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Abstract Background Sex as a biological variable is not a common consideration in molecular mechanistic or preclinical studies of retinal diseases. Understanding the sexual dimorphism of adult RPE and retina under physiological conditions is an important first step in improving our understanding of sex-based physio-pathological mechanisms. Methods Isobaric tags for relative and absolute quantitation (iTRAQ) were used for quantitative proteomics of male and female mouse retina and RPE (10 mice of each sex for each tissue type). Differentially expressed proteins were subjected to Gene Ontology (GO) analysis and Ingenuity Pathway Analysis (IPA). Results Differential expression analysis identified 21 differentially expressed proteins in the retina and 58 differentially expressed proteins in the RPE. Ingenuity pathway analysis identified the top canonical pathways differentially activated in the retina to be calcium transport I, nucleotide excision repair, molecular transport and cell death and survival. In the RPE, the top canonical pathways were calcium signaling, dilated cardiomyopathy signaling, actin cytoskeletal signaling and cellular assembly and organization. Conclusions These results provide insights into sex differences in the retina and RPE proteome of mice and begin to shed clues into the sexual dimorphism seen in retinal diseases.

Abstract Background Inclusion in public health research of young people from low-income households and those from minority ethnic groups remains low. It is recognised that there is a need to change the way in which research is conducted so that it becomes more inclusive. The aim of this work was to identify novel and innovative ways to maximise recruitment and inclusion of diverse participants when doing co-production within very short time frames for emergency responses. Method We conducted interviews with young people from low-income and minority ethnic backgrounds, and members or leaders of groups or organisations supporting or representing young people from underserved communities. Results A total of 42 participants took part in an interview. This included 30 young people from low income or minority ethnic backgrounds and 12 community leaders/service providers. Of the 30 young people, 26 participants identified as female and 12 participants identified as being from a minority ethnic background. Participants discussed a number of interrelated barriers to research involvement and identified ways in which barriers may be reduced. Prejudice and discrimination experienced by young people from underserved communities has led to substantial mistrust of educational and governmental establishments. Rigid and unfamiliar research practices further limit the involvement of young people. Four themes were identified as ways of supporting involvement, including: making opportunities available for young people, adaptations to research governance, understanding and acknowledging challenges faced by young people, and ensuring reciprocal benefits. Conclusion This research explored barriers to engagement in rapid public health co-production. Working with communities to co-produce rapid recruitment and research procedures to suit the needs and the context in which young people live is necessary.

Background Acute respiratory infections are a common reason for consultation with primary and emergency healthcare services. Identifying individuals with a bacterial infection is crucial to ensure appropriate treatment. However, it is also important to avoid overprescription of antibiotics, to prevent unnecessary side effects and antimicrobial resistance. We conducted a systematic review to summarise evidence on the diagnostic accuracy of symptoms, signs and point-of-care tests to diagnose bacterial respiratory tract infection in adults, and to diagnose two common respiratory viruses, influenza and respiratory syncytial virus. Methods The primary approach was an overview of existing systematic reviews. We conducted literature searches (22 May 2023) to identify systematic reviews of the diagnostic accuracy of point-of-care tests. Where multiple reviews were identified, we selected the most recent and comprehensive review, with the greatest overlap in scope with our review question. Methodological quality was assessed using the Risk of Bias in Systematic Reviews tool. Summary estimates of diagnostic accuracy (sensitivity, specificity or area under the curve) were extracted. Where no systematic review was identified, we searched for primary studies. We extracted sufficient data to construct a 2 × 2 table of diagnostic accuracy, to calculate sensitivity and specificity. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies version 2 tool. Where possible, meta-analyses were conducted. We used GRADE to assess the certainty of the evidence from existing reviews and new analyses. Results We identified 23 reviews which addressed our review question; 6 were selected as the most comprehensive and similar in scope to our review protocol. These systematic reviews considered the following tests for bacterial respiratory infection: individual symptoms and signs; combinations of symptoms and signs (in clinical prediction models); clinical prediction models incorporating C-reactive protein; and biological markers related to infection (including C-reactive protein, procalcitonin and others). We also identified systematic reviews that reported the accuracy of specific tests for influenza and respiratory syncytial virus. No reviews were found that assessed the diagnostic accuracy of white cell count for bacterial respiratory infection, or multiplex tests for influenza and respiratory syncytial virus. We therefore conducted searches for primary studies, and carried out meta-analyses for these index tests. Overall, we found that symptoms and signs have poor diagnostic accuracy for bacterial respiratory infection (sensitivity ranging from 9.6% to 89.1%; specificity ranging from 13.4% to 95%). Accuracy of biomarkers was slightly better, particularly when combinations of biomarkers were used (sensitivity 80–90%, specificity 82–93%). The sensitivity and specificity for influenza or respiratory syncytial virus varied considerably across the different types of tests. Tests involving nucleic acid amplification techniques (either single pathogen or multiplex tests) had the highest diagnostic accuracy for influenza (sensitivity 91–99.8%, specificity 96.8–99.4%). Limitations Most of the evidence was considered low or very low certainty when assessed with GRADE, due to imprecision in effect estimates, the potential for bias and the inclusion of participants outside the scope of this review (children, or people in hospital). Future work Currently evidence is insufficient to support routine use of point-of-care tests in primary and emergency care. Further work must establish whether the introduction of point-of-care tests adds value, or simply increases healthcare costs. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR159948. Plain language summary What is the problem? Respiratory infections are a common cause of illness. Currently, healthcare professionals use clinical experience to decide whether an infection is caused by a virus or bacteria, and whether antibiotics are needed. However, this is not always easy to establish. We tried to identify the effectiveness of rapid tests (with results in under 45 minutes) at distinguishing between viral and bacterial respiratory infections. What did we do? We identified and summarised all the existing reviews and studies in this area. We looked at many different tests which aim to distinguish between bacterial and viral causes of respiratory infections. In particular, we assessed: individual symptoms and signs (such as the presence of cough, or a fever) combinations of symptoms and signs (the presence or absence of multiple symptoms) various ‘biomarker’ tests (blood tests for evidence that the body has used its defence mechanisms) We also looked at specific tests for flu and respiratory syncytial virus, which are common causes of viral infection. What did we find? The reviews we found showed symptoms and signs were not able to identify bacterial infections in people accurately. The accuracy of biomarker tests was slightly better, particularly when multiple markers were used. The accuracy of rapid tests for flu and respiratory syncytial virus varied; the most accurate tests were those that detect viral genetic material. We also found studies showing that genetic tests that identify many viruses at once (multiplex tests) were very accurate. However, most of the evidence we identified was not robust. There were concerns about the conduct of some of the studies. In some cases there was uncertainty whether a test was really accurate enough to be useful. Therefore there is still doubt about whether any of these tests will be useful additions to current clinical care.

