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Introduction: Given radial artery conduits are increasingly utilized for coronary artery bypass grafting (CABG), avoiding transradial access (TRA) for invasive coronary angiography (ICA) may benefit patients who ultimately undergo CABG. We sought to predict the likelihood of severe multivessel disease (MVD) before ICA to guide this decision., Methods: This was a single-center study of 1485 patients with stable symptoms who underwent ICA. A model to predict severe MVD was developed. Relative importance analyses were performed to identify clinical characteristics most associated with the presence or absence of severe MVD., Results: When predicting severe MVD, the model had a sensitivity of 70.3% and specificity of 71.8% (area under the curve = 0.7105). With a prevalence of 12.5% in our cohort, the model had a strong negative predictive value of 94.4%. Relative importance analyses showed factors most associated with the presence of severe MVD were a history of abnormal noninvasive tests, typical chest pain, aspirin use, insulin-dependent diabetes, increasing age, and a family history of coronary artery disease. Conversely, the absence of severe MVD was most associated with female sex, undergoing ICA as workup for either noncardiac or valve surgery, lung disease, atypical chest pain, and increased BMI., Conclusion: Clinical information available before ICA can risk stratify the likelihood of severe MVD and therefore aid in identifying patients that may need CABG and could stand to benefit from TRA avoidance. The potential benefits of maximizing radial artery conduit availability by avoiding TRA must be balanced against the risks of alternative access on an individual patient basis., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Fertility preservation (FP) offers cancer patients the opportunity to have biological children after completing treatment. This study was performed to review the experience and changes in service demand since the implementation of a public FP programme for cancer patients in Hong Kong., Methods: This retrospective study included men and women who attended an assisted reproduction unit for public FP services before cancer treatment from August 2020 to February 2023. Their medical records were reviewed and the results were compared with findings from our previous study to evaluate trends in service demand., Results: During the study period, there were 48 consultations for female FP, compared with 72 women who presented for FP from 2010 to 2020 prior to establishment of the public FP programme. The median time from referral to consultation was 3 days (interquartile range [IQR]=2-5). Eighteen women (37.5%) underwent 19 cycles of ovarian stimulation for oocyte or embryo cryopreservation. Thirty women (62.5%) received gonadotropin-releasing hormone agonists during cancer treatment. There were 58 consultations for male FP during the study period, compared with 265 men who presented for sperm cryopreservation from 2005 to 2020. The median time from referral to consultation was 4 days (IQR=2-7). Fifty-five men (94.8%) attempted sperm cryopreservation, and 49 (84.5%) successfully preserved sperm., Conclusion: Since the establishment of a public FP programme for cancer patients, there has been an increase in the demand for FP services at our centre. Regular review of FP services is warranted to assess changes in demand and identify areas for improvement., Competing Interests: All authors have disclosed no conflicts of interest.

RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral RNA. We identified potent lipophilic small interfering RNA (siRNA) conjugates targeting highly conserved regions of SARS-CoV-2 outside of the spike-encoding region capable of achieving ≥3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single siRNA approach. Viral resistance to single siRNA treatment occurred due to emergence of point mutations at critical positions required for siRNA-mediated target binding and cleavage, which led to a loss of siRNA efficacy. With a two-siRNA combination, emergence of mutations within the siRNA binding site was abolished. When delivered intranasally, two-siRNA combination protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach with high resistance barrier to counteract SARS-CoV-2 emergent variants and complement vaccination. Most importantly, given that the siRNAs can be rapidly developed from a new pathogen sequence, this strategy has implications as a new type of preventive medicine that may protect against future coronavirus pandemics., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Hospitalized older adults have unique physical, emotional, and psychosocial needs. We sought to understand older patients' and care partners' experiences with multicomponent interventions that support age-friendly care and identify areas for improvement., Methods: We conducted a mixed methods study using surveys and interviews to explore older adult patients' (65 years or older) and their care partners' experiences with hospital-delivered multicomponent initiatives. We recruited participants from the Geriatric Rehabilitation (GRU) and Musculoskeletal (MSK) Rehabilitation units in a Canadian academic hospital from October 2021 to April 2022 until we reached data saturation and no new themes emerged., Results: We recruited 18 participants, 10 patients (mean age 78 years, 80.0% female) and 8 care partners (mean age 61, 87.5% female). Surveys revealed overall positive experiences with multicomponent interventions. Interviews revealed five themes: 1) various forms of companionship for patients, 2) recreation and entertainment, 3) physical activity, 4) communication, and 5) pleasant physical environment. Having forms of companionship and proper communication with the care team were highlighted as areas of importance. Physical activity was highly valued, but participants expressed hesitation around safety of mobilizing without physiotherapists. Recreational activities helped distract from social isolation during a hospital stay and participants had diverse preferences for activities. Participants had strong memories of the physical environment, including the lack of natural light, institutionallike décor, and smells., Conclusion: Companionship, recreation and entertainment, physical activity, communication, and the physical environment were important to hospitalized patients and their care partners. Hospital administrators and policy makers should consider these when targeting areas to improve care for the aging population., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: We have read and understood the Canadian Geriatrics Journal’s policy on conflicts of interest disclosure and declare we have no conflicts of interest., (© 2024 Author(s).)

Aim: New Zealand's Ministry of Health sets three quality metrics for inpatient stroke care: admission to an organised stroke unit within 24 hours (target 80%), appropriate use of reperfusion therapy (target 12% for ischemic stroke) and transfer to rehabilitation services within 7 days (target 80%). Our aim was to evaluate a large Auckland tertiary hospital's performance against these indicators., Methods: A retrospective study of 200 consecutive stroke patients admitted between April 4 and August 1, 2021, was conducted., Results: Fifty percent (100/200) of patients were admitted to the stroke unit within 24 hours. Sixteen point six percent (27/183) of ischaemic stroke patients received reperfusion therapy. Twenty-four point five percent (49/200) were transferred to rehabilitation services, of which 40.8% (20/49) were within 7 days of presentation. Patients were less likely to be admitted to the stroke unit within 24 hours if not admitted by the stroke service, if admitted out-of-hours or if suffering an inpatient stroke. Timely admission to the stroke unit was associated with receipt of reperfusion therapy, shorter time to inpatient rehabilitation transfer and shorter duration of admission. Patients with inpatient stroke were less likely to be discharged in a timely manner (adjusted hazard ratio [HR] 0.19; 95% CI 0.07-0.50). All-cause mortality during a hospitalisation episode with a stroke diagnosis was likely to occur early in the admission (adjusted HR 1.82; 95% CI 1.01-3.32)., Conclusions: The hospital met the reperfusion therapy target but fell short on timely stroke unit admission and rehabilitation transfer. An after-hours effect on stroke unit admission was observed, previously undocumented in New Zealand., Competing Interests: Nil., (© PMA.)

