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Ticks obtain a blood meal by lacerating small blood vessels and ingesting the blood that flows to the feeding site, which triggers various host responses. However, ticks face the challenge of wound healing, a process involving hemostasis, inflammation, cell proliferation and migration, and remodeling, hindering blood acquisition. To overcome these obstacles, tick salivary glands produce an array of bioactive molecules. Here, we characterize ixochymostatin, an Ixodes scapularis protein belonging to the trypsin inhibitor-like (TIL) family. It is expressed in multiple developmental stages and in tick salivary glands and acts as a slow and tight-binding inhibitor of chymase, cathepsin G, and chymotrypsin. Predictions for the tertiary structure complex between ixochymostatin and chymase suggest a direct interaction between the inhibitor reactive site loop and protease active sites. In vitro, ixochymostatin protects the endothelial cell barrier against chymase degrading action, decreasing cell permeability. In vivo, it reduces vascular permeability induced by chymase and compound 48/80, a mast cell degranulator agonist, in a mouse model. Additionally, ixochymostatin inhibits the chymase-dependent generation of vasoconstrictor peptides. Antibodies against ixochymostatin neutralize its inhibitory properties, with epitope mapping identifying potential neutralization regions. Ixochymostatin emerges as a novel tick protein modulating host responses against tick feeding, facilitating blood acquisition., 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. Published by Elsevier B.V.)

Background: Respiratory care departments are experiencing an increased need to demonstrate value in the care they deliver. Value efficiency is a concept that incorporates the value of individual treatments into the normal operations of a department. The purpose of this study was to describe respiratory care leaders' attitudes about the value of services provided by respiratory care departments., Methods: An electronic survey was distributed via social media, professional networks, and a manager work group. The survey was targeted to directors, managers, and supervisors of respiratory care departments. We asked questions related to value, services, and barriers to implementation of value efficiency. Data analysis was descriptive., Results: We received 116 responses; 86% were from managers or directors. The 5 most valuable services delivered were invasive mechanical ventilation (82%), noninvasive ventilation or CPAP (71%), protocol-driven care (47%), code team (44%), and rapid response team (41%). The 5 least valuable services delivered by respiratory care departments were electrocardiograms (63%), stress testing (44%), lung expansion therapies (41%), sleep studies staffed by the respiratory care department (36%), and smoking cessation education (36%). The primary barrier to value efficiency was physician prescribing practices (68%). There was general agreement that physicians support respiratory therapy protocols (71%), value should be considered when evaluating respiratory care services (95%), and directing resources to more valuable services if possible (73%). Respondents did not agree that hospital administrators understand respiratory therapy workflow and full-time equivalent needs (35%) nor that hospital administrators would be supportive if we reduced services (18%)., Conclusions: In a small sample of respiratory therapy leaders, there was limited consensus on what respiratory care services are the most and least valuable. Lack of consensus on high- and low-value services and physician prescribing practice were the primary barriers to value efficiency. Nearly all respondents felt value should be considered when evaluating respiratory care services., (Copyright © 2024 by Daedalus Enterprises.)

Introduction: Young people with chronic health conditions are among the most at risk of having poor social connections, however, little is known about their experiences of loneliness and social isolation. We aimed to describe the perspectives and experiences of loneliness and social isolation among young people with chronic physical conditions., Methods: We searched MEDLINE, Embase, PsycINFO, CINAHL, and CENTRAL from inception to May 2023 for qualitative studies that described the perspectives of loneliness and social isolation in young people aged 10-24 years with chronic physical conditions. Findings from the included studies were analyzed using thematic synthesis., Results: We included 35 studies across 12 countries involving 723 participants (56% female). Most studies (63%) were conducted in young people with cancer. Four major themes were identified: suffering from repercussions of disease (struggling with body image and physical changes, intensified disconnection while hospitalized); hindering relationships with peers and friends (missing out on formative experiences, feeling stuck behind, restrictive parental attitudes); grappling with social exclusion (facing concerns alone, bullying and ostracism); seeking social support and self-help (reliance on family, kindness and empathy from friends, developing rapport with healthcare professionals, discovering self in adversity)., Conclusions: Symptoms, treatments, and hospitalizations limited young people's social participation and ability to maintain friendships, and this was compounded by social exclusion and bullying. Supportive friends, family, and healthcare professionals helped mitigate feelings of isolation. Interventions and strategies are needed to improve social support and foster meaningful connections. This can be achieved through education and awareness initiatives that promote inclusion in schools and the community, as well as efforts to enhance social support and continuity of care in hospitals., (© 2024 Foundation for Professionals in Services to Adolescents.)