BackgroundThe COVID-19 pandemic created unprecedented challenges for people with type 2 diabetes (T2D) and prediabetes to access in-person health care support. Primary care teams accelerated plans to implement digital health technologies (DHTs), such as remote consultations and digital self-management. There is limited evidence about whether there were inequalities in how people with T2D and prediabetes adjusted to these changes. ObjectiveThis study aimed to explore how people with T2D and prediabetes adapted to the reduction in in-person health support and the increased provision of support through DHTs during the COVID-19 pandemic and beyond. MethodsA purposive sample of people with T2D and prediabetes was recruited by text message from primary care practices that served low-income areas. Semistructured interviews were conducted by phone or video call, and data were analyzed thematically using a hybrid inductive and deductive approach. ResultsA diverse sample of 30 participants was interviewed. There was a feeling that primary care had become harder to access. Participants responded to the challenge of accessing support by rationing or delaying seeking support or by proactively requesting appointments. Barriers to accessing health care support were associated with issues with using the total triage system, a passive interaction style with health care services, or being diagnosed with prediabetes at the beginning of the pandemic. Some participants were able to adapt to the increased delivery of support through DHTs. Others had lower capacity to use DHTs, which was caused by lower digital skills, fewer financial resources, and a lack of support to use the tools. ConclusionsInequalities in motivation, opportunity, and capacity to engage in health services and DHTs lead to unequal possibilities for people with T2D and prediabetes to self-care and receive care during the COVID-19 pandemic. These issues can be addressed by proactive arrangement of regular checkups by primary care services and improving capacity for people with lower digital skills to engage with DHTs.

IntroductionCancer therapies predispose childhood cancer survivors to various treatment-related late effects, which contribute to a higher symptom burden, chronic health conditions (CHCs), and premature mortality. Regular monitoring of symptoms between clinic visits is useful for timely medical consultation and interventions that can improve quality of life (QOL). The Health Share Study aims to utilize mHealth to collect patient-generated health data (PGHD; daily symptoms, momentary physical health status) and develop survivor-specific risk prediction scores for mitigating adverse health outcomes including poor QOL and emergency room admissions. These personalized risk scores will be integrated into the hospital-based electronic health record (EHR) system to facilitate clinician communications with survivors for timely management of late effects.MethodsThis prospective study will recruit 600 adult survivors of childhood cancer from the St. Jude Lifetime Cohort study. Data collection include 20 daily symptoms via a smartphone, objective physical health data (physical activity intensity, sleep performance, and biometric data including resting heart rate, heart rate variability, oxygen saturation, and physical stress) via a wearable activity monitor, patient-reported outcomes (poor QOL, unplanned healthcare utilization) via a smartphone, and clinically ascertained outcomes (physical performance deficits, onset of/worsening CHCs) assessed in the survivorship clinic. Participants will complete health surveys and physical/functional assessments in the clinic at baseline, 2) report daily symptoms, wear an activity monitor, measure blood pressure at home over 4 months, and 3) complete health surveys and physical/functional assessments in the clinic 1 and 2 years from the baseline. Socio-demographic and clinical data abstracted from the EHR will be included in the analysis. We will invite 20 cancer survivors to investigate suitable formats to display predicted risk information on a dashboard and 10 clinicians to suggest evidence-based risk management strategies for adverse health outcomes.AnalysisMachine and statistical learning will be used in prediction modeling. Both approaches can handle a large number of predictors, including longitudinal patterns of daily symptoms/other PGHD, along with cancer treatments and socio-demographics.ConclusionThe individualized risk prediction scores and added communications between providers and survivors have the potential to improve survivorship care and outcomes by identifying early clinical presentations of adverse events.

Introduction High-quality shared decision-making (SDM) is a priority of health services, but only achieved in a minority of surgical consultations. Improving SDM for surgical patients may lead to more effective care and moderate the impact of treatment consequences. There is a need to establish effective ways to achieve sustained and large-scale improvements in SDM for all patients whatever their background. The ALPACA Study aims to develop, pilot and evaluate a decision support intervention that uses real-time feedback of patients’ experience of SDM to change patients’ and healthcare professionals’ decision-making processes before adult elective surgery and to improve patient and health service outcomes.Methods and analysis This protocol outlines a mixed-methods study, involving diverse stakeholders (adult patients, healthcare professionals, members of the community) and three National Health Service (NHS) trusts in England. Detailed methods for the assessment of the feasibility, usability and stakeholder views of implementing a novel system to monitor the SDM process for surgery automatically and in real time are described. The study will measure the SDM process using validated instruments (CollaboRATE, SDM-Q-9, SHARED-Q10) and will conduct semi-structured interviews and focus groups to examine (1) the feasibility of automated data collection, (2) the usability of the novel system and (3) the views of diverse stakeholders to inform the use of the system to improve SDM. Future phases of this work will complete the development and evaluation of the intervention.Ethics and dissemination Ethical approval was granted by the NHS Health Research Authority North West-Liverpool Central Research Ethics Committee (reference: 21/PR/0345). Approval was also granted by North Bristol NHS Trust to undertake quality improvement work (reference: Q80008) overseen by the Consent and SDM Programme Board and reporting to an Executive Assurance Committee.Trial registration number ISRCTN17951423; Pre-results.