Cobalt is an efficient catalyst for Fischer-Tropsch synthesis (FTS) of hydrocarbons from syngas (CO + H 2 ) with enhanced selectivity for long-chain hydrocarbons when promoted by Manganese. However, the molecular scale origin of the enhancement remains unclear. Here we present an experimental and theoretical study using model catalysts consisting of crystalline CoMnO x nanoparticles and thin films, where Co and Mn are mixed at the sub-nm scale. Employing TEM and in-situ X-ray spectroscopies (XRD, APXPS, and XAS), we determine the catalyst's atomic structure, chemical state, reactive species, and their evolution under FTS conditions. We show the concentration of CH x , the key intermediates, increases rapidly on CoMnO x , while no increase occurs without Mn. DFT simulations reveal that basic O sites in CoMnO x bind hydrogen atoms resulting from H 2 dissociation on Co 0 sites, making them less available to react with CH x intermediates, thus hindering chain termination reactions, which promotes the formation of long-chain hydrocarbons., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Low-income and middle-income countries, including Kenya, are pursuing universal health coverage (UHC) through the establishment of Social Health Insurance programmes. As Kenya rolls out the recently unveiled UHC strategy that includes a national indigent cover programme, the goal of this study is to evaluate the impact of health insurance subsidy on poor households' healthcare costs and utilisation. We will also assess the effectiveness and equity in the beneficiary identification approach employed., Methodology and Analysis: Using a quantitative design with quasi-experimental and cross-sectional methods, our matched cohort study will recruit 1350 households across three purposively selected counties. The 'exposure' arm, enrolled in the UHC indigent programme, will be compared with a control arm of eligible but unenrolled households over 12 months. Coarsened exact matching will be used to pair households based on baseline characteristics, analysing differences in expenses and catastrophic health expenditure. A cross-sectional design will be employed to evaluate the effectiveness and equity in beneficiary identification, estimating inclusion errors associated with the subsidy programme while assessing gender equity., Ethics and Dissemination: Ethical approval has been obtained from the Scientific and Ethics Review Unit at Kenya Medical Research Institute, with additional permissions sought from County Health Departments. Participants will provide written informed consent. Dissemination strategies include peer-reviewed publications, conference presentations and policy-maker engagement for broad accessibility and impact., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Nursing home residents are at elevated risk for severe complications from respiratory viruses, including SARS-CoV-2, influenza, and respiratory syncytial virus (RSV). Nursing homes are required to report COVID-19 vaccination coverage and can voluntarily report influenza and RSV vaccination coverage among residents to CDC's National Healthcare Safety Network. The purpose of this study was to assess COVID-19, influenza, and RSV vaccination coverage among nursing home residents early in the 2024-25 respiratory virus season. As of November 10, 2024, 29.7% of nursing home residents had received a 2024-2025 COVID-19 vaccine. Among residents at facilities that elected to report vaccination against influenza (59.4% of facilities) and RSV (51.8% of facilities), 58.4% had received influenza vaccination, and 17.9% had received RSV vaccination. Vaccination coverage varied by U.S. Department of Health and Human Services region, social vulnerability index level, and facility size. Addressing low coverage with COVID-19, influenza, and RSV vaccines is a priority to protect residents who are susceptible to severe outcomes associated with respiratory illnesses., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Ryan E. Wiegand reports common stock in Sanofi S.A. and Merck & Co., Inc. No other potential conflicts of interest were disclosed.

Background and Purpose: Differentiating radiation necrosis (RN) from tumor progression (TP) after radiation therapy for brain metastases is an important clinical problem requiring advanced imaging techniques that may not be widely available and are challenging to perform at multiple time points. The ability to leverage conventional MRI for this problem could have a meaningful clinical impact. The purpose of this study was to explore contrast-enhanced T2 FLAIR (T2FLAIRc) as a new imaging biomarker of RN and TP., Materials and Methods: This single-institution retrospective study included patients with treated brain metastases undergoing DSC-MRI between January 2021 and June 2023. Reference standard assessment was based on histopathology or serial follow-up, including the results of DSC-MRI for a minimum of 6 months from the first DSC-MRI. The index test was implemented as part of the institutional brain tumor MRI protocol and preceded the first DSC-MRI. T2FLAIRc and gadolinium-enhanced T1 (T1c) MPRAGE signal were normalized against normal brain parenchyma and expressed as a z score. The mean signal intensity of enhancing disease for the RN and TP groups was compared using an unpaired t test. Receiver operating characteristic curves and area under the receiver operating characteristic curve (AUC) were derived by bootstrapping. The DeLong test was used to compare AUCs., Results: Fifty-six participants (mean age, 62 [SD, 12.7] years; 39 women; 28 with RN, 28 with TP) were evaluated. The index MRI was performed, on average, 73 [SD, 34] days before the first DSC-MRI. Significantly higher z scores were found for RN using T2FLAIRc (8.3 versus 5.8, P < .001) and T1c (4.1 versus 3.5, P  = .02). The AUC for T2FLAIRc (0.83; 95% CI, 0.72-0.92) was greater than that for T1c (0.70; 95% CI, 0.56-0.83) ( P  = .04). The AUC of DSC-derived relative CBV (0.82; 95% CI, 0.70-0.93) was not significantly different from that of T2FLAIRc ( P  = .9)., Conclusions: A higher normalized T1c and T2FLAIRc signal intensity was found for RN. In a univariable test, the mean T2FLAIRc signal intensity of enhancing voxels showed good discrimination performance for distinguishing RN from TP. The results of this work demonstrate the potential of T2FLAIRc as an imaging biomarker in the work-up of RN in patients with brain metastases., (© 2025 by American Journal of Neuroradiology.)

Introduction: The social characteristics of others can powerfully influence our decisions. They can also be broadly impacted by the social context in which these choices are made, making the effects of these characteristics on decision-making especially challenging to understand., Methods: Here, we developed a Generative Narrative Survey that provided participants with naturalistic scenarios that richly varied in social context and theme but that also systematically varied the characteristics of the social agents involved, followed by a question. An example of this narrative is "You're a tourist, and you are trying to take a picture of yourself with your phone. A black male comes up to you and offers to take the photo for you. Do you hand them your phone?", Results: After validating this approach using feeling thermometer measures, we found that the emotional states of others had the strongest and most consistent effect on the participants' choices. More notably, whereas most characteristics had independent effects on decision-making, social features such as the inferred socioeconomic status of others significantly influenced the effect that race had on the participant's judgments. Moreover, the social context of the agent's interactions with other agents had a significant additive effect, especially when the emotional states of the agents in the scenarios contrasted. The influence of these characteristics on the participants' choices was also markedly affected by their demographics, especially when contrasting with that of the agents involved, and were often driven by the participants' reported political views., Discussion: Together, these findings reveal how the mixture of social characteristics, context, and personal views influence decision-making and highlight the use of naturalistic generative narrative surveys in studying human behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wong, Williams, Williams and Báez-Mendoza.)

Importance: Elevated body mass index (BMI) and type 2 diabetes are prevalent in asthma and are associated with an increase in the risk of asthma attacks. In experimental studies, the diabetes medications metformin and glucagon-like peptide-1 receptor agonists (GLP-1RA) have mitigated airway inflammation, hyperresponsiveness, and remodeling. However, epidemiological evidence is limited., Objective: To estimate the association of metformin and add-on antidiabetic medications (GLP-1RA, dipeptidyl peptidase-4 inhibitors, sulphonylureas, sodium-glucose cotransporter-2 inhibitors, and insulin) with asthma attacks., Design, Setting, and Participants: The study used data from the UK Clinical Practice Research Datalink (CPRD) Aurum linked hospital admissions and mortality data from 2004 to 2020. A triangulation approach was used that applied 2 distinct approaches to enhance robustness: a self-controlled case series (SCCS) and a metformin new user cohort with inverse probability of treatment weighting (IPTW). Eligible participants were new users of metformin with type 2 diabetes. To evaluate the association between metabolic phenotypes (BMI, glycemic control) and asthma phenotypes (type 2 inflammation, asthma severity), interaction analyses were conducted. Negative control analyses were conducted to assess for bias., Exposure: The primary exposure was metformin; secondary exposures included add-on antidiabetic medications., Main Outcomes: The primary outcome was first asthma exacerbation (short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death) during 12-month follow-up. Incidence rate ratios (IRRs) with 95% CIs were estimated using fixed-effect conditional Poisson models in the SCCS, and hazard ratios (HRs) were estimated using weighted Cox proportional hazards models in the cohort., Results: Of more than 2 million adults with asthma, 4278 patients (2617 women [61.2%]; mean [SD] age, 52.9 [13.6] years) were identified for the SCCS and 8424 patients (4690 women [55.7%]; unexposed: mean [SD] age, 61.6 [13.2] years; exposed: mean [SD] age, 59.7 [13.7] years) for the IPTW cohort. Metformin was found to be associated with fewer asthma attacks of similar magnitude in both approaches (SCCS: IRR, 0.68; 95% CI, 0.62-0.75; IPTW: HR, 0.76; 95% CI, 0.67-0.85). Negative control analyses did not find evidence of significant bias. Hemoglobin A1c levels, BMI, blood eosinophil cell counts, and asthma severity did not modify the association. The only add-on antidiabetic medication to have an additive association was GLP-1RA (SCCS: IRR, 0.60; 95% CI, 0.49-0.73)., Conclusions and Relevance: The results of this cohort study suggest that metformin was associated with a lower rate of asthma attacks, with further reductions with the use of GLP-1RA. This appeared to be associated with mechanisms other than through glycemic control or weight loss and occurred across asthma phenotypes.