The most recent Sudan virus (SUDV) outbreak in Uganda was first detected in September 2022 and resulted in 164 laboratory-confirmed cases and 77 deaths. There are no approved vaccines against SUDV. Here, we investigated the protective efficacy of ChAdOx1-biEBOV in cynomolgus macaques using a prime or a prime-boost regimen. ChAdOx1-biEBOV is a replication-deficient simian adenovirus vector encoding SUDV and Ebola virus (EBOV) glycoproteins (GPs). Intramuscular vaccination induced SUDV and EBOV GP-specific immunoglobulin G responses and neutralizing antibodies. Upon challenge with SUDV, vaccinated animals showed signs of disease like those observed in control animals, and no differences in survival outcomes were measured among all 3 groups. Viral load in blood samples and in tissue samples obtained after necropsy were not significantly different between groups. Overall, this study highlights the importance of evaluating vaccines in multiple animal models and demonstrates the importance of understanding protective efficacy in both animal models and human hosts., Competing Interests: Potential conflicts of interest. T. L. reports consulting fees from Vaccitech on an unrelated project, has received honorarium from Seqirus on an unrelated project, and is named as an inventor on a patent application for a vaccine against SARS-CoV-2. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Exclusive enteral nutrition (EEN) is a first-line therapy for pediatric Crohn's disease (CD), but protective mechanisms remain unknown. We established a prospective pediatric cohort to characterize the function of fecal microbiota and metabolite changes of treatment-naive CD patients in response to EEN (German Clinical Trials DRKS00013306). Integrated multi-omics analysis identified network clusters from individually variable microbiome profiles, with Lachnospiraceae and medium-chain fatty acids as protective features. Bioorthogonal non-canonical amino acid tagging selectively identified bacterial species in response to medium-chain fatty acids. Metagenomic analysis identified high strain-level dynamics in response to EEN. Functional changes in diet-exposed fecal microbiota were further validated using gut chemostat cultures and microbiota transfer into germ-free Il10-deficient mice. Dietary model conditions induced individual patient-specific strain signatures to prevent or cause inflammatory bowel disease (IBD)-like inflammation in gnotobiotic mice. Hence, we provide evidence that EEN therapy operates through explicit functional changes of temporally and individually variable microbiome profiles., Competing Interests: Declaration of interests D. Haller served on the Microbiome Expert Panel from Reckitt Benckiser Health Limited. T.S. received lecture honoraria from Nutricia and MSD and travel support from Abbvie and Ferring outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This work describes the demographics and practice characteristics of physician assistants/associates (PAs) practicing in rheumatology., Methods: We examined 2022 cross-sectional data from the National Commission on Certification of PAs (NCCPA). The investigation included demographics and practice characteristics of PAs working in rheumatology compared to those working in all other specialties. We analyzed data using descriptive and bivariate statistics comparing the two groups., Results: In 2022, 430 PAs self-reported practicing in rheumatology. The median age of these PAs was 39 years, and 84.7% self-identified as female. They primarily (78.8%) worked in office-based private practices and were more likely to engage in telemedicine services (62.5%) than their colleagues in all other specialties. PAs in rheumatology typically worked similar hours as their peers in other medical disciplines but saw a higher proportion of patients in the 61-80 range. At the same time, PAs in rheumatology reported slightly higher job satisfaction and lower burnout symptom rates compared to PAs practicing in other disciplines., Conclusions: Understanding PAs' characteristics and employment settings in rheumatology is crucial to estimating the health workforce supply and demand in this discipline. Further research should explore the economics of PAs in rheumatology, including aspects of teamwork, scope of practice, patient outcomes, and satisfaction., (This article is protected by copyright. All rights reserved.)

Background: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH - , high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH - to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC., Methods: Patients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH - , 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023., Results: Intravenous P-AscH - increased serum ascorbate levels from micromolar to millimolar levels. P-AscH - added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH - did not negatively impact quality of life or increase the frequency or severity of adverse events., Conclusions: P-AscH - infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578)., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

This study investigated the real-world incidence rate of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents. A retrospective cohort of 479 adult patients was assessed between January 2015 and July 2023. Overall, a rare rate of 0.4% (2/479) of possible serotonin syndrome with tedizolid was identified. Given that concomitant serotonergic agents were commonly used, further study is warranted to determine causality., Competing Interests: The authors declare no conflict of interest.

Cardiovascular diseases (CVDs) are complex, encompassing many types of heart pathophysiologies and associated etiologies. Radiotherapy studies have shown that fractionated radiation exposure at high doses (3-17 Gy) to the heart increases the incidence of CVD. However, the effects of low doses of radiation on the cardiovascular system or the effects from space travel, where radiation and microgravity are important contributors to damage, are not clearly understood. Herein, the adverse outcome pathway (AOP) framework was applied to develop an AOP to abnormal vascular remodeling from the deposition of energy. Following the creation of a preliminary pathway with the guidance of field experts and authoritative reviews, a scoping review was conducted that informed final key event (KE) selection and evaluation of the Bradford Hill criteria for the KE relationships (KERs). The AOP begins with a molecular initiating event of deposition of energy; ionization events increase oxidative stress, which when persistent concurrently causes the release of pro-inflammatory mediators, suppresses anti-inflammatory mechanisms and alters stress response signaling pathways. These KEs alter nitric oxide levels leading to endothelial dysfunction, and subsequent abnormal vascular remodeling (the adverse outcome). The work identifies evidence needed to strengthen understanding of the causal associations for the KERs, emphasizing where there are knowledge gaps and uncertainties in both qualitative and quantitative understanding. The AOP is anticipated to direct future research to better understand the effects of space on the human body and potentially develop countermeasures to better protect future space travelers., (© 2024 The Author(s). Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society.)