Background: Following critical illness, family members are often required to adopt caregiving responsibilities. Anxiety and depression are common long term problems for both patients and caregivers. However, at present, it is not known how the trajectories of these symptoms compare between patients and caregivers., Objectives: The aim of this study was to investigate and compare the trajectories of anxiety and depression in patients and caregivers in the first year following critical illness., Methods: This study analyses data from a prospective multicentre cohort study of patients and caregivers who underwent a complex recovery intervention following critical illness. Paired patients and caregivers were recruited. The Hospital Anxiety and Depression Scale was used to evaluate symptoms of anxiety and depression at three timepoints: baseline; 3 months; and 12 months in both patient and caregivers. A linear mixed-effects regression model was used to evaluate the trajectories of these symptoms over the first year following critical illness., Results: 115 paired patients and caregivers, who received the complex recovery intervention, were recruited. There was no significant difference in the relative trajectory of depressive symptoms between patients and caregivers in the first 12 months following critical illness (p = 0.08). There was, however, a significant difference in the trajectory of anxiety symptoms between patients and caregivers during this time period (p = 0.04), with caregivers seeing reduced resolution of symptoms in comparison to patients., Conclusions: Following critical illness, symptoms of anxiety and depression are common in both patients and caregivers. The trajectory of symptoms of depression was similar between caregivers and patients; however, there was a significantly different recovery trajectory in symptoms of anxiety. Further research is required to understand the recovery pathway of caregivers in order to design effective interventions., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Intraperitoneal (IP) aminoglycosides (AGs) continue to be the cornerstone of empiric management of peritonitis. AG dosing during automated peritoneal dialysis (APD), however, has not been well studied in patients with peritonitis. We sought to identify differences in AG exposure in the peritoneum and plasma for two different dosing regimens with little supporting evidence in patients on APD with peritonitis., Methods: A retrospective design that utilised the peritoneal and plasma concentration-time data from a prior study of 18 continuous ambulatory peritoneal dialysis (CAPD) patients with peritonitis to generate an in silico peritoneal and plasma PK model. This model was then used to compare via simulation using Phoenix© WinNonlin Software with IP AG dosing for a loading-dose regimen (1.5 mg/kg first dose) versus a fixed-dose regimen (0.6 mg/kg/d) in patients on APD with peritonitis., Results: Outcome measures were (1) percentage of time where peritoneal peak concentrations/minimal inhibitory concentration (MIC) ratio >10, (2) AUC/MIC > 74 and (3) plasma Cmin concentrations. Both regimens resulted in > 90% optimal peak/MIC ratio and AUC/MIC ratios on days 1 and 5 of the dose protocol. The loading-dose regimen resulted in IP exposures that were 2.5 times greater in the peritoneal compartment on day 1. By day 5, both protocols resulted in similar accumulation of AG plasma Cmin concentrations of 2.5-3.4 mg/L versus 2.4-3.3 mg/L, respectively, for the loading-dose regimen versus fixed-dose regimen., Conclusions: The current international guidelines for the treatment of peritoneal dialysis-associated peritonitis can continue to recommend the fixed-dose regimen for those on APD with the addition of plasma Cmin monitoring after 3 days to assess for drug accumulation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Female genital mutilation (FGM) is a global public health concern. However, reconstructive surgery remains unavailable in many countries., Objectives: This scoping review, guided by Joanna Briggs Institute (JBI) principles, explores indications, referral routes, eligibility, care pathways and clinical outcomes of reconstructive surgery for FGM., Search Strategy: Medical Subject Headings (MeSH) terms and subject headings were searched in EMBASE, MEDLINE, SCOPUS, Web of Science and publicly available trial registers., Selection Criteria: Any primary experimental and quasi-experimental study addressing reconstructive surgery for FGM, and its impact on women, published before June 2023., Data Collection and Analysis: After removing duplicates from the search results, titles and abstracts were screened and data were extracted. Disagreements were resolved through panel discussion. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram depicts the search results and inclusion process., Main Results: A total of 40 studies were included. Multidisciplinary teams were involved in 40% (16/40) of the studies, and psychosexual counselling was offered in 37.5% (15/40) of studies. Clitoral reconstruction using Foldes' technique was predominant (95%, 38/40). A total of 7274 women underwent some form of reconstruction. Post-surgery improvement was reported in 94% of the cases (6858/7274). The complication rate was 3% (207/7722 women with reconstruction)., Conclusions: Further research and clinical trials are needed. Although the outcomes suggest improved sexual function and quality of life post-surgery, the evidence remains limited. Advocating surgical reconstruction for survivors of FGM is vital for addressing health disparities and potential cost-effectiveness., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Purpose of Review: Diabetes is the most common cause of kidney disease in individuals that receive a kidney transplant, and those without pre-existing diabetes are at greater risk of developing diabetes following kidney transplant. A class of diabetes treatment medications called glucagon-like peptide-1 receptor agonists (GLP-1RA) has seen recent widespread use for people with diabetes or obesity, with efficacy for improved glycemic control, weight loss, and reduced risk of cardiovascular events. Given these benefits, and indications for use that often co-occur in kidney transplant recipients, use of GLP-1RAs warrants consideration in this population. Therefore, we sought to review the current literature to better understand the mechanisms of action, clinical application, and person-centred considerations of GLP-1RAs in kidney transplant recipients., Sources of Information: Original articles were identified between December 2023 and July 2024 from electronic databases including the Ovid MEDLINE database, PubMed, and Google Scholar using terms "kidney transplant," "GLP-1," "glucagon-like peptide-1 receptor agonist," and "diabetes.", Methods: A comprehensive review of the literature was conducted to explore the relationship between GLP-1RAs and kidney transplant recipients. We reviewed the current state of evidence across the research disciplines of basic or fundamental science, clinical and health services research, and person-centred equity science, and highlighted important knowledge gaps that offer opportunities for future research., Key Findings: Numerous clinical studies have demonstrated the benefit of GLP-1RAs in people with and without diabetic kidney disease, including decreased risk of cardiovascular events. However, there is a paucity of high-quality randomized controlled trials and observational studies analyzing use of GLP-1RAs in kidney transplant recipients. Evidence of benefit in this population is therefore limited to small studies or inferred from research conducted in nontransplant populations. Growing evidence from preclinical and clinical studies may elucidate renoprotective mechanisms of GLP-1RAs and remove barriers to application of these drugs in the transplant recipient population. Individuals who are female, non-white, have lower socioeconomic status, and live in rural communities are at greater risk of diabetes and have lower uptake of GLP-1RAs. There is a need for clinical trials across diverse kidney transplant populations to estimate the efficacy of GLP-1RAs on important health outcomes., Limitations: The search strategy for this narrative review may not have been sensitive to identify all relevant articles. Our search was limited to English language articles., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Midlife and older women who experience intimate partner violence (IPV) often have less access to supports and services than younger women. There is far less focus on research and supports for midlife and older women compared to younger women experiencing IPV, and often, neither elder abuse nor IPV services meet their needs. Few interventions are available to meet the needs of midlife and older women., Objective: The goal of this randomized controlled trial is to test the effectiveness of an advocacy intervention for midlife and older women who experience IPV and to learn from the experiences of those who implement and participate in the program., Methods: This trial is a 2-arm, unblinded, parallel, pragmatic randomized controlled trial with a qualitative component. Eligible participants will be women who live in the Maritime provinces of Canada (New Brunswick, Nova Scotia, and Prince Edward Island), who are in midlife and older (aged approximately ≥50 years), and who are currently in a relationship with an abusive partner or have recently left an abusive partner. Facilitators will be trained to deliver the intervention. The intervention will be entirely virtual and will consist of 2 components: (1) an empowerment component, which will involve sharing resources and information with the women; and (2) a social support component, which will include providing support and encouragement to women for 12 weeks. Quantitative effectiveness data will be collected from all trial participants at baseline, 3 months after the intervention, and 9 months after the intervention about the incidence and severity of IPV, physical and mental health, and safety behaviors and strategies. Qualitative interviews will be conducted with the facilitators and intervention group participants. Control group participants will receive a static, nontailored version of the advocacy intervention for midlife and older women (AIM) intervention materials after baseline data collection., Results: A total of 12 facilitators have been trained to deliver the AIM intervention to trial participants. Participant recruitment and data collection will be completed in January 2025. Data analysis will continue throughout the data collection period, and the results will be disseminated by December 2025., Conclusions: This research will result in the adaptation and testing of a program to support and empower midlife and older women in the Maritime provinces of Canada who experience IPV., Trial Registration: International Standard Randomized Controlled Trial Registry ISRCTN30646991; https://doi.org/10.1186/ISRCTN30646991., International Registered Report Identifier (irrid): DERR1-10.2196/57886., (©Lori Weeks, Kathleen Allen, Catherine Holtmann, Joni Leger, Suzanne Dupuis-Blanchard, Colleen MacQuarrie, Marilyn Macdonald, Elaine Moody, Christie Stilwell, Heather Helpard, Danie Gagnon. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 30.10.2024.)

Background: Sex as a biological variable is not a common consideration in molecular mechanistic or preclinical studies of retinal diseases. Understanding the sexual dimorphism of adult RPE and retina under physiological conditions is an important first step in improving our understanding of sex-based physio-pathological mechanisms., Methods: Isobaric tags for relative and absolute quantitation (iTRAQ) were used for quantitative proteomics of male and female mouse retina and RPE (10 mice of each sex for each tissue type). Differentially expressed proteins were subjected to Gene Ontology (GO) analysis and Ingenuity Pathway Analysis (IPA)., Results: Differential expression analysis identified 21 differentially expressed proteins in the retina and 58 differentially expressed proteins in the RPE. Ingenuity pathway analysis identified the top canonical pathways differentially activated in the retina to be calcium transport I, nucleotide excision repair, molecular transport and cell death and survival. In the RPE, the top canonical pathways were calcium signaling, dilated cardiomyopathy signaling, actin cytoskeletal signaling and cellular assembly and organization., Conclusions: These results provide insights into sex differences in the retina and RPE proteome of mice and begin to shed clues into the sexual dimorphism seen in retinal diseases., (© 2024. The Author(s).)