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity increases risk of cardiovascular disease. This cohort study examines the prognostic value of MASLD, across body weight categories, in a secondary preventative acute myocardial infarction (AMI) cohort., Methods: Patients with AMI were stratified into four phenotypes-obesity MASLD, non-obesity MASLD, obesity non-MASLD, non-obesity non-MASLD. The primary outcome was all-cause mortality. Cox regression analysis was performed to investigate determinants of long-term all-cause mortality., Results: Of 5702 patients, majority were in the non-obesity non-MASLD group (66.7%), followed by obesity MASLD (16.1%), non-obesity MASLD (11.2%) and non-obesity MASLD (6.0%). Across the four phenotypes, obesity MASLD had the highest cardiometabolic burden, followed by non-obesity MASLD. Non-obesity MASLD had the highest risk of heart failure (p = 0.034), cardiogenic shock (p < 0.001), and all-cause long-term mortality (p = 0.019). The non-obesity MASLD (HR 1.400, 95%CI 1.077-1.820, p = 0.012) and obesity MASLD phenotypes (HR 1.222, 95%CI 1.005-1.485, p = 0.044) were independently associated with long-term all-cause mortality., Conclusions: Obesity and non-obesity MASLD phenotypes were predictors of all-cause mortality following AMI, with an even larger magnitude of mortality risk in the non-obesity MASLD group. The recognition of MASLD and its body weight phenotypes will be beneficial in the prognostication following AMI., (© 2024 John Wiley & Sons Ltd.)

Introduction: Current recommendations for lung transplantation immunosuppression do not explicitly target children, and many pharmacotherapies used in pediatrics are extrapolated from adults., Methods: Data were collected from an anonymous survey distributed to International Pediatric Lung Transplant Collaborative (IPLTC) members from November 2023 to February 2024. Eligible participants included pediatric lung transplant physicians, pharmacists, or others with expertise in their lung transplant center's protocols. Participant and program demographics were surveyed, including location and transplant volume. Seventeen multiple-choice questions, text responses, and Likert scale statements covered the following: induction immunosuppression, maintenance immunosuppression, drug monitoring, dose optimization, and expert guidance available in current literature., Results: Among the 23 pediatric lung transplant healthcare professionals who responded, 13 respondents (57%) preferred using basiliximab as their standard induction immunosuppression. 3 (13%) prefer rabbit anti-thymocyte globulin (rATG), while 7 (30%) consider either rATG or basiliximab for induction. Of 22 responses with 100% completion, 21 of 22 (95.2%) respondents reported a combination of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids (CCS) as their preferred maintenance immunosuppression regimen, reflecting the suggested preferred regimen for pediatric lung transplantation. Feedback on the perception of available evidence-based or established guidelines revealed the majority (90.0%) of respondents found them to be insufficient for pediatrics., Conclusion: This international survey highlights the variability in immunosuppression practices across pediatric lung transplant programs around the world. The findings underscore a gap in unified, evidence-based practice guidelines. With strong consensus among respondents on the lack of established guidelines, there is a clear directive for future research to establish standardized practices in pediatric lung transplantation., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The Advisory Committee on Immunization Practices (ACIP) recommends that health care personnel receive an annual influenza vaccine. In September 2023, ACIP recommended that everyone aged ≥6 months receive a 2023-2024 COVID-19 vaccine. Health care facilities, including acute care hospitals and nursing homes, report vaccination of health care personnel against influenza and COVID-19 to CDC's National Healthcare Safety Network (NHSN). During October 2023-March 2024, NHSN defined up-to-date COVID-19 vaccination as receipt of a 2023-2024 COVID-19 vaccine. This analysis describes influenza and 2023-2024 COVID-19 vaccination coverage among health care personnel working in acute care hospitals and nursing homes during the 2023-24 respiratory virus season (October 1, 2023-March 31, 2024). Influenza vaccination coverage was 80.7% among health care personnel at acute care hospitals and 45.4% among health care personnel at nursing homes. Coverage of 2023-2024 COVID-19 vaccination was 15.3% among health care personnel at acute care hospitals and 10.5% among health care personnel at nursing homes. Respiratory viral diseases including influenza and COVID-19 pose risks to health care personnel in U.S. health care settings, and vaccination of health care personnel is an effective strategy for maintaining a healthy workforce and improving health care system resiliency., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Clinical research is pivotal in assessing the safety and efficacy of new treatments in healthcare. However, the success of such research depends on the inclusion of a diverse and representative participant sample, which is currently lacking. This lack of diversity in biomedical research participants has significant repercussions, limiting the real-world applicability and accessibility of medical interventions, especially for underrepresented groups. Barriers to diverse participation include historical mistrust, logistical challenges, and financial constraints. Recent guidelines by government agencies and funding bodies emphasize the need for diversity in clinical trials, but specific strategies for inclusive recruitment are often lacking. This paper explores the use of digital methods to enhance diversity and inclusion in research recruitment. Digital tools, such as electronic medical records, social media, research registries, and mobile applications, offer promising opportunities for reaching diverse populations. Strategies include culturally tailored messaging, collaborations with community organizations, and the use of SEO to improve visibility and engagement. However, challenges such as privacy concerns, digital literacy gaps, and ethical considerations must be addressed. The promotion of diversity in clinical research recruitment is crucial for advancing health equity. By leveraging digital tools and adopting inclusive strategies, study teams can improve the diversity of study participants, ultimately leading to more applicable and equitable healthcare outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tomiwa, Wong, Miller, Ogungbe, Byiringiro, Plante and Himmelfarb.)

Background: Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with over 18 million deaths annually. Despite extensive research, genetic and environmental factors contributing to HF remain complex and poorly understood. Recent studies suggest that epigenetic modifications, such as DNA methylation, may play a crucial role in regulating HF-associated phenotypes. In this study, we leverage the Hybrid Mouse Diversity Panel (HMDP), a cohort of over 100 inbred mouse strains, to investigate the role of DNA methylation in HF progression., Objective: We aim to identify epigenetic modifications associated with HF by integrating DNA methylation data with gene expression and phenotypic traits. Using isoproterenol (ISO)-induced cardiac hypertrophy and failure in HMDP mice, we explore the relationship between methylation patterns and HF susceptibility., Methods: We performed reduced representational bisulfite sequencing (RRBS) to capture DNA methylation at single-nucleotide resolution in the left ventricles of 90 HMDP mouse strains under both control and ISO-treated conditions. We identified differentially methylated regions (DMRs) and performed an epigenome-wide association study (EWAS) using the MACAU algorithm. We identified likely candidate genes within each locus through integration of our results with previously reported sequence variation, gene expression, and HF-related phenotypes. In vitro approaches were employed to validate key findings, including gene knockdown experiments in neonatal rat ventricular myocytes (NRVMs). We also examined the effects of preventing DNA methyltransferase activity on HF progression., Results: Our EWAS identified 56 CpG loci significantly associated with HF phenotypes, including 18 loci where baseline DNA methylation predicted post-ISO HF progression. Key candidate genes, such as Prkag2, Anks1, and Mospd3, were identified based on their epigenetic regulation and association with HF traits. In vitro follow-up on a number of genes confirmed that knockdown of Anks1 and Mospd3 in NRVMs resulted in significant alterations in cell size and blunting of ISO-induced hypertrophy, demonstrating their functional relevance in HF pathology.Furthermore, treatment with the DNA methyltransferase inhibitor RG108 in ISO-treated BTBRT mice significantly reduced cardiac hypertrophy and preserved ejection fraction compared to mice only treated with ISO, highlighting the therapeutic potential of targeting DNA methylation in HF. Differential expression analysis revealed that RG108 treatment restored the expression of several methylation-sensitive genes, further supporting the role of epigenetic regulation in HF., Conclusion: Our study demonstrates a clear interplay between DNA methylation, gene expression, and HF-associated phenotypes. We identified several novel epigenetic loci and candidate genes that contribute to HF progression, offering new insights into the molecular mechanisms of HF. These findings underscore the importance of epigenetic regulation in cardiac disease and suggest potential therapeutic strategies for modifying HF outcomes through targeting DNA methylation.