Bone loss, commonly seen in osteoporosis, is a condition that entails a progressive decline of bone mineral density and microarchitecture, often seen in post-menopausal women. Bone loss has also been widely reported in astronauts exposed to a plethora of stressors and in patients with osteoporosis following radiotherapy for cancer. Studies on mechanisms are well documented but the causal connectivity of events to bone loss development remains incompletely understood. Herein, the adverse outcome pathway (AOP) framework was used to organize data and develop a qualitative AOP beginning from deposition of energy (the molecular initiating event) to bone loss (the adverse outcome). This qualitative AOP was developed in collaboration with bone loss research experts to aggregate relevant findings, supporting ongoing efforts to understand and mitigate human system risks associated with radiation exposures. A literature review was conducted to compile and evaluate the state of knowledge based on the modified Bradford Hill criteria. Following review of 2029 studies, an empirically supported AOP was developed, showing the progression to bone loss through many factors affecting the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The structural, functional, and quantitative basis of each proposed relationship was defined, for inference of causal changes between key events. Current knowledge and its gaps relating to dose-, time- and incidence-concordance across the key events were identified, as well as modulating factors that influence linkages. The new priorities for research informed by the AOP highlight areas for improvement to enable development of a quantitative AOP used to support risk assessment strategies for space travel or cancer radiotherapy., (© 2024 The Author(s). Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society.)

Understanding radiation-induced non-cancer effects on the central nervous system (CNS) is essential for the risk assessment of medical (e.g., radiotherapy) and occupational (e.g., nuclear workers and astronauts) exposures. Herein, the adverse outcome pathway (AOP) approach was used to consolidate relevant studies in the area of cognitive decline for identification of research gaps, countermeasure development, and for eventual use in risk assessments. AOPs are an analytical construct describing critical events to an adverse outcome (AO) in a simplified form beginning with a molecular initiating event (MIE). An AOP was constructed utilizing mechanistic information to build empirical support for the key event relationships (KERs) between the MIE of deposition of energy to the AO of learning and memory impairment through multiple key events (KEs). The evidence for the AOP was acquired through a documented scoping review of the literature. In this AOP, the MIE is connected to the AO via six KEs: increased oxidative stress, increased deoxyribonucleic acid (DNA) strand breaks, altered stress response signaling, tissue resident cell activation, increased pro-inflammatory mediators, and abnormal neural remodeling that encompasses atypical structural and functional alterations of neural cells and surrounding environment. Deposition of energy directly leads to oxidative stress, increased DNA strand breaks, an increase of pro-inflammatory mediators and tissue resident cell activation. These KEs, which are themselves interconnected, can lead to abnormal neural remodeling impacting learning and memory processes. Identified knowledge gaps include improving quantitative understanding of the AOP across several KERs and additional testing of proposed modulating factors through experimental work. Broadly, it is envisioned that the outcome of these efforts could be extended to other cognitive disorders and complement ongoing work by international radiation governing bodies in their review of the system of radiological protection., (© 2024 The Author(s). Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society.)

Cataracts are one of the leading causes of blindness, with an estimated 95 million people affected worldwide. A hallmark of cataract development is lens opacification, typically associated not only with aging but also radiation exposure as encountered by interventional radiologists and astronauts during the long-term space mission. To better understand radiation-induced cataracts, the adverse outcome pathway (AOP) framework was used to structure and evaluate knowledge across biological levels of organization (e.g., macromolecular, cell, tissue, organ, organism and population). AOPs identify a sequence of key events (KEs) causally connected by key event relationships (KERs) beginning with a molecular initiating event to an adverse outcome (AO) of relevance to regulatory decision-making. To construct the cataract AO and retrieve evidence to support it, a scoping review methodology was used to filter, screen, and review studies based on the modified Bradford Hill criteria. Eight KEs were identified that were moderately supported by empirical evidence (e.g., dose-, time-, incidence-concordance) across the adjacent (directly linked) relationships using well-established endpoints. Over half of the evidence to justify the KER linkages was derived from the evidence stream of biological plausibility. Early KEs of oxidative stress and protein modifications had strong linkages to downstream KEs and could be the focus of countermeasure development. Several identified knowledge gaps and inconsistencies related to the quantitative understanding of KERs which could be the basis of future research, most notably directed to experiments in the range of low or moderate doses and dose-rates, relevant to radiation workers and other occupational exposures., (© 2024 Crown copyright, His Majesty the King in Right of Canada and The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland. Reproduced with the permission of the Minister of Health Canada.)

Issue Addressed: Despite increasing interest in citizen science as an approach to engage members of the public in research and decision making about health and wellbeing, there is a lack of practical evidence to guide policy and practice organisations to utilise these approaches. In this study we investigated how and why citizen science came to be incorporated into the work of two policy organisations., Methods: We offer two in-depth case studies of Australian government organisations which have utilised citizen science in environmental and healthy ageing policy. Interviews with organisational informants and relevant documents were analysed inductively to explore how citizen science came to be adopted, legitimised and supported., Results: Citizen science was utilised to address multiple organisational objectives, including increasing community participation in science; enhancing individuals' wellbeing, learning, and skills, and generating data to support research and policy in a relatively cost-effective manner. In both cases, grant funding was a mechanism to support citizen science, with project delivery facilitated through academic-policy partnerships and led by external academic or community partners., Conclusion: Although citizen science is relatively new in policy and practice settings, this study underscores the value of these approaches in realising co-benefits for organisations, academics, and community members. The support and advocacy of senior managers as 'champions', and a willingness to invest in trialling new approaches to address policy problems are necessary ingredients to foster acceptance and legitimacy of citizen science. SO WHAT?: Citizen science initiatives can be strategically utilised by health promotion organisations to enact priorities related to genuine community involvement, support research and innovation and facilitate collaboration and partnerships between academic, policy and community stakeholders., (© 2024 The Authors. Health Promotion Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of Australian Health Promotion Association.)