Objectives: Self-medication with antibiotics is common practice in many low- and middle-income countries (LMIC). This review synthesizes the qualitative evidence on influences on perceptions and practices in relation to self-medication by the public with antibiotics in LMIC., Methods: A systematic search was conducted of relevant medical, international and social science databases. Searching, screening, data extraction and quality appraisal followed standard methods. A meta-ethnographic approach was used for synthesis, starting with translation of studies and using a line-of-argument approach to develop the final themes., Results: The search identified 78 eligible studies. Antibiotics were understood as a powerful, potentially dangerous but effective medicine for treating infections. This perception was strongly influenced by the common experience of being prescribed antibiotics for infections, both individually and collectively. This contributed to an understanding of antibiotics as a rational treatment for infection symptoms that was sanctioned by medical authorities. Accessing antibiotics from medical professionals was often difficult logistically and financially. In contrast, antibiotics were readily available over the counter from local outlets. People viewed treating infection symptoms with antibiotics as rational practice, although they were concerned about the risks to the individual and only took them when they believed they were needed., Conclusions: A new model to explain self-medication with antibiotics is presented. This uses the socio-ecological model to integrate influences that operate at individual, community and wider socioeconomic levels, drawing on theories of medical authority and the medicalization and commercialization of health. Interventions to reduce overuse of antibiotics in LMIC need to address both clinical practice and community self-medication practices together., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician's Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25 bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control., (© 2024. The Author(s).)

Objective: To develop and assess the face and construct validity of the Clinician-reported Genetic testing Utility InDEX (C-GUIDE TM ) for genetic testing in prenatal care., Methods: Following a literature review and consultation with clinical experts, a preliminary draft of C-GUIDE Prenatal was developed. Its face and content validity were then assessed by 19 prenatal genetics' providers using interviews and surveys. Feedback informed further revisions. To test construct validity, four geneticist raters completed C-GUIDE on a retrospective sample of cases that received prenatal genetic testing and completed a concurrent global assessment of utility of these cases using an anchor item. A generalized estimating equations model was used to adjust for rater correlation and measure the association between C-GUIDE scores, global item scores, and potential clinical variables., Results: To develop C-GUIDE Prenatal, 7 items were removed, 10 items were modified, and 4 items were added. For 101 cases rated for validation, on average, a 1-point increase in the global item score was associated with an increase of 1.1 in the C-GUIDE score (p=0.04). Compared to uninformative results, informative positive and informative negative results were associated with a mean increase of 10.7 (SE=1.05) (p<0.001) and 5.6 (SE=1.85) (p<0.001), respectively. As indications for testing, known/familial variants were associated with a mean increase in the C-GUIDE score of 4.7 (SE=2.21) (p < 0.001) compared to ultrasound findings. C-GUIDE scores increased by a mean of 3.0 (SE=0.23) among cases for whom pregnancies were ongoing compared to those for whom they were not (p<0.01)., Conclusions: The significant positive associations between C-GUIDE total and the global item score and between C-GUIDE total, result type, indication for testing, and pregnancy status in the expected directions provide evidence of construct validity., (Copyright © 2024. Published by Elsevier Inc.)

Background: Coordinated specialty care (CSC) programs for first episodes of psychosis are increasingly offered in the United States. A component of CSC programs is active family engagement in treatment, though research on the impact of this engagement is limited. This study examined the characteristics of families engaged compared to families not engaged in treatment, and the impact of family engagement on client participation and medication adherence over the first 6 months of treatment., Methods: Using data from the Early Psychosis Intervention Network (EPINET) research hub in Minnesota (EPI-MINN), we compared two groups of individuals: clients who had a family member(s) engaged in their treatment vs. clients who did not. Family engagement was defined as any treatment services provided to a family member(s) by CSC clinical staff. The groups were compared on intake demographic variables, duration of untreated psychosis (DUP), hospitalizations, symptom severity, and functioning. A comparison of the total number of treatment visits during the first 6 months of treatment was tested using both nonparametric (Mann Whitney U) and parametric (ANCOVA) tests. Group comparisons on self ratings of "intent to attend visits," "intent to complete the program," and medication adherence were tested with ANCOVA and Chi-Square., Results: Family-engaged clients were younger, with less years of education, and more often White; clients without family engagement were more often Black. Family engagement was positively associated with increased total number of visits for all interventions with the exceptions of client peer support and case management visits. Family engagement increased clients' self-reported intent to attend visits, though not intention to complete the program, which was moderately to markedly high in both groups. No differences were noted with medication adherence, with high rates of adherence across the entire study sample., Conclusions: Overall, results of the study support the benefits of family engagement in CSC on client participation, though future research is needed to understand why Black families are less engaged and what treatment adaptations are needed to reduce these racial differences. The results also support the value of CSC programs for medication adherence, a critical factor in symptom reduction and mental health recovery., (© 2024. The Author(s).)

The enteric nervous system (ENS) consists of an extensive network of neurons and glial cells embedded within the wall of the gastrointestinal (GI) tract. Alterations in neuronal distribution and function are strongly associated with GI dysfunction. Current methods for assessing neuronal distribution suffer from undersampling, partly due to challenges associated with imaging and analyzing large tissue areas, and operator bias due to manual analysis. We present the Gut Analysis Toolbox (GAT), an image analysis tool designed for characterization of enteric neurons and their neurochemical coding using two-dimensional images of GI wholemount preparations. GAT is developed in Fiji, has a user-friendly interface, and offers rapid and accurate segmentation via custom deep learning (DL)-based cell segmentation models developed using StarDist, as well as a ganglia segmentation model in deepImageJ. We apply proximal neighbor-based spatial analysis to reveal differences in cellular distribution across gut regions using a public dataset. In summary, GAT provides an easy-to-use toolbox to streamline routine image analysis tasks in ENS research. GAT enhances throughput, allowing rapid unbiased analysis of larger tissue areas, multiple neuronal markers and numerous samples., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Many thousands and, in some cases, millions of individuals from the major crop and livestock species have been genotyped and phenotyped for the purpose of genomic selection. 'Ultimate genotypes', in which the marker allele haplotypes with the most favorable effects on a target trait or traits in the population are combined together in silico, can be constructed from these datasets. Ultimate genotypes display up to six times the performance of the current best individuals in the population, as demonstrated for net profit in dairy cattle (incorporating a range of economic traits), yield in wheat and 100-seed weight in chickpea. However, current breeding strategies that aim to assemble ultimate genotypes through conventional crossing take many generations. As a hypothetical thought piece, here, we contemplate three future pathways for rapidly achieving ultimate genotypes: accelerated recombination with gene editing, direct editing of whole-genome haplotype sequences and synthetic biology., (© 2024. Springer Nature America, Inc.)