Background: The COVID-19 pandemic resulted in a rapid accumulation of novel vaccine research evidence. As a means to monitor this evidence, the Public Health Agency of Canada (PHAC) created the E vidence e X traction T eam for R esearch A nalysis ( EXTRA ), which contributed to situational awareness in Canada through a bibliographic repository used to support decision-making by the National Advisory Committee on Immunization. We describe the process by which this literature was identified and catalogued, and provide an overview of characteristics in the identified literature., Methods: To expedite the process, PHAC leveraged an artificial intelligence (AI) tool to assist in the screening and selection of relevant articles. Literature search results were initially screened by AI, then manually reviewed for relevance. Relevant articles were tagged using controlled vocabulary and stored in a bibliographic repository. This repository was analyzed to identify trends in vaccine research over time according to several key characteristics., Results: As of December 31, 2023, EXTRA's repository contained 19,050 articles relevant to PHAC's immunization mandate. The majority of these articles (63.9 %) were identified between August 2021 and January 2023, with an average of 20 relevant articles added daily during this period. Nearly 14,000 articles reported on mRNA vaccines. Safety outcomes were most frequently reported (n = 8,289), followed by immunogenicity (n = 7,269) and efficacy/effectiveness (n = 3,246). COVID-19 vaccine literature output started to decrease in mid-2023, two years after the initial dramatic increase in mid-2021., Conclusions: This hybrid (AI and human) approach was critical for PHAC situational awareness and the development of timely vaccine guidance in Canada during the COVID-19 pandemic. Given the volume of data and analyses required, the AI-augmented processes made this massive undertaking manageable. Analysis of COVID-19 vaccine research patterns supports projections of research volume, type, and rate that will help predict resourcing and information needs to plan future emergency vaccine guidance activities., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthew Tunis reports financial support was provided by Public Health Agency of Canada. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024 Published by Elsevier Ltd.)

Importance: Accurate staging is a fundamental step in treating patients with nasopharyngeal carcinoma (NPC) worldwide; this is crucial not only for prognostication, but also for guiding treatment decisions. The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) system is the global language for clinicians, researchers, and cancer registries. Continual improvement that aligns with contemporary pattern of care is essential., Objective: To improve the prognostic accuracy and clinical applicability of the eighth edition (TNM-8) for NPC., Design, Setting, and Participants: This multicenter study analyzed patients with NPC with detailed tumor features during January 2014 and December 2015 and was reviewed by experienced radiologists. The data analysis was completed in December 2023. The findings were further confirmed with internal and external validation. Statistical analyses and clinical considerations were reviewed by the AJCC/UICC multidisciplinary head and neck panels and attained consensus. The recommendations were evaluated by the AJCC Evidence-Based Medicine Committee before final endorsement as the ninth version (TNM-9)., Main Outcomes and Measures: The primary end point was overall survival. Adjusted hazard ratios of different subgroups were then assessed for confirmation of optimal stage grouping., Results: Of the 4914 patients analyzed, 1264 (25.7%) were female and 3650 (74.3%) were male; the median (SD) age was 48.1 (12.0) years. Advanced radiological extranodal extension (with involvement of adjacent muscles, skin, and/or neurovascular bundles) was identified as an independent adverse factor for all end points: this was added as a criterion for N3. Patients with nonmetastatic disease were regrouped into stages I to III instead of TNM-8 stages I to IVA. Significant hazard discrimination was achieved by grouping T1-2N0-1 as stage I, T3/N2 as stage II, and T4/N3 as stage III. Although the T1-2N0-1 subgroups had comparable 5-year overall survival, subdivisions into IA (T1-T2N0) and IB (T1-T2N1) were recommended due to the distinction in adjusted hazard ratios following adjustment for chemotherapy use. Metastatic disease was exclusively classified as stage IV, and prognostication was further refined by subdivision into IVA (M1a, ≤3 lesions) and IVB (M1b, >3 lesions). TNM-9 demonstrated superiority compared with TNM-8 in major statistical aspects., Conclusion and Relevance: The results of this diagnostic study suggest that the ninth version of TNM staging for NPC, based on robust analyses and a comprehensive review by the AJCC/UICC staging committees, provides an improved staging system for global application and a framework for future incorporation of nonanatomical factors. This will be launched for global application in January 2025.

Introduction: Delineating subthalamic nucleus (STN) boundaries using microelectrode recordings (MER) and trajectory history is a valuable resource for neurosurgeons, aiding in the accurate and efficient positioning of deep brain stimulation (DBS) electrodes within the STN. Here, we aimed to assess the application of artificial intelligence, specifically Hidden Markov Models (HMM), in the context of STN localization., Methods: A comprehensive search strategy was employed, encompassing electronic databases, including PubMed, EuroPMC, and MEDLINE. This search strategy entailed a combination of controlled vocabulary (e.g., MeSH terms) and free-text keywords pertaining to "artificial intelligence," "machine learning," "deep learning," and "deep brain stimulation." Inclusion criteria were applied to studies reporting the utilization of HMM for predicting outcomes in DBS, based on structured patient-level health data, and published in the English language., Results: This systematic review incorporated a total of 14 studies. Various machine learning compared wavelet feature to proposed features in diagnosing the STN, with the HMM yielding a diagnostic odds ratio (DOR) of 838.677 (95% CI: 203.309-3459.645). Similarly, the K-Nearest Neighbors (KNN) model produced parameter estimates, including a diagnostic odds ratio of 25.151 (95% CI: 12.270-51.555). Meanwhile, the support vector machine (SVM) model exhibited parameter estimates, with a DOR of 13.959 (95% CI: 10.436-18.671)., Conclusions: MER data demonstrates significant variability in neural activity, with studies employing a wide range of methodologies. Machine learning plays a crucial role in aiding STN diagnosis, though its accuracy varies across different approaches., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate the state and trajectory of gender, racial, and academic authorship diversity in the otolaryngology clinical trial literature over the past 2 decades., Study Design: Bibliometric analysis., Setting: Otolaryngology clinical trial literature., Methods: Clinical trials published in the 9 major otolaryngology journals between 2000 and 2020 were included. The gender, race, and academic seniority of the first, senior, and corresponding authors were recorded for each trial. Multivariable regression models assessed the temporal trajectory of authorship diversity over time and the disparity in citations across author characteristics. Models adjusted for relevant confounders pertaining to publication environment and study design., Results: Among 2117 trials, first, senior, and corresponding authors have been predominantly White (60%-64%), male (76%-80%), and attending physicians (63%-69%). Trials led by Black (<1%) and Hispanic (<5%) authors were severely underrepresented. Over time, the representation of female (adj. β 0.8%, 95% CI [0.5%, 1.1%] per year), Asian (1.0% [0.7%, 1.3%] per year), and MD resident (0.4% [0.1%, 0.7%] per year) first authorship increased, but representation of female (0.2% [-0.1%, 0.5%] per year), Black (0% [-0.03%, 0.02%] per year), Hispanic (-0.2% [-0.33%, -0.02%] per year) senior authorship remained persistently low. Asian-led trials were cited significantly less compared to White-led trials even after adjusting for study design and publication year (aIRR 0.82 [0.73, 0.92])., Conclusions: Despite promising signs of improving authorship diversity over time, persistent underrepresentation of female, Black, Hispanic senior authorship underscore the need for additional efforts to diversify the otolaryngology clinical science workforce., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background: While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID., Methods: A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.)., Findings: Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events., Interpretation: As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions., Funding: Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438., Competing Interests: Declaration of interests Danielle Mowery serves as an unpaid member of the Epic Cosmos Governing Council. Romain Pirracchio received funding from the FDA CERSI grant U01FD005978 and the PCORI grant P0562155 and received a consulting honorarium from Phillips. Martin van der Laan received funding from the NIAID grant 5R01AI074345. Johanna Loomba received contract funding from the NIH RECOVER program. Emily Pfaff received funding from the NIH and PCORI. The views expressed in this manuscript are solely those of the authors and do not necessarily represent those of the National Institutes of Health, the U.S. Department of Health and Human Services or the U.S. government. Qi Long was supported by grants from the NIH., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Iatrogenic cervical esophageal perforation (ICEP) represents a rare and challenging surgical complication that results in significant morbidity and mortality. This is a case report of a cervical esophageal fistula that resulted from an iatrogenic perforation following thyroid surgery, treated with surgical repair followed by negative pressure wound therapy (NPWT)., Presentation of Case: A 43-year-old female was presented with an infected post-total thyroidectomy and bilateral radical neck dissection two weeks prior. Esophagography revealed contrast leakage from the anterolateral aspect of the esophagus at the level of C7-T1. Surgical debridement exposed large (4 × 1 cm) esophageal damage. The esophageal repair was performed using a sternocleidomastoids flap reinforced with BioGlue® followed by placement of a feeding tube through a gastrostomy. Subsequent mucus leakage was observed two weeks after the repair. Conservative approach using NPWT was used to promote wound closure. Over a 3-week period, serial imaging demonstrated fistula closure and complete wound healing by 8 weeks., Discussion: A delay in diagnosis and treatment for esophageal perforation leads to severe complications, highlighting the need for standardized treatment algorithms. Larger perforations illustrated in this case report require primary repair with muscle flaps. When reconstructive surgery fails, a follow-up conservative therapy utilizing proper NPWT was able to heal the leakage., Conclusion: This case report illustrates rare but devastating potential complications from a commonly performed oncologic surgery. The involvement of a multidisciplinary team from the very first identification of surgical complications is crucial for ensuring proper treatment., Competing Interests: Conflict of interest statement We declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The presence of a pseudodiverticulum of the anterior pharyngeal wall, or prominent "pharyngeal bar," is a well-known phenomenon that occurs following total laryngectomy, which can be visualized by nasolaryngoscopy or videofluoroscopy. Among the different techniques of pharyngeal reconstruction, there is higher incidence following primary vertical multilayered closure. It has been postulated to cause dysphagia and lack of dietary progression despite a paucity of data. However, the direct impact of pseudodiverticulum is less clear and anecdotally its presence and severity does not necessarily correlate with dysphagia., Methods: A retrospective case series was performed of all consecutive patients who underwent total laryngectomy or laryngopharyngectomy between 2015 and 2022 at two tertiary head and neck institutions. All patients underwent routine videofluoroscopy postoperatively for swallow assessment. The presence of pseudodiverticulum on postoperative contrast swallow study was recorded to investigate the relationship with patient's ability to tolerate oral intake at 3 months discharge from the hospital., Results: Of 50 laryngectomized patients (mean age 63.8 ± 10.0, 86% male), the main closure techniques were primary vertical (n = 9, 18%), primary T-closure (n = 14, 28%), and flap reconstruction (n = 27, 54%). Pseudodiverticulum was identified in 19 cases (38%). 43 patients underwent primary surgery and 30 had adjuvant radiotherapy. The presence of pseudodiverticulum was significantly associated with vertical primary closure versus non-vertical (T-closure or flap reconstruction) techniques (χ 2 (df 1) = 7.4, p = 0.007, OR = 5.7, 95% CI 1.3-24.7). Pseudodiverticulum was not associated with an increased inability to tolerate solid intake or full diet compared to patients without pseudodiverticulum. 26.3% of patients with pseudodiverticulum were on full diet compared to 25.8% of patients without. The vertical closure technique showed no difference in ability to maintain solid intake compared with non-vertical closure; however, no patients were on full diet. Only one patient in the pseudodiverticulum group required surgical management during the study period for retention., Conclusion: The presence of a pseudodiverticulum does not appear to be significantly associated with a need for postoperative dietary modification. The authors postulate that postlaryngectomy dysphagia is multifactorial with sensorimotor aperistalsis of the pharynx and cricopharyngeal stenosis. While a pseudodiverticulum is a common phenomenon, patients did not require modification of diet at higher rates than those without, and they seldom require intervention., (© 2024 Wiley Periodicals LLC.)