Background: This study aimed to identify patterns of overall, team, and individual sport participation and examine the prospective associations between these patterns and loneliness in young people., Methods: We analyzed data from 4241 young people, from waves 3 (8-9 y) to 9 (20-21 y) of the Longitudinal Study of Australian Children. We conducted latent class analyses to identify overall and team versus individual sport participation trajectories and used adjusted log-Poisson regression models to examine the associations between these trajectories and loneliness at wave 9., Results: Latent class analyses identified 4 distinct overall sport participation classes which were labeled: nonparticipants (24%), dropouts (42%), initiators (7%), and consistent participants (27%). Compared with nonparticipants, consistent participants had a lower risk of loneliness (risk ratios = 0.69; 95% CIs, 0.59-0.81). Latent class analyses also identified 4 distinct team versus individual sport participation classes: team and individual sport nonparticipants (38%), individual sport participants (14%), moderate team sport participants (14%), and high team sport participants (34%). Compared with the team and individual sport nonparticipants, the high team sports participants had a lower risk of loneliness (risk ratios = 0.70; 95% CIs, 0.53-0.92)., Conclusions: Young people who continued participating in sport in general, and particularly in team sport, had a reduced risk of loneliness. Continued participation in sports should be promoted to improve a range of physical, mental, and social health benefits. Furthermore, team-based sport can provide additional health and well-being benefits, including reduced loneliness due to the group nature of participation.

Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few Food and Drug Administration-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (half-life < 2 hours) with a ratio that is stable over time and unaffected by enzymes or binding to proteins in plasma. LEN exhibits low systemic clearance (CL) in nonclinical species and humans; however, in all species, the observed CL was higher than the in vitro predicted CL. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole-body autoradiography in rats. LEN does not distribute to brain, consistent with being a P-glycoprotein (P-gp) substrate. Mechanistic drug disposition studies with [ 14 C]LEN in intravenously dosed bile duct-cannulated rats and dogs showed a substantial amount of unchanged LEN (31%-60% of dose) excreted in feces, indicating that intestinal excretion (IE) was a major clearance pathway for LEN in both species. Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Renal excretion was < 1% of dose in both species. In plasma, almost all radioactivity was unchanged LEN. Low levels of metabolites in excreta included LEN conjugates with glutathione, pentose, and glucuronic acid, which were consistent with metabolites formed in vitro in H μ rel hepatocyte cocultures and those observed in human. Our studies highlight the importance of IE for efflux substrates that are highly metabolically stable compounds with slow elimination rates. SIGNIFICANCE STATEMENT: LEN is a long-acting injectable that exists as conformationally stable atropisomers. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates., (Copyright © 2024 by The Author(s).)