Purpose of Program: The ongoing shortage of organs for transplant combined with the highest prevalence of end-stage kidney disease (ESKD) in Canada has resulted in long wait times for a deceased donor transplant in Manitoba. Therefore, the Transplant Manitoba Adult Kidney Program has ongoing quality improvement initiatives to expand the deceased donor pool. This clinical transplant protocol describes an age-targeted program intended to increase the use of transplants with a kidney donor profile index (KDPI) >85 by allocating them to suitable pre-consented recipients age ≥65 with low wait times. The goal is to improve survival and quality of life for older recipients by maximizing a previously under-utilized donor pool., Sources of Information: Scoping literature review; Transplant Manitoba deceased donor audit; and key stakeholder engagement with patient partners, inter-disciplinary health care providers, and health system leaders., Methods: The alternative donor pool criteria include deceased donor kidneys with KDPI 86-100 or another concern for graft longevity but are otherwise suitable for transplantation. Patients with no living donor, age ≥65, low wait times and otherwise eligible for transplant listing will be educated, and if suitable, pre-consented for the age-targeted program. All patients remain eligible for a standard criteria donor according to the local allocation criteria. The age-targeted program waitlist follows the same provincial allocation rules using wait time, panel reactive antibody (PRA), and human leukocyte antigen (HLA) match points for determining rank order. If an age-targeted recipient experiences early graft loss from a KDPI 86-100 kidney within 12 months from transplant, their cumulative wait time, including time with the transplant, will be reinstated upon relisting., Key Findings: Transplant Manitoba's provincial allocation rules do not permit bypassing top of the list recipients for kidney offers; therefore, transplant providers were previously reluctant to utilize KDPI 86-100 donor kidneys to top of the list recipients eligible for higher quality kidneys. This age-targeted program facilitates allocation of KDPI 86-100 kidneys to suitable older pre-consented recipients with low wait times, who may obtain a survival and quality of life benefit from these transplants. This approach expands the utilized deceased donor pool to benefit all Manitobans awaiting a deceased donor kidney transplant., Limitations: This program was launched in January 2023, and there are no data reported on outcomes given the small numbers and abbreviated follow-up., Implications: The goal of this quality improvement project is to improve access to deceased donor kidney transplantation for Manitobans with ESKD. This program was developed with patient and provider feedback, including multimedia patient education materials which may be helpful for other programs. We anticipate this program is a safe and effective way to expand access to deceased donor kidney transplantation using a previously under-utilized donor pool., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Bluetongue virus (BTV) is a prevalent midge-borne pathogen that infects ruminant species worldwide. BTV infections range from asymptomatic to lethal, with mechanisms that determine the severity of infection remaining largely undefined. Although it is relatively poorly understood, the immune response to BTV infection is thought to be critical for both the propagation of disease as well as the resolution of infection. To bridge this gap in knowledge, we infected cohorts of sheep and muntjac deer with two serotypes of BTV (BTV10 and BTV17) for longitudinal analysis (30 days). Interestingly, species-specific differences were observed. Circulating virus was detected early and remained detectable for the duration of the sheep study, while infections in muntjac showed faltering detection of BTV10 at 3 weeks post infection. The magnitude of the immune response was subdued in the muntjac when compared to the sheep cohorts, though similar responses were observed. We also assessed midge viral uptake and the ability to replicate BTV. Midges successfully fed on both species, yet those that fed on sheep resulted in more efficient BTV transmission. Our findings demonstrate that differences in BTV infections, immune responses, and vector competence across host species and serotypes will impact global BTV emergence and strategies for mitigation.

Background: The impact of clinical factors and social determinants of health on treatment patterns and health care costs among patients with HCC is unknown., Methods: Using 100% Medicare Fee-For-Service claims and a commercial multipayor claims database, we identified patients diagnosed with HCC from January 1, 2017, to December 31, 2020. Surveillance receipt was defined 12 months prior to HCC diagnosis, whereas treatment and health care costs were assessed post-HCC diagnosis. Multinomial logistic regression was used to assess the association between demographics, social determinants of health, and surveillance or HCC treatment. Multivariable generalized linear regression was used to identify factors associated with total health care costs., Results: Of the 32,239 patients with HCC (mean age 68 y, 67% male, 73% White), 70% received surveillance and only half (51%) received any treatment. Curative treatment receipt was higher among those with prior surveillance (24% with CT/MRI and 18% with ultrasound vs. 9% with no surveillance). Curative treatment was independently associated with HCC surveillance and inversely associated with Black race, lower education level, and diagnosis in the year 2020 (COVID-19 year). Higher health care costs were independently associated with Black race, low English proficiency, living alone, and diagnosis in 2018-2020, and inversely associated with CT/MRI-based surveillance., Conclusions: Race and social determinants of health were independently associated with curative treatment receipt and health care costs. Increasing access to high-quality HCC surveillance may improve treatment receipt and reduce health disparities among patients with HCC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Objectives To present a single-center experience of laparoscopic management of acute small bowel obstruction (ASBO) based on seven years of data and demonstrate its suitability for the United Kingdom (UK). Methods A retrospective review of case notes to evaluate postoperative outcomes was conducted. All emergency small bowel obstructions treated laparoscopically were included. The cases that were converted to a laparotomy were excluded. Demographics (age, sex), American Society of Anesthesiologists (ASA) grade, indication for surgery, duration of stay, complications, requirement of stoma, requirement of intensive treatment unit/high dependency unit (ITU/HDU), reoperation/readmissions, and 30-day mortality were noted. The results were tabulated and analyzed accordingly. Results There were 119 patients studied, with a median age of 66 (range: 17-97). The sex ratio was 62 females to 57 males. Primary etiologies of adhesion bands (49.5%, 59) and hernia (31.9%, 38) were the most common. Minor and major complications were 15 (12.6%) and 37 (31%), respectively. Three (2.5%) patients passed away within 30 days of surgery. The median length of stay (LOS) was eight days. The median LOS subgroup analysis showed nine days for adhesiolysis and six days for hernias. Discussion This study shows that there is significant heterogeneity in outcomes regarding small bowel obstruction around the world. We have demonstrated similar to better results in our center relative to other prominent centers in the UK. This can be attributed to the patient cohort, presentation, and physiological status on admission, delay to surgery, and associated co-morbidities to name a few. Conclusion This study indicates that laparoscopic surgery is a safe approach to treating ASBO, provided adequate expertise and infrastructure are available., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Subramanian et al.)

Determining the extent and duration of infectiousness of individuals with pulmonary tuberculosis (TB) is critical for various aspects of TB care, including decisions regarding isolation. Studies suggest considerable heterogeneity in infectiousness of people with pulmonary TB. Pre-treatment, measures of bacillary burden including sputum smear microscopy, culture time-to-positivity, and Xpert MTB/RIF cycle threshold (Ct) value, predict the risk of transmission to contacts. Index patients with smear negative disease pose lower infectious risk than those who have smear-positive disease, and household contact infection is more likely with index patients who have lower Xpert Ct values. Newer tools that enable detection of Mycobacterium tuberculosis complex (Mtb complex) from cough aerosol sampling and face mask sampling may be better predictors of contact infection risk. Clinical factors such as cough strength and frequency, and presence of cavitation on chest imaging, may also assist with risk prediction. Post-treatment, smear and culture status are poor predictors of infectiousness. While the exact duration of infectiousness post treatment initiation remains uncertain, data from human-to-guinea pig transmission studies and clinical studies suggest effective treatment results in a rapid decline in infectiousness, irrespective of smear or culture conversion. This is largely supported by early bactericidal activity and transcriptomic studies, and cough aerosol sampling studies, although a subset of patients may have persistent cough aerosol positivity. These findings can enable a more nuanced approach to isolation decision making, while further research studies are awaited., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Competing Interests: Financial/Nonfinancial Disclosures None declared.

