Attenuating enzymatic degradation of endocannabinoids (eCBs) by fatty acid amide hydrolase (FAAH) reduces cannabis withdrawal symptoms in preclinical and clinical studies. In mice, blocking cyclooxygenase-2 (COX-2) activity increases central eCB levels by inhibiting fatty acid degradation. This placebo-controlled study examined the effects of the FDA-approved COX-2 selective inhibitor, celecoxib, on cannabis withdrawal, 'relapse', and circulating eCBs in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (12M, 3F) completed a crossover study comprising two 11-day study phases (separated by >14 days for medication clearance). In each phase, the effects of daily BID placebo (0 mg) or celecoxib (200 mg) on cannabis (5.3% THC) intoxication, withdrawal symptoms (4 days of inactive cannabis self-administration) and 'relapse' (3 days of active cannabis self-administration following abstinence) were assessed. Outcome measures included mood, cannabis self-administration, sleep, food intake, cognitive performance, tobacco cigarette use and circulating eCBs and related lipids. Under placebo maintenance, cannabis abstinence produced characteristic withdrawal symptoms (negative mood, anorexia and dreaming) relative to cannabis administration and was associated with increased OEA (a substrate of FAAH) and oleic acid (metabolite of OEA), with no change in eCB levels. Compared to placebo, celecoxib improved subjective (but not objective) measures of sleep and did not affect mood or plasma levels of eCBs or associated lipids and increased cannabis craving. The overall absence of effects on cannabis withdrawal symptoms, self-administration or circulating eCBs relative to placebo, combined with an increase in cannabis craving, suggests celecoxib does not show promise as a potential pharmacotherapy for CUD., (© 2022 Society for the Study of Addiction.)

Congenital neurodevelopmental anomalies are present from birth and are characterized by an abnormal development of one or more structures of the brain. Brain structural anomalies are highly comorbid with neurodevelopmental and neuropsychiatric disorders such as intellectual disability, autism spectrum disorders, epilepsy, and schizophrenia, and 80% are of genetic origin. We aim to address an important neurobiological question: How many genes regulate the normal anatomy of the brain during development. To do so, we developed a quantitative approach for the assessment of a total of 106 neuroanatomical parameters in mouse mutant embryos at embryonic day 18.5 across two planes commonly used in brain anatomical studies, the coronal and sagittal planes. In this article we describe the techniques we developed and explain why ultrastandardized procedures involving embryonic mouse brains are even more of prime importance for morphological phenotyping than adult mouse brains. We focus our analysis on brain size anomalies and on the most frequently altered brain regions including the cortex, corpus callosum, hippocampus, ventricles, caudate putamen, and cerebellum. Our protocols allow a standardized histology pipeline from embryonic mouse brain preparation to sectioning, staining, and scanning and neuroanatomical analyses at well-defined positions on the coronal and sagittal planes. Together, our protocols will help scientists in deciphering congenital neurodevelopmental anomalies and anatomical changes between groups of mouse embryos in health and genetic diseases. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Fixation and preparation of embryonic mouse brain samples Basic Protocol 2: Sectioning, staining, and scanning of embryonic mouse brain sections Basic Protocol 3: Coronal neuroanatomical measurements of embryonic mouse brain structures Basic Protocol 4: Sagittal neuroanatomical measurements of embryonic mouse brain structures., (© 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.)

Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex., (© 2022. The Author(s).)