Quantification of protein-ligand interactions is crucial for understanding the protein's biological function and for drug discovery. In this study, we employed three distinct approaches for determination of protein-ligand binding affinities by a thermal shift assay using a single ligand concentration. We present the results of the comparison of the performance of the conventional curve fitting (CF) method and two newly introduced methods - assuming zero heat capacity change across small temperature ranges (ZHC) and utilizing the unfolding equilibrium constant (UEC); the latter has the advantage of reducing calculations by obtaining the unfolding equilibrium constant directly from the experimental data. Our results highlight superior performance of the ZHC and UEC methods over the conventional CF method in estimating the binding affinity, irrespective of the ligand concentration. In addition, we evaluated how the new methods can be applied to high-throughput screening for potential binders, when the enthalpy (Δ H L ) and molar heat capacity change (Δ C PL ) of ligand binding are unknown. Our results suggest that, in this scenario, using the -300 cal K -1 mol -1 assumption for Δ C pL and either -5 kcal mol -1 or the average enthalpy efficiency-based estimation for Δ H L ( T ) can still provide reasonable estimates of the binding affinity. Incorporating the new methods into the workflow for screening of small drug-like molecules, typically conducted using single-concentration libraries, could greatly simplify and streamline the drug discovery process., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Physical activity (PA) and weight management are critical for cardiovascular disease (CVD) secondary prevention. However, PA adherence during or after cardiac rehabilitation is low. Here, we assess the feasibility and acceptability of the Australian football-themed Aussie Fans in Training (Aussie-FIT) program and associated trial procedures when adapted for men with CVD., Method: A pragmatic randomised control trial, with waitlist control arm, and follow-up measures at 3 and 6 months. Men with a CVD diagnosis and body mass index ≥25 kg/m 2 were recruited from community and clinical settings, and randomised, following baseline measures of health and health behaviours. The intervention arm attended 12 face-to-face football-themed education and PA sessions. Feasibility (recruitment, retention, attendance, and adherence to trial procedures) was assessed via mixed methods., Results: A total of 74% (64/86) of participants expressing interest met the eligibility criteria. Of those, 49 men (mean age=61.4, standard deviation=9.5, mean body mass index=31.3, standard deviation=4.2) were randomised. Program attendance rates (87% attended ≥80% of sessions) and retention (92%) were high. Trial retention at the primary end point (3 months) was high (86%) and at the 6-month follow-ups reduced to 67%. Program and trial procedures were acceptable, except for the request to visit a pathologist for the blood draw., Conclusions: Using a football theme and setting may be a feasible way to engage men with CVD in health behaviour change. Given the existing pilot evidence for men at risk of CVD, and that recruitment rates were under the target, trialling a program for men with or at risk of CVD is recommended., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: There is evidence that the transition to retirement can bring social challenges and may increase loneliness. Few studies have examined the impact of retirement on loneliness; most have been conducted in Western countries. It is important to examine the differences in loneliness postretirement across countries to identify patterns and risk factors that might influence the health and well-being of older adults. We aimed to examine the effect of retirement on loneliness among older adults in Australia, China and the USA., Methods: Longitudinal analysis of data from population-based samples of Australian, Chinese and American adults over 50. Lagged and fully lagged adjusted models were applied. Social engagement was examined as an effect modifier and a sensitivity analysis was conducted among urban participants., Results: Retirees had a higher predicted prevalence of loneliness than non-retirees in Australia (19.4% (95% CI 18.0% to 20.9%) vs 17.0% (95% CI 15.7% to 18.4%)) and in the USA (19.3% (95% CI 17.5% to 21.1%) vs 15.7% (95% CI 14.3% to 17.3%)). These differences were significant only in the USA. In China, loneliness was significantly lower in those who had retired (10.0% (95% CI 7.9% to 12.5%) vs 17.1% (95% CI 15.7% to 18.5%)). In Australia and the USA, voluntary retirees had the lowest loneliness and involuntary retirees had the highest. Social engagement did not modify the association between retirement and loneliness., Conclusions: Our findings imply that the effect of retirement should be considered within a cultural context to inform suitable and effective strategies to alleviate loneliness., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Loneliness and social isolation are risk factors for poor health, but few effective interventions are deployable at scale. This study was conducted to determine whether acts of kindness can reduce loneliness and social isolation, improve mental health, and neighbourhood social cohesion., Method: Three randomized controlled trials (RCTs) were conducted in the USA, UK, and Australia, involving a total of 4284 individuals aged 18-90 years old, randomized to the KIND challenge intervention or a waitlist control group. Participants allocated to the intervention were asked to do at least one act of kindness per week within a four-week period. The primary outcome was loneliness and secondary outcomes included measures of social isolation, mental health, and neighbourhood social cohesion., Results: There was a significant, albeit small, intervention effect after four weeks for reduced loneliness in the USA and the UK, but not for Australia. Relative to controls, KIND challenge participants also showed significantly reduced social isolation and social anxiety in the USA, and reduced stress in Australia. There was also reduced neighbourhood conflict in the USA, increased number of neighbourhood contacts in the USA and Australia, greater neighbourhood stability and feelings of neighbourhood importance in the UK, and better neighbourhood social relationships in Australia., Conclusion: Promoting the provision of social support through small acts of kindness to neighbours has the potential to reduce loneliness, social isolation and social anxiety, and promote neighbourhood relationships, suggesting a potential strategy for public health campaigns., Trial Registration: Clinical Trials Registry. NCT04398472. Registered 21 st May 2020., (© 2024. The Author(s).)

As one of the most important cellular housekeepers, autophagy directly affects cellular health, homeostasis, and function. Even though the mechanisms behind autophagy are well described, how molecular alterations and dysfunctions can lead to pathology in disease contexts still demands deeper investigation. Proteomics is a widely employed tool used to investigate molecular alterations associated with pathological states and has proven useful in identifying alterations in protein expression levels and post-translational modifications in autophagy. In this narrative review, we expand on the molecular mechanisms behind autophagy and its regulation, and further compile recent literature associating autophagy disturbances in context of brain disorders, utilizing discoveries from varying models and species from rodents and cellular models to human post-mortem brain samples. To outline, the canonical pathways of autophagy, the effects of post-translational modifications on regulating each step of autophagy, and the future directions of proteomics in autophagy will be discussed. We further aim to suggest how advancing proteomics can help further unveil molecular mechanisms with regard to neurological disorders., (© 2024 International Society for Neurochemistry.)