Background: Acute respiratory infections are a common reason for consultation with primary and emergency healthcare services. Identifying individuals with a bacterial infection is crucial to ensure appropriate treatment. However, it is also important to avoid overprescription of antibiotics, to prevent unnecessary side effects and antimicrobial resistance. We conducted a systematic review to summarise evidence on the diagnostic accuracy of symptoms, signs and point-of-care tests to diagnose bacterial respiratory tract infection in adults, and to diagnose two common respiratory viruses, influenza and respiratory syncytial virus., Methods: The primary approach was an overview of existing systematic reviews. We conducted literature searches (22 May 2023) to identify systematic reviews of the diagnostic accuracy of point-of-care tests. Where multiple reviews were identified, we selected the most recent and comprehensive review, with the greatest overlap in scope with our review question. Methodological quality was assessed using the Risk of Bias in Systematic Reviews tool. Summary estimates of diagnostic accuracy (sensitivity, specificity or area under the curve) were extracted. Where no systematic review was identified, we searched for primary studies. We extracted sufficient data to construct a 2 × 2 table of diagnostic accuracy, to calculate sensitivity and specificity. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies version 2 tool. Where possible, meta-analyses were conducted. We used GRADE to assess the certainty of the evidence from existing reviews and new analyses., Results: We identified 23 reviews which addressed our review question; 6 were selected as the most comprehensive and similar in scope to our review protocol. These systematic reviews considered the following tests for bacterial respiratory infection: individual symptoms and signs; combinations of symptoms and signs (in clinical prediction models); clinical prediction models incorporating C-reactive protein; and biological markers related to infection (including C-reactive protein, procalcitonin and others). We also identified systematic reviews that reported the accuracy of specific tests for influenza and respiratory syncytial virus. No reviews were found that assessed the diagnostic accuracy of white cell count for bacterial respiratory infection, or multiplex tests for influenza and respiratory syncytial virus. We therefore conducted searches for primary studies, and carried out meta-analyses for these index tests. Overall, we found that symptoms and signs have poor diagnostic accuracy for bacterial respiratory infection (sensitivity ranging from 9.6% to 89.1%; specificity ranging from 13.4% to 95%). Accuracy of biomarkers was slightly better, particularly when combinations of biomarkers were used (sensitivity 80-90%, specificity 82-93%). The sensitivity and specificity for influenza or respiratory syncytial virus varied considerably across the different types of tests. Tests involving nucleic acid amplification techniques (either single pathogen or multiplex tests) had the highest diagnostic accuracy for influenza (sensitivity 91-99.8%, specificity 96.8-99.4%)., Limitations: Most of the evidence was considered low or very low certainty when assessed with GRADE, due to imprecision in effect estimates, the potential for bias and the inclusion of participants outside the scope of this review (children, or people in hospital)., Future Work: Currently evidence is insufficient to support routine use of point-of-care tests in primary and emergency care. Further work must establish whether the introduction of point-of-care tests adds value, or simply increases healthcare costs., Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR159948.

Food systems drive human and environmental change, reflect diverse cultural and ecological contexts, and, in their diversity, can bolster nutrition and planetary health. Ignoring structural inequities in food system transformations risks offsetting potential gains. We summarize current evidence on the context-dependent implications of EAT-Lancet goals and propose six priority areas to guide equitable food system transformations, targeting food and nutrition security, just sustainability and cultural diversity. Priority areas-namely, diverse and nutritious food access, food industry regulation, climate-resilient food production, localized, small-scale food systems, cultural diversity and social well-being-can be achieved through public, private and civil society action., (© 2024. Springer Nature Limited.)

Background: The current landscape of organ donation and transplantation (ODT) registries is not well established. This narrative review sought to identify and characterize the coverage, structure, and data capture of ODT registries globally., Methods: We conducted a literature search using Ovid Medline and web searches to identify ODT registries from 2000 to 2023. A list of ODT registries was compiled based on publications of registry design, studies, and reports. Extracted data elements included operational features of registries and the types of donor and recipient data captured., Results: We identified 129 registries encompassing patients from all continents except Antarctica. Most registries were active, received funding from government or professional societies, were national in scope, included both adult and pediatric patients, and reported patient-level data. Registries included kidney (n = 99), pancreas (n = 32), liver (n = 44), heart (n = 35), lung (n = 30), intestine (n = 15), and islet cell (n = 5) transplants. Most registries captured donor data (including living versus deceased) and recipient features (including demographics, cause of organ failure, and posttransplant outcomes) but there was underreporting of other domains (eg, donor comorbidities, deceased donor referral rates, waitlist statistics)., Conclusions: This review highlights existing ODT registries globally and serves as a call for increased visibility and transparency in data management and reporting practices. We propose that standards for ODT registries, a common data model, and technical platforms for collaboration, will enable a high-functioning global ODT system responsive to the needs of transplant candidates, recipients, and donors., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Data regarding the mortality trends in pulmonary embolism (PE)-related mortality in patients with concomitant pulmonary hypertension (PH) are lacking. We assessed the trends in PE-related mortality in patients with concomitant PH in the United States (US) over the past 2 decades and during the first year of the COVID-19 pandemic using data from the Centers for Disease Control and Prevention's (CDC) Wide-ranging ONline Data for Epidemiologic Research (WONDER) dataset., Methods: Mortality data were retrieved from the publicly available CDC WONDER mortality dataset from 2003 to 2020. Age-adjusted mortality rates (AAMRs), per 100,000 population, were assessed using Joinpoint regression modelling and expressed as estimated average annual percentage change (AAPC) with relative 95% CIs and stratified by urbanicity, sex, age, and race/ethnicity., Results: Over the study period, the AAMR for PE/PH-related mortality linearly increased (AAPC: +4.3% [95% CI: 3.7 to 4.9], p < 0.001) without sex differences. The AAMR increase was more pronounced in White individuals (AAPC: +4.8% [95% CI: 4.1 to 5.5], p < 0.001) and in subjects living in rural areas (AAPC: +5.1% [95% CI: 3.8 to 6.4], p < 0.001) compared to those living in urban areas. During the first year of the COVID-19 pandemic there was a significant excess in PE/PH-related mortality among women, older than 65 years and living in rural areas., Conclusions: The rate of PE/PH-related mortality in the US is increasing. Although the early diagnosis of PH in patients with acute PE has become easier with improved diagnostic modalities, the mortality rate of these patients remains high., Competing Interests: Declaration of conflicting interestsGregory Piazza received research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corporation, and consulting fees from Pfizer, Boston Scientific Corporation, Janssen, and Amgen. The other authors have no conflicts of interest to declare.