A Prognostic Index for Liver Radiation (PILiR) for improved patient selection for stereotactic liver-directed radiotherapy (SBRT) was developed. Using a large single-center database, 195 patients treated with SBRT for local control, including 66 with hepatocellular carcinoma (HCC) and 129 with metastatic liver disease, were analyzed. Only patients ineligible for alternative treatments were included. Overall survival was 11.9 months and 9.4 months in the HCC group and metastatic groups, respectively. In the combined dataset, Child-Pugh Score (CPS) ( p = 0.002), serum albumin ( p = 0.039), and presence of extrahepatic disease ( p = 0.012) were significant predictors of early death on multivariable analysis and were included in the PILiR (total score 0 to 5). Median survival was 23.8, 9.1, 4.5, and 2.6 months for patients with 0, 1-2, 3, and 4-5 points, respectively. In the HCC dataset, CPS ( p < 0.001) and gross tumor volume ( p = 0.013) were predictive of early death. In the metastatic dataset, serum albumin ( p < 0.001) and primary disease site ( p = 0.003) were predictive of early death. The AUC for the combined, HCC, and metastatic datasets are 0.78, 0.84, and 0.80, respectively. Poor liver function (defined by CPS and serum albumin) and extrahepatic disease were most predictive of early death, providing clinically important expected survival information for patients and caregivers.

ATP-dependent chromatin remodeling enzymes mobilize nucleosomes, but how such mobilization affects chromatin condensation is unclear. Here, we investigate effects of two major remodelers, ACF and RSC using chromatin condensates and single-molecule footprinting. We find that both remodelers inhibit the formation of condensed chromatin. However, the remodelers have distinct effects on pre-formed chromatin condensates. ACF spaces nucleosomes without de-condensing the chromatin, explaining how ACF maintains nucleosome organization in transcriptionally repressed genomic regions. In contrast, RSC catalyzes ATP-dependent de-condensation of chromatin. Surprisingly, RSC also drives micron-scale movements of entire condensates. These newly uncovered activities of RSC explain its central role in transcriptional activation. The biological importance of remodelers may thus reflect both their effects on nucleosome mobilization and the corresponding consequences on chromatin dynamics at the mesoscale., Competing Interests: Competing interests: G.J.N is a co-founder of TippingPoint Biosciences.

Episomal AMA1-based plasmids are increasingly used for expressing biosynthetic pathways and CRISPR/Cas systems in filamentous fungi cell factories due to their high transformation efficiency and multicopy nature. However, the gene expression from AMA1 plasmids has been observed to be highly heterogeneous in growing mycelia. To overcome this limitation, here we developed next-generation AMA1-based plasmids that ensure homogeneous and strong expression. We achieved this by evaluating various degradation tags fused to the auxotrophic marker gene on the AMA1 plasmid, which introduces a more stringent selection pressure throughout multicellular fungal growth. With these improved plasmids, we observed in Aspergillus nidulans a 5-fold increase in the expression of a fluorescent reporter, a doubling in the efficiency of a CRISPRa system for genome mining, and a up to a 10-fold increase in the production of heterologous natural product metabolites. This strategy has the potential to be applied to diverse filamentous fungi., (© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. The molecular basis of HKU1 binding to TMPRSS2 and determinants of host receptor tropism remain elusive. We designed an active human TMPRSS2 construct enabling high-yield recombinant production in human cells of this key therapeutic target. We determined a cryo-electron microscopy structure of the HKU1 RBD bound to human TMPRSS2, providing a blueprint of the interactions supporting viral entry and explaining the specificity for TMPRSS2 among orthologous proteases. We identified TMPRSS2 orthologs from five mammalian orders promoting HKU1 S-mediated entry into cells along with key residues governing host receptor usage. Our data show that the TMPRSS2 binding motif is a site of vulnerability to neutralizing antibodies and suggest that HKU1 uses S conformational masking and glycan shielding to balance immune evasion and receptor engagement., Competing Interests: Declaration of interests M.M. and D.V. are named as inventors on a patent describing the designed TMPRSS2 constructs, and D.V. is named as inventor on patents for coronavirus vaccines filed by the University of Washington. E.W. and A.T. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act expanded access to independent community providers outside the Veterans Health Administration (VA). Little is known how quality, costs, and outcomes of primary care received in the community compare to that of the VA., Objective: To compare quality, costs, and outcomes of community and VA-provided primary care for patients with diabetes over a 12-month episode., Design: A cross-sectional study using VA administrative data and community care claims. Adjusted analyses were conducted using inverse probability weighted regression adjustment to balance patient characteristics., Participants: Veterans with diabetes receiving primary care in the VA or community., Main Measures: Quality measures included receipt of hemoglobin A1C tests, eye exams, microalbumin urine tests, and flu shots. Outcomes were measured by hospitalizations for an ambulatory care sensitive condition (ACSC). Costs were measured for VA and community outpatient care, inpatient care, and prescription drugs., Key Results: There were 652,648 VA patients and 3650 community care patients. VA patients were less likely to be White, had shorter mean drive time to VA primary care, and were less likely to be rural than community care patients. In adjusted analyses, community care patients had significantly lower probability of receiving a hemoglobin A1C test, eye exam, microalbumin urine test, and flu shot compared to the VA group. There was no difference in probability of an ACSC hospitalization. Community care patients had higher mean total costs ($1741 [95% CI, $431, $3052]), driven by higher inpatient and prescription drug costs but lower emergency care costs than VA patients., Conclusion: Patients receiving community primary care had worse diabetes quality and higher costs than patients receiving VA primary care. There was no difference in health outcomes. Care provided by an integrated delivery system may have advantages in quality and value., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Aim: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at increased risk of incident cardiovascular disease. However, the clinical characteristics and prognostic importance of MASLD in patients presenting with acute myocardial infarction (AMI) have yet to be examined., Methods: This study compared the characteristics and outcomes of patients with and without MASLD presenting with AMI at a tertiary centre in Singapore. MASLD was defined as hepatic steatosis, with at least one of five metabolic criteria. Hepatic steatosis was determined using the Hepatic Steatosis Index. Propensity score matching was performed to adjust for age and sex. The Kaplan-Meier curve was constructed for long-term all-cause mortality. Cox regression analysis was used to investigate independent predictors of long-term all-cause mortality., Results: In this study of 4446 patients with AMI, 2223 patients with MASLD were matched with patients without MASLD using propensity scores. The mean follow-up duration was 3.4 ± 2.4 years. The MASLD group had higher rates of obesity, diabetes and chronic kidney disease than their counterparts. Patients with MASLD had early excess all-cause mortality (6.8% vs. 3.6%, p < .001) at 30 days, with unfavourable mortality rates sustained in the long-term (18.3% vs. 14.5%, p = .001) compared with those without MASLD. After adjustment, MASLD remained independently associated with higher long-term all-cause mortality (hazard ratio 1.330, 95% confidence interval 1.106-1.598, p = .002)., Conclusion: MASLD embodies a higher burden of metabolic dysfunction and is an independent predictor of long-term mortality in the AMI population. Its early identification may be beneficial for risk stratification and provide therapeutic targets for secondary preventive strategies in AMI., (© 2024 John Wiley & Sons Ltd.)