Background: Clinician trust in machine learning-based clinical decision support systems (CDSSs) for predicting in-hospital deterioration (a type of predictive CDSS) is essential for adoption. Evidence shows that clinician trust in predictive CDSSs is influenced by perceived understandability and perceived accuracy., Objective: The aim of this study was to explore the phenomenon of clinician trust in predictive CDSSs for in-hospital deterioration by confirming and characterizing factors known to influence trust (understandability and accuracy), uncovering and describing other influencing factors, and comparing nurses' and prescribing providers' trust in predictive CDSSs., Methods: We followed a qualitative descriptive methodology conducting directed deductive and inductive content analysis of interview data. Directed deductive analyses were guided by the human-computer trust conceptual framework. Semistructured interviews were conducted with nurses and prescribing providers (physicians, physician assistants, or nurse practitioners) working with a predictive CDSS at 2 hospitals in Mass General Brigham., Results: A total of 17 clinicians were interviewed. Concepts from the human-computer trust conceptual framework-perceived understandability and perceived technical competence (ie, perceived accuracy)-were found to influence clinician trust in predictive CDSSs for in-hospital deterioration. The concordance between clinicians' impressions of patients' clinical status and system predictions influenced clinicians' perceptions of system accuracy. Understandability was influenced by system explanations, both global and local, as well as training. In total, 3 additional themes emerged from the inductive analysis. The first, perceived actionability, captured the variation in clinicians' desires for predictive CDSSs to recommend a discrete action. The second, evidence, described the importance of both macro- (scientific) and micro- (anecdotal) evidence for fostering trust. The final theme, equitability, described fairness in system predictions. The findings were largely similar between nurses and prescribing providers., Conclusions: Although there is a perceived trade-off between machine learning-based CDSS accuracy and understandability, our findings confirm that both are important for fostering clinician trust in predictive CDSSs for in-hospital deterioration. We found that reliance on the predictive CDSS in the clinical workflow may influence clinicians' requirements for trust. Future research should explore the impact of reliance, the optimal explanation design for enhancing understandability, and the role of perceived actionability in driving trust., (©Jessica M Schwartz, Maureen George, Sarah Collins Rossetti, Patricia C Dykes, Simon R Minshall, Eugene Lucas, Kenrick D Cato. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 12.05.2022.)

Compared to other regions, the drivers of diversification in Africa are poorly understood. We studied a radiation of insects with over 100 species occurring in a wide range of habitats across the Afrotropics to investigate the fundamental evolutionary processes and geological events that generate and maintain patterns of species richness on the continent. By investigating the evolutionary history of Bicyclus butterflies within a phylogenetic framework, we inferred the group's origin at the Oligo-Miocene boundary from ancestors in the Congolian rainforests of central Africa. Abrupt climatic fluctuations during the Miocene (ca. 19-17 Ma) likely fragmented ancestral populations, resulting in at least eight early-divergent lineages. Only one of these lineages appears to have diversified during the drastic climate and biome changes of the early Miocene, radiating into the largest group of extant species. The other seven lineages diversified in forest ecosystems during the late Miocene and Pleistocene when climatic conditions were more favorable-warmer and wetter. Our results suggest changing Neogene climate, uplift of eastern African orogens, and biotic interactions have had different effects on the various subclades of Bicyclus, producing one of the most spectacular butterfly radiations in Africa. [Afrotropics; biodiversity; biome; biotic interactions; Court Jester; extinction; grasslands; paleoclimates; Red Queen; refugia forests; dependent-diversification; speciation.]., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Systematic Biologists.)

Objective: To identify the risk factors home healthcare (HHC) clinicians associate with patient deterioration and understand how clinicians respond to and document these risk factors., Methods: We interviewed multidisciplinary HHC clinicians from January to March of 2021. Risk factors were mapped to standardized terminologies (eg, Omaha System). We used directed content analysis to identify risk factors for deterioration. We used inductive thematic analysis to understand HHC clinicians' response to risk factors and documentation of risk factors., Results: Fifteen HHC clinicians identified a total of 79 risk factors that were mapped to standardized terminologies. HHC clinicians most frequently responded to risk factors by communicating with the prescribing provider (86.7% of clinicians) or following up with patients and caregivers (86.7%). HHC clinicians stated that a majority of risk factors can be found in clinical notes (ie, care coordination (53.3%) or visit (46.7%))., Discussion: Clinicians acknowledged that social factors play a role in deterioration risk; but these factors are infrequently studied in HHC. While a majority of risk factors were represented in the Omaha System, additional terminologies are needed to comprehensively capture risk. Since most risk factors are documented in clinical notes, methods such as natural language processing are needed to extract them., Conclusion: This study engaged clinicians to understand risk for deterioration during HHC. The results of our study support the development of an early warning system by providing a comprehensive list of risk factors grounded in clinician expertize and mapped to standardized terminologies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)