Rationale: New pulmonary rehabilitation models can improve access to this effective but underutilised treatment for people with chronic respiratory disease, however cost effectiveness has not been determined., Objective: To compare the cost effectiveness of telerehabilitation, including videoconferencing and synchronous supervision, to standard center-based pulmonary rehabilitation., Methods: Prospective economic analyses were undertaken from a societal perspective alongside a randomised controlled equivalence trial in which adults with stable chronic respiratory disease undertook an 8-week outpatient center-based program or telerehabilitation. Clinical assessment for effectiveness (Chronic Respiratory Disease Questionnaire dyspnoea domain [CRQ-D] score) was undertaken at baseline, following pulmonary rehabilitation and 12-month follow-up. Individual-level administrative and self-report healthcare cost data were collected over 12 months following the program (Australian dollars, 2020) Results: There were no between-group differences for effectiveness (CRQ-D MD -0.2 [SE 1.0], p=0.61) or total costs ($565 [5452], p=0.92) over 12 months. On the cost effectiveness plane, 97.4% of estimates fell between the equivalence margins for effectiveness. Application of a range of values for cost margin demonstrated a 95% probability that telerehabilitation was equivalent to center-based pulmonary rehabilitation when the threshold was $11,000. Results were robust to approach, sensitivity and subgroup analyses. The internal rate of return was 134% over 5 years. Program completion (regardless of model) was associated with a significant reduction in total costs in the following 12 months (β $-17,960, 95%CI -29,967 to -5952). Conclusions This study supports delivery of telerehabilitation as a cost-effective alternative model of pulmonary rehabilitation for people with chronic respiratory disease.

Background: Multiple studies have linked COVID-19 to a higher incidence of thromboembolic disorders. However, the association of COVID-19 with other potentially life-threatening complications, such as splanchnic vein thrombosis, is less well understood. This study aims to assess the prevalence, patient characteristics, clinical presentation, and outcomes of patients with portal vein thrombosis (PVT) and COVID-19. Methods: This was a retrospective observational study. From all positive patients for a reverse-transcription polymerase chain reaction (RT-PCR) swab test from March 2020 to June 2020, we included those who were older than 18 years, had received abdominal contrast-enhanced computed tomography (CT) in the 6 months following the positive RT-PCR swab, and had no previously known splanchnic vein thrombosis. Results: A total of 60 patients with abdominal CT were selected from all those positive for SARS-CoV-2 ( n = 2987). The prevalence of PVT was 3/60 (5%). The mean age was 66.1 ± 16.5 years and 51.7% were male. In two of the three patients, there was no underlying pathology as a risk factor for PVT and one of them presented cirrhosis. The number of days from the start of COVID-19 symptoms until the PVT diagnosis were 21, 12, and 10 days. Anticoagulation treatment achieved recanalization in 100% of cases. During a mean follow-up of 803 days, none of the patients experienced long-term complications. Conclusions: Portal vein thrombosis is uncommon, and its incidence may be higher in COVID-19 patients. A greater understanding of the features of this disease in the context of COVID-19 could aid towards its diagnosis and allow for early detection and management.

Bluetongue (BT) is a Culicoides midge-borne hemorrhagic disease affecting cervids and ruminant livestock species, resulting in significant economic losses from animal production and trade restrictions. Experimental animal infections using the α/β interferon receptor knockout IFNAR mouse model and susceptible target species are critical for understanding viral pathogenesis, virulence, and evaluating vaccines. However, conducting experimental vector-borne transmission studies with the vector itself are logistically difficult and experimentally problematic. Therefore, experimental infections are induced by hypodermic injection with virus typically derived from baby hamster kidney (BHK) cells. Unfortunately, for many U.S. BTV serotypes, it is difficult to replicate the severity of the disease seen in natural, midge-transmitted infections by injecting BHK-derived virus into target host animals. Using the IFNAR BTV murine model, we compared the virulence of traditional BHK cell-derived BTV-17 with C. sonorensis midge (W8) cell-derived BTV-17 to determine whether using cells of the transmission vector would provide an in vitro virulence aspect of vector-transmitted virus. At both low and high doses, mice inoculated with W8-BTV-17 had an earlier onset of viremia, earlier onset and peak of clinical signs, and significantly higher mortality compared to mice inoculated with BHK-BTV-17. Our results suggest using a Culicoides W8 cell-derived inoculum may provide an in vitro vector-enhanced infection to more closely represent disease levels seen in natural midge-transmitted infections while avoiding the logistical and experimental complexity of working with live midges.

Malaria and Typhoid fever are prevalent diseases in tropical regions, and both are exacerbated by unclear protocols, drug resistance, and environmental factors. Prompt and accurate diagnosis is crucial to improve accessibility and reduce mortality rates. Traditional diagnosis methods cannot effectively capture the complexities of these diseases due to the presence of similar symptoms. Although machine learning (ML) models offer accurate predictions, they operate as "black boxes" with non-interpretable decision-making processes, making it challenging for healthcare providers to comprehend how the conclusions are reached. This study employs explainable AI (XAI) models such as Local Interpretable Model-agnostic Explanations (LIME), and Large Language Models (LLMs) like GPT to clarify diagnostic results for healthcare workers, building trust and transparency in medical diagnostics by describing which symptoms had the greatest impact on the model's decisions and providing clear, understandable explanations. The models were implemented on Google Colab and Visual Studio Code because of their rich libraries and extensions. Results showed that the Random Forest model outperformed the other tested models; in addition, important features were identified with the LIME plots while ChatGPT 3.5 had a comparative advantage over other LLMs. The study integrates RF, LIME, and GPT in building a mobile app to enhance the interpretability and transparency in malaria and typhoid diagnosis system. Despite its promising results, the system's performance is constrained by the quality of the dataset. Additionally, while LIME and GPT improve transparency, they may introduce complexities in real-time deployment due to computational demands and the need for internet service to maintain relevance and accuracy. The findings suggest that AI-driven diagnostic systems can significantly enhance healthcare delivery in environments with limited resources, and future works can explore the applicability of this framework to other medical conditions and datasets.

Kelps are vital for marine ecosystems, yet the genetic diversity underlying their capacity to adapt to climate change remains unknown. In this study, we focused on the kelp Macrocystis pyrifera a species critical to coastal habitats. We developed a protocol to evaluate heat stress response in 204 Macrocystis pyrifera genotypes subjected to heat stress treatments ranging from 21 °C to 27 °C. Here we show that haploid gametophytes exhibiting a heat-stress tolerant (HST) phenotype also produced greater biomass as genetically similar diploid sporophytes in a warm-water ocean farm. HST was measured as chlorophyll autofluorescence per genotype, presented here as fluorescent intensity values. This correlation suggests a predictive relationship between the growth performance of the early microscopic gametophyte stage HST and the later macroscopic sporophyte stage, indicating the potential for selecting resilient kelp strains under warmer ocean temperatures. However, HST kelps showed reduced genetic variation, underscoring the importance of integrating heat tolerance genes into a broader genetic pool to maintain the adaptability of kelp populations in the face of climate change., (© 2024. The Author(s).)