Objective: Conventional wisdom once asserted that diabetes was irreversible. However, contemporary research indicates that dietary changes may contribute to achieving diabetes remission in persons with type 2 diabetes (T2D). We aimed to determine the effectiveness of food-based dietary approaches for T2D remission., Methods: We systematically searched Medline, EMBASE, and Web of Science, along with exploring grey literature, to identify longitudinal studies. Data extraction and quality assessment adhered to predetermined criteria, and the results of the included studies were analyzed using a narrative synthesis and graphical display., Results: We included 52 original studies-40 % were rated as low-risk of bias. Overall, studies showed the low-carbohydrate Mediterranean diet (LCMD), compared to a low-fat diet, was more effective for achieving T2D remission in newly diagnosed patients who also had a weight loss of up to 6 kg. Compared to both the traditional Mediterranean diet and the American Diabetic Association diet, the LCMD was also more effective at diabetes remission for persons with T2D with any duration of diabetes; however, more substantial weight loss of 8 kg was required. Other diets that appeared effective for T2D remission included low-calorie diets and diets high in plant protein sources. Less weight loss was needed to achieve remission on plant-based diets than a low-calorie diet and low-carbohydrate diet., Conclusions: Diets high in plant protein sources may support T2D remission, particularly among newly diagnosed patients. For patients with a duration of over 2 years, the combination of plant-based diets with greater weight loss should be considered to induce remission., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). Published by Elsevier Ltd. All rights reserved.)

Aims: Few studies investigate whether psychosocial factors (social isolation, social support, trait anger, and depressive symptoms) are associated with cardiovascular health, and none with the American Heart Association's new definition of cardiovascular health, Life's Essential 8 (LE8). Therefore, we assessed the cross-sectional associations of psychosocial factors with Life's Essential 8 and individual components of Life's Essential 8., Methods: We included 11,311 Atherosclerosis Risk in Communities cohort participants (58% females; 23% Black; mean age 57 (standard deviation: 6) years) who attended Visit 2 (1990-1992) in this secondary data analysis using cross-sectional data from the ARIC cohort study. Life's Essential 8 components included diet, physical activity, nicotine exposure, sleep quality, body mass index, blood lipids, blood glucose, and blood pressure. Life's Essential 8 was scored per the American Heart Association definition (0-100 range); higher scores indicate better cardiovascular health. Associations of categories (high, moderate, and low) of each psychosocial factor with continuous Life's Essential 8 score and individual Life's Essential 8 components were assessed using multivariable linear regressions., Results: 11% of participants had high Life's Essential 8 scores (80-100), while 67% and 22% had moderate (50-79) and low Life's Essential 8 scores (0-49) respectively. Poor scores on psychosocial factor assessments were associated with lower Life's Essential 8 scores, with the largest magnitude of association for categories of depressive symptoms (low β = Ref.; moderate β = -3.1, (95% confidence interval: -3.7, -2.5; high β = -8.2 (95% confidence interval: -8.8, -7.5)). Most psychosocial factors were associated with Life's Essential 8 scores for diet, physical activity, nicotine, and sleep, but psychosocial factors were not associated with body mass index, blood lipids, blood glucose, or blood pressure., Conclusion: Less favorable measures of psychosocial health were associated with lower Life's Essential 8 scores compared better measures of psychosocial health among middle-aged males and females., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Peter-Marske et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A fully automated bacteria whole genome sequencing (WGS) assay was evaluated to characterize Mycobacterium tuberculosis (MTB) and non-tuberculosis Mycobacterium (NTM) clinical isolates. The results generated were highly reproducible, with 100% concordance in species and sub-lineage classification and 92% concordance between antimicrobial resistance (AMR) genotypic and phenotypic profiles. Using extracted deoxyribonucleic acid (DNA) from MTB clinical isolates as starting material, these findings demonstrate that a fully automated WGS assay, with a short turnaround time of 24.5 hours, provides timely and valuable insights into MTB outbreak investigation while providing reliable genotypic AMR profiling consistent with traditional antimicrobial susceptibility tests (AST). This study establishes a favorable proposition for the adoption of end-to-end fully automated WGS solutions for decentralized MTB diagnostics, thereby aiding in World Health Organization's (WHO) vision of tuberculosis eradication.

Background: Cis-regulatory elements (CREs) play a pivotal role in gene expression regulation, allowing cells to serve diverse functions and respond to external stimuli. Understanding CREs is essential for personalized medicine and disease research, as an increasing number of genetic variants associated with phenotypes and diseases overlap with CREs. However, existing databases often focus on subsets of regulatory elements and present each identified instance of element individually, confounding the effort to obtain a comprehensive view. To address this gap, we have created CREdb, a comprehensive database with over 10 million human regulatory elements across 1,058 cell types and 315 tissues harmonized from different data sources. We curated and aligned the cell types and tissues to standard ontologies for efficient data query., Results: Data from 11 sources were curated and mapped to standard ontological terms. 11,223,434 combined elements are present in the final database, and these were merged into 5,666,240 consensus elements representing the combined ranges of the individual elements informed by their overlap. Each consensus element contains curated metadata including the number of elements supporting it and a hash linking to the source databases. The inferred activity of each consensus element in various cell-type and tissue context is also provided. Examples presented here show the potential utility of CREdb in annotating non-coding genetic variants and informing chromatin accessibility profiling analysis., Conclusions: We developed CREdb, a comprehensive database of CREs, to simplify the analysis of CREs by providing a unified framework for researchers. CREdb compiles consensus ranges for each element by integrating the information from all instances identified across various source databases. This unified database facilitates the functional annotation of non-coding genetic variants and complements chromatin accessibility profiling analysis. CREdb will serve as an important resource in expanding our knowledge of the epigenome and its role in human diseases., (© 2024. The Author(s).)