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8 + T cells. METRNL was secreted by CD8 + T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8 + T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8 + TILs., Competing Interests: Declaration of interests C.M.J. is a consultant for Egret Therapeutics with equity interests in the company. He is an inventor on a patent filed by Johns Hopkins University for using immune checkpoint agonists to treat cerebrovascular disorders. He receives research support from Biohaven, InCephalo, and Grifols. Johns Hopkins University has filed a provisional patent on METRNL blockade for cancer treatment on which C.M.J., M.L., A.P., H.B., and J.C. are inventors. E.S. consults for Lepton Pharmaceuticals and Galaria and consults for and holds equity in Lyell Immunopharma. C.B. is a consultant for Depuy-Synthes and Bionaut Labs. C.L.M. has multiple patents in the field of CAR T cell therapy; is an equity holder, director, and consultant for Syncopation Life Sciences and Link Cell Therapies; and is an equity holder and consultant for Lyell Immunopharma, Mammoth Biosciences, Ensoma Therapeutics, and Apricity Bio. She also consults for Immatics, Glaxo Smith Kline, and Bristol Myers Squibb. H.B. is a consultant for Perosphere, AsclepiX Therapeutics, StemGen, Accelerating Combination Therapies, Catalio Nexus Fund II. LLC, LikeMinds, Inc. Acuity Bio Corp, InSightec, Galen Robotics, and Nurami Medical. M.L. has received research support from Arbor, BMS, Accuray, Tocagen, Biohaven, Kyrin-Kyowa, and Biohaven; has been a consultant to Tocagen, VBI, InCephalo Therapeutics, Pyramid Bio, Merck, BMS, Insightec, Biohaven, Sanianoia, Hemispherian, Black Diamond Therapeutics, and Novocure; is a shareholder of Egret Therapeutics; and has patents for focused radiation + checkpoint inhibitors, local chemotherapy + checkpoint inhibitors, and checkpoint agonists for neuro-inflammation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Fecal microbial transplantation (FMT) offers promise for treating ulcerative colitis (UC), though the mechanisms underlying treatment failure are unknown. This study harnessed longitudinally collected colonic biopsies (n = 38) and fecal samples (n = 179) from 19 adults with mild-to-moderate UC undergoing serial FMT in which antimicrobial pre-treatment and delivery mode (capsules versus enema) were assessed for clinical response (≥ 3 points decrease from the pre-treatment Mayo score). Colonic biopsies underwent dual RNA-Seq; fecal samples underwent parallel 16S rRNA and shotgun metagenomic sequencing as well as untargeted metabolomic analyses. Pre-FMT, the colonic mucosa of non-responsive (NR) patients harbored an increased burden of bacteria, including Bacteroides, that expressed more antimicrobial resistance genes compared to responsive (R) patients. NR patients also exhibited muted mucosal expression of innate immune antimicrobial response genes. Post-FMT, NR and R fecal microbiomes and metabolomes exhibited significant divergence. NR metabolomes had elevated concentrations of immunostimulatory compounds including sphingomyelins, lysophospholipids and taurine. NR fecal microbiomes were enriched for Bacteroides fragilis and Bacteroides salyersiae strains that encoded genes capable of taurine production. These findings suggest that both effective mucosal microbial clearance and reintroduction of bacteria that reshape luminal metabolism associate with FMT success and that persistent mucosal and fecal colonization by antimicrobial-resistant Bacteroides species may contribute to FMT failure., (© 2024. The Author(s).)

Background: Cross-sectional studies show associations between loneliness, social isolation and physical inactivity. Cohort studies are shedding light on these relationships and further longitudinal investigations are needed., Purpose: This study aimed to assess the longitudinal and bidirectional associations between loneliness, social isolation, and physical inactivity., Methods: Data were drawn from five annual waves of the Household and Labour Dynamics of Australia Survey (2015-2019), providing a sample of 17,303 persons (mean age = 46.3 years [SD = 18.0], 49.4% female). Relationships between loneliness, social isolation, and physical inactivity were examined using cross-lagged panel modeling, with estimation of simultaneous cross-lagged effects across each wave. Models adjusted for sociodemographic factors, chronic disease status, psychological distress, and mutually for social isolation or loneliness. Moderation of associations by sex was explored., Results: There were modest lagged effects of physical inactivity on loneliness across the survey waves (odds ratio 1.16 [95% confidence interval 1.04-1.29] to 1.20 [1.07, 1.33]). A lagged effect of physical inactivity upon social isolation was only present across three of the waves (odds ratio 1.20 [1.02-1.41] to 1.23 [1.05-1.42]). While loneliness and social isolation showed lagged effects upon physical inactivity, these did not persist with adjustment for psychological distress., Conclusions: Longitudinal analysis found that physical inactivity consistently predicted loneliness, but not social isolation. After adjustment for confounding, loneliness and social isolation were not predictive of physical inactivity. While the strength of the associations was modest, further investigation is warranted of the type and dose of physical activity that is most beneficial for reducing loneliness., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

Quantitative characterization of lung structures by morphometrical or stereological analysis of histological sections is a powerful means of elucidating pulmonary structure-function relations. The overwhelming majority of studies, however, fix lungs for histology at pressures outside the physiological/pathophysiological respiratory volume range. Thus, valuable information is being lost. In this perspective article, we argue that investigators performing pulmonary histological studies should consider whether the aims of their studies would benefit from fixation at functional transpulmonary pressures, particularly those of end-inspiration and end-expiration. We survey the pressures at which lungs are typically fixed in preclinical structure-function studies, provide examples of conditions that would benefit from histological evaluation at functional lung volumes, summarize available fixation methods, discuss alternative imaging modalities, and discuss challenges to implementing the suggested approach and means of addressing those challenges. We aim to persuade investigators that modifying or complementing the traditional histological approach by fixing lungs at minimal and maximal functional volumes could enable new understanding of pulmonary structure-function relations.

Physical activity (PA) is important for prevention of falls and chronic disease in older adults. We aimed to examine the interrelated influences upon PA in culturally diverse older adults who completed a short-term exercise program, to inform maintenance strategies, using a mixed-methods design. Eighty-two past participants from the " Stepping On " © program were surveyed examining ongoing participation, social and cognitive determinants of PA, mental and physical functioning, and fear of falls. Semi-structured interviews were undertaken with 34 respondents regarding enablers and barriers, cultural factors, and preferences for PA. Data were collected in English, Chinese, Arabic, Punjabi, or Hindi. Cultural factors minimally affected PA participation. There was low perceived availability of PA opportunities. Health difficulties not only discouraged but also motivated participation. Social connection was a facilitator and could be used to support maintenance. Older adults may benefit from assistance in accessing PA opportunities and clinical guidance about the benefits of ongoing PA., 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.