Background: There is an intricate connection between eating disorders and trauma. Despite this, traditional eating disorders education for health professions has not taken a trauma-informed approach., Aim: We aimed to explore the reflections of graduate entry dietetic and undergraduate nursing students who participated in a trauma-informed, co-designed education innovation that focussed on an individual's storied lived experience., Methods: We applied an interpretive lens in this qualitative inquiry-based study. Graduate entry dietetic and undergraduate nursing students participated in this study. The lived experience, co-designed workshops (n = 35) were embedded in the curricula with an optional follow-up discussion with the lived experience and academic educators. Students were asked to write their key reflections on a sticky note at the end of the workshop. Thematic analysis of the student reflections was completed by the research team including the lived experience educator and academics., Results: A total of 442 sticky notes were collected; 145 from the dietetic and 297 from the nursing students. Analysis of the dietetic and nursing students' reflections generated six themes: 1) Do no harm, 2) Seeing beyond the diagnosis, 3) Language matters, 4) Humanise the relationship, 5) Recovery in the context of healing, and 6) Significance of hope. There was consistency across the reflections for the two different disciplines., Conclusions: Co-designed lived experience eating disorders education that honours the living experiences and complexities of eating disorders can deepen health profession students' understandings of how they can work with, rather than against, people living with and recovering from eating disorders through a trauma-informed approach., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Dystonia is a common, debilitating, and often treatment refractory motor symptom of cerebral palsy (CP), affecting 70-80% of this population based on research assessments. However, routine clinical evaluation for dystonia in CP has failed to match these expected numbers. Addressing this diagnostic gap is a medical imperative because the presence of dystonia rules in or out certain treatments for motor symptoms in CP. Therefore, our objective was to optimize rates of clinical dystonia screening to improve rates of clinical dystonia diagnosis., Methods: Using the quality improvement (QI) infrastructure of the Cerebral Palsy Research Network (CPRN), we developed and implemented interventions to increase the documentation percentage of five features of dystonia in young people with CP, aged 3-21 years old. This QI initiative was implemented by seven physiatry and pediatric movement disorders physicians at four tertiary-care pediatric hospitals between 10/10/21 and 7/1/23. We collected visit data cross-sectionally across all participating sites every 2 weeks and tracked our progress using control charts., Results: We assessed 847 unique visits, mostly for established patients (719/847, 85%) who were 9.2 years old on average (95% CI 8.8-9.5). By 4/10/22, the mean percentage of dystonia screening elements documented across all sites rose from 39% to 90% and the mean percentage of visits explicitly documenting the presence or absence of dystonia rose from 65% to 94%. By 10/23/22, the percentage of visits diagnosing dystonia rose from 57% to 74%. These increases were all sustained through the end of the study period in 7/1/23., Discussion: Using a rigorous QI-driven process across four member sites of a North American learning health network (CPRN), we demonstrated that we could increase screening for dystonia and that this was associated with increased clinical dystonia diagnosis, matching expected research-based rates. We propose that similar screening should take place across all sites caring for people with CP.

Importance: In the setting of an active pandemic the impact of public vaccine hesitancy on healthcare workers has not yet been explored. There is currently a paucity of literature that examines how patient resistance to disease prevention in general impacts practitioners., Objectives: The COVID-19 pandemic created unprecedented healthcare challenges with impacts on healthcare workers' wellbeing. Vaccine hesitancy added complexity to providing care for unvaccinated patients. Our study qualitatively explored experiences of healthcare providers caring for unvaccinated patients with severe COVID-19 infection in the intensive care setting., Design: We used interview-based constructivist grounded theory methodology to explore experiences of healthcare providers with critically ill unvaccinated COVID-19 patients., Setting and Participants: Healthcare providers who cared for unvaccinated patients with severe COVID-19 respiratory failure following availability of severe acute respiratory syndrome coronavirus 2 vaccines were recruited from seven ICUs located within two large academic centers and one community-based hospital. We interviewed 24 participants, consisting of eight attending physicians, seven registered nurses, six critical care fellows, one respiratory therapist, one physiotherapist, and one social worker between March 2022 and September 2022 (approximately 1.5 yr after the availability of COVID-19 vaccines in Canada)., Analysis: Interviews were recorded, transcribed, de-identified, and coded to identify emerging themes. The final data was analyzed to generate the thematic framework. Reflexivity was employed to reflect upon and discuss individual pre-conceptions and opinions that may impact collection and interpretation of the data., Results: Healthcare providers maintained dedication toward professionalism during provision of care, at the cost of suffering emotional turmoil from the pandemic and COVID-19 vaccine hesitancy. Evolving sources of stress associated with vaccine hesitancy included ongoing high volumes of critically ill patients, resource shortages, and visitation restrictions, which contributed to perceived emotional distress, empathy loss, and professional dissatisfaction. As a result, there were profound personal and professional consequences for healthcare professionals, with perceived impacts on patient care., Conclusions: Our study highlights struggles of healthcare providers in fulfilling professional duties while navigating emotional stressors unique to vaccine hesitancy. System-based interventions should be explored to help providers navigate biases and moral distress, and to foster resilience for the next major healthcare system strain., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Early detection of hepatocellular carcinoma (HCC) is crucial for improving patient outcomes, but we lack robust clinical biomarkers. This study aimed to identify a metabolite and/or lipid panel for early HCC detection., Methods: We developed a high-resolution liquid chromatography mass spectrometry (LC-MS)-based profiling platform and evaluated differences in the global metabolome and lipidome between 28 pre-diagnostic serum samples from patients with cirrhosis who subsequently developed HCC (cases) and 30 samples from patients with cirrhosis and no HCC (controls). We linked differentially expressed metabolites and lipids to their associated genes, proteins, and transcriptomic signatures in publicly available datasets. We used machine learning models to identify a minimal panel to distinguish between cases and controls., Results: Among cases compared with controls, 124 metabolites and 246 lipids were upregulated, while 208 metabolites and 73 lipids were downregulated. The top upregulated metabolites were glycoursodeoxycholic acid, 5-methyltetrahydrofolic acid, octanoyl-coenzyme A, and glycocholic acid. Elevated lipids comprised glycerol lipids, cardiolipin, and phosphatidylethanolamine, whereas suppressed lipids included oxidized phosphatidylcholine and lysophospholipids. There was an overlap between differentially expressed metabolites and lipids and previously published transcriptomic signatures, illustrating an association with liver disease severity. A panel of 12 metabolites that distinguished between cases and controls with an area under the receiver operating curve of 0.98 for the support vector machine (interquartile range, 0.9-1)., Conclusion: Using prediagnostic serum samples, we identified a promising metabolites panel that accurately identifies patients with cirrhosis who progressed to HCC. Further validation of this panel is required., Competing Interests: The authors have no conflict of interest to declare., (© 2024 Powell et al.)

Chromosomal chaos may have aided their moves to fresh water and land.

Myxedema coma is an uncommon and life-threatening manifestation of severe hypothyroidism. Its occurrence in the pediatric population is exceptionally rare and can result from long-standing untreated hypothyroidism or nonadherence to treatment. Identifying this condition can be challenging because it requires a high level of clinical suspicion along with thyroid function testing. We present a 17-year-old female with a history of anxiety who had widespread nonspecific symptoms, including persistent bradycardia, which were found to be caused by hypothyroidism. Our goal is to raise awareness of the varied clinical manifestations of pediatric myxedema to promote early recognition and prompt medical interventions that can lead to better outcomes., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)