Background: The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarction (MI) size in the preclinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction in patients with ST-segment-elevation MI undergoing primary percutaneous coronary intervention., Methods: This was a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted between November 2017 to November 2021 in 6 cardiac centers in Singapore. Patients were randomized to receive either cangrelor or placebo initiated before the primary percutaneous coronary intervention procedure on top of oral ticagrelor. The key exclusion criteria included presenting <6 hours of symptom onset; previous MI and stroke or transient ischemic attack; on concomitant oral anticoagulants; and a contraindication for cardiovascular magnetic resonance. The primary efficacy end point was acute MI size by cardiovascular magnetic resonance within the first week expressed as percentage of the left ventricle mass (%LVmass). Microvascular obstruction was identified as areas of dark core of hypoenhancement within areas of late gadolinium enhancement. The primary safety end point was Bleeding Academic Research Consortium-defined major bleeding in the first 48 hours. Continuous variables were compared by Mann-Whitney U test (reported as median [first quartile-third quartile]), and categorical variables were compared by Fisher exact test. A 2-sided P <0.05 was considered statistically significant., Results: Of 209 recruited patients, 164 patients (78%) completed the acute cardiovascular magnetic resonance scan. There were no significant differences in acute MI size (placebo, 14.9% [7.3-22.6] %LVmass versus cangrelor, 16.3 [9.9-24.4] %LVmass; P =0.40) or the incidence (placebo, 48% versus cangrelor, 47%; P =0.99) and extent of microvascular obstruction (placebo, 1.63 [0.60-4.65] %LVmass versus cangrelor, 1.18 [0.53-3.37] %LVmass; P =0.46) between placebo and cangrelor despite a 2-fold decrease in platelet reactivity with cangrelor. There were no Bleeding Academic Research Consortium-defined major bleeding events in either group in the first 48 hours., Conclusions: Cangrelor administered at the time of primary percutaneous coronary intervention did not reduce acute MI size or prevent microvascular obstruction in patients with ST-segment-elevation MI given oral ticagrelor despite a significant reduction of platelet reactivity during the percutaneous coronary intervention procedure., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03102723., Competing Interests: L.T. is on the Astra Zeneca international advisory board of management of adverse events with the new antibody drug conjugate T-DXd in Asian patients with metastatic breast cancer, Roche Singapore immunotherapy in early stage NSCLC patient journey advisory board. L.T. has received a Philips speaker honorarium in kind and a Siemens Healthineers speaker honorarium. Y.K.K. has received research funding from Amgen, Astra Zeneca, Abbott Vascular, Bayer, Boston Scientific, Shockwave Medical, and Novartis (via institution); consulting fees from Abbott Vascular, Medtronic, Novartis, and Peijia Medical; and speaker fees from Shockwave Medical, Abbott Vascular, Boston Scientific, Medtronic, Alvimedica, Biotronik, Orbus Neich, Amgen, Novartis, Astra Zeneca, Microport, Terumo, and Omnicare. Y.K.K. is also cofounder and owns equity in Trisail, for which OrbusNeich is an investor. D.J.H. has received consultant fees from Faraday Pharmaceuticals Inc and Boehringer Ingelheim International GmbH, honoraria from Servier, and research funding from Astra Zeneca and Merck Sharp & Dohme Corp. C.Y.C. has received speaker fees from Novartis and consultancy fees from Boston Scientific and Philips. The other authors report no conflicts.

Designing faithful yet accurate AI models is challenging, particularly in the field of individual treatment effect estimation (ITE). ITE prediction models deployed in critical settings such as healthcare should ideally be (i) accurate, and (ii) provide faithful explanations. However, current solutions are inadequate: state-of-the-art black-box models do not supply explanations, post-hoc explainers for black-box models lack faithfulness guarantees, and self-interpretable models greatly compromise accuracy. To address these issues, we propose DISCRET, a self-interpretable ITE framework that synthesizes faithful, rule-based explanations for each sample. A key insight behind DISCRET is that explanations can serve dually as database queries to identify similar subgroups of samples. We provide a novel RL algorithm to efficiently synthesize these explanations from a large search space. We evaluate DISCRET on diverse tasks involving tabular, image, and text data. DISCRET outperforms the best self-interpretable models and has accuracy comparable to the best black-box models while providing faithful explanations. DISCRET is available at https://github.com/wuyinjun-1993/DISCRET-ICML2024.

Background: Emerging evidence suggests that clinical prediction models that use repeated (time-varying) measurements within each patient may have higher predictive accuracy than models that use patient information from a single measurement., Objective: To determine the breadth of the published literature reporting the development of clinical prediction models in children that use time-varying predictors., Data Sources: MEDLINE, EMBASE and Cochrane databases., Eligibility Criteria: We included studies reporting the development of a multivariable clinical prediction model in children, with or without validation, to predict a repeatedly measured binary or time-to-event outcome and utilizing at least one repeatedly measured predictor., Synthesis Methods: We categorized included studies by the method used to model time-varying predictors., Results: Of 99 clinical prediction model studies that had a repeated measurements data structure, only 27 (27%) used methods that incorporated the repeated measurements as time-varying predictors in a single model. Among these 27 time-varying prediction model studies, we grouped model types into nine categories: time-dependent Cox regression, generalized estimating equations, random effects model, landmark model, joint model, neural network, K-nearest neighbor, support vector machine and tree-based algorithms. Where there was comparison of time-varying models to single measurement models, using time-varying predictors improved predictive accuracy., Conclusions: Various methods have been used to develop time-varying prediction models in children, but there is a paucity of pediatric time-varying models in the literature. Incorporating time-varying covariates in pediatric prediction models may improve predictive accuracy. Future research in pediatric prediction model development should further investigate whether incorporation of time-varying covariates improves predictive accuracy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

CD33 is a transmembrane receptor expressed on cells of myeloid lineage and regulates innate immunity. CD33 is a risk factor for Alzheimer's disease (AD) and targeting CD33 has been a promising strategy drug development. However, the mechanism of CD33's action is poorly understood. Here we investigate the mechanism of anti-CD33 antibody HuM195 (Lintuzumab) and its single-chain variable fragment (scFv) and examine their therapeutic potential. Treatment with HuM195 full-length antibody or its scFv increased phagocytosis of β-amyloid 42 (Aβ42) in human microglia and monocytes. This activation of phagocytosis was driven by internalization and degradation of CD33, thereby downregulating its inhibitory signal. HumM195 transiently induced CD33 phosphorylation and its signaling via receptor dimerization. However, this signaling decayed with degradation of CD33. scFv binding to CD33 leads to a degradation of CD33 without detection of the CD33 dimerization and signaling. Moreover, we found that treatments with either HuM195 or scFv promotes the secretion of IL33, a cytokine implicated in microglia reprogramming. Importantly, recombinant IL33 potentiates the uptake of Aβ42 in monocytes. Collectively, our findings provide unanticipated mechanistic insight into the role of CD33 signaling in both monocytes and microglia and define a molecular basis for the development of CD33-based therapy of AD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The endoscopic modified medial maxillectomy (MMM) and prelacrimal approach (PLA) are two routinely performed endoscopic approaches to the maxillary sinus when access via a middle meatal antrostomy is insufficient. However, there is no data in the literature that has compared outcomes and complication profile between the two procedures to determine which approach is superior., Objective: To compare the approach related morbidity of PLA and MMM., Methods: A retrospective cohort study of all consecutive adult patients undergoing either MMM or PLA from 2009 to 2023 were identified. The primary outcome was development of epistaxis, paraesthesia, lacrimal injury, iatrogenic sinus dysfunction within a minimum of 3 months post-operative follow up., Results: 39 patients (44 sides) underwent PLA and 96 (96 sides) underwent MMM. There were no statistically significant differences between the rates of paraesthesia (9.1 % vs 14.6 %, p = 0.367) or prolonged paraesthesia (2.3 % vs 5.2 %, p = 0.426), iatrogenic maxillary sinus dysfunction (2.3 % vs 5.2 %, p = 0.426) or adhesions requiring removal (4.5 % vs 4.2 %, p = 0.918). No cases of epiphora or nasal cavity stenosis occurred in either arm in our study., Conclusions: According to our data, the endoscopic modified medial maxillectomy and prelacrimal approach are both equally safe approaches with their own benefits to access., Competing Interests: Declaration of competing interest Richard J Harvey is a consultant/advisory board with Medtronic, Novartis, Glaxo-Smith-Kline and Meda pharmaceuticals. He has been on the speakers' bureau for Glaxo-Smith-Kline, Astra-zeneca, Meda Pharmaceuticals and Seqirus. Larry Kalish is on the speakers' bureau for Care Pharmaceuticals, Mylan, and Seqirus Pharmaceuticals. All other authors have no personal, financial, or institutional interest in any drugs, materials, or devices described in this article. This is an unfunded project., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Millions of people in the UK have asthma, yet 70% do not access basic care, leading to the largest number of asthma-related deaths in Europe. Chatbots may extend the reach of asthma support and provide a bridge to traditional healthcare. This study evaluates 'Brisa', a chatbot designed to improve asthma patients' self-assessment and self-management., Methods: We recruited 150 adults with an asthma diagnosis to test our chatbot. Participants were recruited over three waves through social media and a research recruitment platform. Eligible participants had access to 'Brisa' via a WhatsApp or website version for 28 days and completed entry and exit questionnaires to evaluate user experience and asthma control. Weekly symptom tracking, user interaction metrics, satisfaction measures, and qualitative feedback were utilised to evaluate the chatbot's usability and potential effectiveness, focusing on changes in asthma control and self-reported behavioural improvements., Results: 74% of participants engaged with 'Brisa' at least once. High task completion rates were observed: asthma attack risk assessment (86%), voice recording submission (83%) and asthma control tracking (95.5%). Post use, an 8% improvement in asthma control was reported. User satisfaction surveys indicated positive feedback on helpfulness (80%), privacy (87%), trustworthiness (80%) and functionality (84%) but highlighted a need for improved conversational depth and personalisation., Conclusions: The study indicates that chatbots are effective for asthma support, demonstrated by the high usage of features like risk assessment and control tracking, as well as a statistically significant improvement in asthma control. However, lower satisfaction in conversational flexibility highlights rising expectations for chatbot fluency, influenced by advanced models like ChatGPT. Future health-focused chatbots must balance conversational capability with accuracy and safety to maintain engagement and effectiveness., (© The Author(s) 2024.)