Mechanical ventilation can cause ventilation-induced lung injury (VILI). The concept of stress concentrations suggests that surfactant dysfunction-induced microatelectases might impose injurious stresses on adjacent, open alveoli and function as germinal centers for injury propagation. The aim of the present study was to quantify the histopathological pattern of VILI progression and to test the hypothesis that injury progresses at the interface between microatelectases and ventilated lung parenchyma during low-positive end-expiratory pressure (PEEP) ventilation. Bleomycin was used to induce lung injury with microatelectases in rats. Lungs were then mechanically ventilated for up to 6 h at PEEP = 1 cmH 2 O and compared with bleomycin-treated group ventilated protectively with PEEP = 5 cmH 2 O to minimize microatelectases. Lung mechanics were measured during ventilation. Afterward, lungs were fixed at end-inspiration or end-expiration for design-based stereology. Before VILI, bleomycin challenge reduced the number of open alveoli [N(alvair,par)] by 29%. No differences between end-inspiration and end-expiration were observed. Collapsed alveoli clustered in areas with a radius of up to 56 µm. After PEEP = 5 cmH 2 O ventilation for 6 h, N(alvair,par) remained stable while PEEP = 1 cmH 2 O ventilation led to an additional loss of aerated alveoli by 26%, mainly due to collapse, with a small fraction partly edema filled. Alveolar loss strongly correlated to worsening of tissue elastance, quasistatic compliance, and inspiratory capacity. The radius of areas of collapsed alveoli increased to 94 µm, suggesting growth of the microatelectases. These data provide evidence that alveoli become unstable in neighborhood of microatelectases, which most likely occurs due to stress concentration-induced local vascular leak and surfactant dysfunction. NEW & NOTEWORTHY Low-volume mechanical ventilation in the presence of high surface tension-induced microatelectases leads to the degradation of lung mechanical function via the progressive loss of alveoli. Microatelectases grow at the interfaces of collapsed and open alveoli. Here, stress concentrations might cause injury and alveolar instability. Accumulation of small amounts of alveolar edema can be found in a fraction of partly collapsed alveoli but, in this model, alveolar flooding is not a major driver for degradation of lung mechanics.

Wheat germ (WG), a by-product of flour milling, is rich in bioactive substances that may help improve health complications associated with increased adiposity. This study investigated the effects of WG on gut health, metabolic, and inflammatory markers in adults classified as overweight. We hypothesized that WG, because of its many bioactive components, would improve gut health and metabolic, and inflammatory markers in overweight adults. Forty adults (18-45 years old) and with a body mass index between 25 and 30 kg/m 2 participated in this single-blinded randomized controlled pilot study. Participants consumed the study supplements containing 30 g of either cornmeal (control, CL) or WG daily for 4 weeks. Primary outcome variables were gut health markers including gut microbiota, gut integrity markers, and fecal short-chain fatty acids, whereas secondary outcome variables included metabolic and inflammatory parameters assessed at baseline and at the end of supplementation. Thirty-nine participants (n = 19 and 20 for CL and WG group, respectively) completed the study. The genus Faecalibacterium was significantly higher in the WG group compared to CL post-supplementation but no significant changes in other gut health markers, short-chain fatty acids, inflammatory markers, and lipid profiles were observed. Compared with baseline, WG improved markers of glucose homeostasis including insulin (P = .02), homeostatic model assessment of insulin resistance (P = .03), glycated hemoglobin (P = .07), and the pro-inflammatory adipokine, resistin (P = .04). However, these parameters after intervention were not different with control. Our findings suggest that WG supplementation have modest effects on gut health but may provide an economical option for individuals to improve glycemic control., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this review, we discuss the cutting-edge developments in mass spectrometry proteomics and metabolomics that have brought improvements for the identification of new disease-based biomarkers. A special focus is placed on psychiatric disorders, for example, schizophrenia, because they are considered to be not a single disease entity but rather a spectrum of disorders with many overlapping symptoms. This review includes descriptions of various types of commonly used mass spectrometry platforms for biomarker research, as well as complementary techniques to maximize data coverage, reduce sample heterogeneity, and work around potentially confounding factors. Finally, we summarize the different statistical methods that can be used for improving data quality to aid in reliability and interpretation of proteomics findings, as well as to enhance their translatability into clinical use and generalizability to new data sets.