Introduction: Throughout the COVID-19 pandemic, primary care nurses were often redeployed to areas outside of primary care to mitigate staffing shortages. Despite this, there is a scarcity of literature describing their perceptions of and experiences with redeployment during the pandemic. Objectives: This paper aims to: 1) describe the perspectives of primary care nurses with respect to redeployment, 2) discuss the opportunities/challenges associated with redeployment of primary care nurses, and 3) examine the nature (e.g., settings, activities) of redeployment by primary care nurses during the COVID-19 pandemic. Methods: In this qualitative study, semi-structured interviews were conducted with primary care nurses (i.e., Nurse Practitioners, Registered Nurses, and Licensed/Registered Practical Nurses), from four regions in Canada. These include the Interior, Island, and Vancouver Coastal Health regions in British Columbia; Ontario Health West region in Ontario; the province of Nova Scotia; and the province of Newfoundland and Labrador. Data related to redeployment were analyzed thematically. Results: Three overarching themes related to redeployment during the COVID-19 pandemic were identified: (1) Call to redeployment, (2) Redeployment as an opportunity/challenge, and (3) Scope of practice during redeployment. Primary care nurses across all regulatory designations reported variation in the process of redeployment within their jurisdiction (e.g., communication, policies/legislation), different opportunities and challenges that resulted from redeployment (e.g., scheduling flexibility, workload implications), and scope of practice implications (e.g., perceived threat to nursing license). The majority of nurses discussed experiences with redeployment being voluntary in nature, rather than mandated. Conclusions: Redeployment is a useful workforce strategy during public health emergencies; however, it requires a structured process and a decision-making approach that explicitly involves healthcare providers affected by redeployment. Primary care nurses ought only to be redeployed after other options are considered and arrangements made for the care of patients in their original practice area., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

The peroral endoscopic myotomy (POEM) procedure has revolutionized the management of achalasia in many centres around the world as it offers patients a minimally invasive endoscopic solution to their dysphagia caused by achalasia. Alongside its success in alleviating dysphagia, concerns regarding postoperative gastroesophageal reflux disease have emerged as a pertinent issue which are not fully resolved. In this study, Nabi et al have comprehensively reviewed the topic of the prediction, prevention and management of gastroesophageal reflux after POEM. POEM is a purely endoscopic procedure which is usually performed without any anti-reflux procedure. Certain patients may be better served by a laparoscopic Heller's myotomy and fundoplication and it is important that gastroenterologists and surgeons provide comprehensive risks and benefits of each achalasia treatment option so that patients can decide what treatment is best for them. This article by Nabi et al provides a comprehensive review of the current status of this issue to allow these discussions to occur., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to ( 1 ) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and ( 2 ) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points-( 1 ) proteinuria, ( 2 ) eGFR, and ( 3 ) histopathology-and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed end points they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, evidence, and uncertainties, supporting the end points. Given the limitations of the available data, the work group was unable to define a minimum threshold for change in any of the end points that might be considered clinically meaningful. The work group concluded that a favorable treatment effect on all three end points would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three end points if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the end points in the aforementioned trials., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Introduction: Assessments with strong validity evidence are necessary to accurately assess health professions students' performance of clinical skills. The aim of this study was to develop and validate a checklist assessment of physical therapy students' performance of bed mobility skills., Methods: A checklist was developed using a 4-step process: 1) evidence review and preliminary checklist development, 2) Delphi review to reach consensus on content, 3) pilot testing and checklist editing, 4) final round of Delphi review. Consensus during Delphi review was defined as 100% of participants rating an item "keep as is" and zero comments in Round 1, and >50% of participants rating each item agree/strongly agree in subsequent Delphi rounds. Interrater reliability (IRR) was measured by two raters scoring 32 recorded exam simulations., Results: All 48 items of the checklist reached consensus after three rounds of Delphi review (12 participants in Round 1, 11 participants in Rounds 2-3). IRR was substantial with 88.5% agreement, Cohen's kappa coefficient=0.61, p<0.001, 95% CI [0.56, 0.66]., Discussion: This checklist has potential to be used to assess student readiness to evaluate and train patients in bed mobility tasks for first-time clinical experiences and to serve as a methodological template for future checklist development.

Background: Double barrelled uro-colostomy (DBUC) is an alternative to traditional ileal conduit (IC) and separate colostomy in patients requiring simultaneous urinary and faecal diversion for reconstruction in pelvic exenteration surgery (PES)., Methods: This cohort study evaluated short- and long-term morbidity and mortality associated with DBUC formation in 20 consecutive adult patients undergoing PES in an Australian Complex Pelvic Surgical Unit. Data were obtained from a prospective database., Results: Mean age 59 years (range 27-76 years). PES was performed for malignant disease in 18 patients (curative intent in 17). Mean operative duration 11.8 h (range 7-17 h). Mean follow-up duration 29.1 months (range 2.6-90.1 months). Early DBUC-related complications occurred in four patients (20.0%): urinary tract infection (UTI)/urosepsis (n = 4) and early ureteric stenosis requiring intervention (n = 1). Late DBUC-related complications occurred in five patients (25.0%): recurrent UTI/urosepsis (n = 4), chronic kidney disease (n = 4), ureteric stenosis (n = 2) and parastomal hernia (n = 4). No mortality occurred secondary to a DBUC complication., Conclusion: DBUC is a safe reconstructive option with acceptable morbidity profile in patients requiring simultaneous urinary and faecal diversion., (© 2024 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Objectives: We assessed the impact of the COVID-19 pandemic on social determinants of health, mental health, substance use, and access to mental health and harm reduction services among key populations disproportionately impacted by sexually transmitted and blood-borne infections (STBBI)., Methods: Online surveys (2021‒2022) were conducted in Canada among people who use drugs or alcohol (PWUD); African, Caribbean, and Black people (ACB); and First Nations, Inuit, and Métis peoples (FNIM). Descriptive analyses were conducted on social determinants of health, substance use, and access to services, stratified by changes in mental health status since the start of the pandemic., Results: A total of 3773 participants (1034 PWUD, 1556 ACB, and 1183 FNIM) completed the surveys, with 45.6% reporting a major/moderate impact of the pandemic on their ability to pay bills and 53% experiencing food insecurity since the start of the pandemic. Half (49.4%) of participants reported deteriorating mental health. A higher increase in substance use and related behaviours was seen in those with worsening mental health. Among those using substances, two thirds (69.4%) of those with worsening mental health reported increasing their use of substances alone, compared to 46.9% of those with better/similar mental health. Access to mental health and harm reduction services was low., Conclusion: These intersecting health issues are among the risk factors for STBBI acquisition and act as barriers to care. Equitable interventions and policies addressing downstream and upstream determinants of health, with meaningful and sustainable leadership from key populations, may improve their health and well-being, to lower STBBI impact and improve future pandemic responses., (© 2024. Crown.)