Background: Digital mental health services are increasingly being provided by employers as health benefit programs that can improve access to and remove barriers to mental health care. Stratified care models, in particular, offer personalized care recommendations that can offer clinically effective interventions while conserving resources. Nonetheless, clinical evaluation is needed to understand their benefits for mental health and their use in a real-world setting., Objective: This study aimed to examine the changes in clinical outcomes (ie, depressive and anxiety symptoms and well-being) and to evaluate the use of stratified blended care among members of an employer-sponsored digital mental health benefit., Methods: In a large prospective observational study, we examined the changes in depressive symptoms (9-item Patient Health Questionnaire), anxiety symptoms (7-item Generalized Anxiety Disorder scale), and well-being (5-item World Health Organization Well-Being Index) for 3 months in 509 participants (mean age 33.9, SD 8.7 years; women: n=312, 61.3%; men: n=175, 34.4%; nonbinary: n=22, 4.3%) who were newly enrolled and engaged in care with an employer-sponsored digital mental health platform (Modern Health Inc). We also investigated the extent to which participants followed the recommendations provided to them through a stratified blended care model., Results: Participants with elevated baseline symptoms of depression and anxiety exhibited significant symptom improvements, with a 37% score improvement in depression and a 29% score improvement in anxiety (P values <.001). Participants with baseline scores indicative of poorer well-being also improved over the study period (90% score improvement; P=.002). Furthermore, over half exhibited clinical improvement or recovery for depressive symptoms (n=122, 65.2%), anxiety symptoms (n=127, 59.1%), and low well-being (n=82, 64.6%). Among participants with mild or no baseline symptoms, we found high rates of maintenance for low depressive (n=297, 92.2%) and anxiety (n=255, 86.7%) symptoms and high well-being (n=344, 90.1%). In total, two-thirds of the participants (n=343, 67.4%) used their recommended care, 16.9% (n=86) intensified their care beyond their initial recommendation, and 15.7% (n=80) of participants underused care by not engaging with the highest level of care recommended to them., Conclusions: Participants with elevated baseline depressive or anxiety symptoms improved their mental health significantly from baseline to follow-up, and most participants without symptoms or with mild symptoms at baseline maintained their mental health over time. In addition, engagement patterns indicate that the stratified blended care model was efficient in matching individuals with the most effective and least costly care while also allowing them to self-determine their care and use combinations of services that best fit their needs. Overall, the results of this study support the clinical effectiveness of the platform for improving and preserving mental health and support the utility and effectiveness of stratified blended care models to improve access to and use of digitally delivered mental health services., (©Lydia G Roos, Sara J Sagui-Henson, Cynthia Castro Sweet, Camille E Welcome Chamberlain, Brooke J Smith. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 24.06.2024.)

Refined management of mechanically ventilation is an obvious target for improving patient outcomes, but is impeded by the nature of data for study and hypothesis generation. The connections between clinical outcomes and temporal development of iatrogenic injuries current lung-protective ventilator settings remain poorly understood. Analysis of lung-ventilator system (LVS) evolution at relevant timescales is frustrated by data volume and multiple sources of heterogeneity. This work motivates, presents, and validates a computational pipeline for resolving LVS systems into the joint evolution of data-conditioned model parameters and ventilator information. Applied to individuals, the workflow yields a concise low-dimensional representation of LVS behavior expressed in phenotypic breath waveforms suitable for analysis. The effectiveness of this approach is demonstrated through application to multi-day observational series of 35 patients. Individual patient analyses reveal multiple types of patient-oriented dynamics and breath behavior to expose the complexity of LVS evolution; less than 10% of phenotype changes related to ventilator settings changes. Dynamics are shown to including both stable and unstable phenotype transitions as well as both discrete and continuous changes unrelated to ventilator settings. At a cohort scale, 721 phenotypes constructed from individual data are condensed into a set of 16 groups that empirically organize around certain settings (positive end-expository pressure and ventilator mode) and structurally similar pressure-volume loop characterizations. Individual and cohort scale phenotypes, which may be refined by hypothesis-specific constructions, provide a common framework for ongoing temporal analysis and investigation of LVS dynamics., Competing Interests: Declarations of Interest None. The authors have no conflicts of interest to disclose.

Importance: Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be further improved, but the efficacy and safety of the combination need to be evaluated., Objective: To examine whether hospitalized smokers treated with varenicline and NRT lozenges achieve higher prolonged smoking abstinence rates compared with those treated with varenicline alone., Design, Setting, and Participants: A double-blind, placebo-controlled randomized clinical trial was conducted in adult medical or surgical inpatients of 5 Australian public hospitals with a history of smoking 10 cigarettes or more per day, interested in quitting, and available for 12-month follow-up between May 1, 2019, and May 1, 2021 (final 12-month data collection in May 2022). Data analysis was performed from June 1 to August 30, 2023., Interventions: A 12-week varenicline regimen was initiated during hospitalization at standard doses in all participants. Participants were randomized to additionally use NRT (2 mg) or placebo lozenges if there was an urge to smoke. Behavioral support (Quitline) was offered to all participants., Main Outcomes and Measures: The primary outcome was biochemically verified sustained abstinence at 6 months. Secondary outcomes included self-reported prolonged abstinence, 7-day point prevalence abstinence (3, 6, and 12 months), and medicine-related adverse events., Results: A total of 320 participants (mean [SD] age, 52.5 [12.1] years; 183 [57.2%] male) were randomized. The conduct of biochemical verification was affected by COVID-19 restrictions; consequently, the biochemically verified abstinence in the intervention vs control arms (18 [11.4%] vs 16 [10.1%]; odds ratio [OR], 1.14; 95% CI, 0.56-2.33) did not support the combination therapy. The secondary outcomes in the intervention vs control arms of 7-day point prevalence abstinence at 6 months (54 [34.2%] vs 37 [23.4%]; OR, 1.71; 95% CI, 1.04-2.80), prolonged abstinence at 12 months (47 [29.9%] vs 30 [19.1%]; OR, 1.77; 95% CI, 1.05-3.00), and 7-day point prevalence abstinence at 12-months (48 [30.6%] vs 31 [19.7%]; OR, 1.79; 95% CI, 1.07-2.99) significantly improved with the combination therapy. The self-reported 6-month prolonged abstinence (61 [38.6%] vs 47 [29.7%]; OR, 1.49; 95% CI, 0.93-2.39) favored the combination therapy but was not statistically significant. Medicine-related adverse events were similar in the 2 groups (102 [74.5%] in the intervention group vs 86 [68.3%] in the control group)., Conclusions and Relevance: In this randomized clinical trial of the combination of varenicline and NRT lozenges in hospitalized adult daily smokers, the combination treatment improved self-reported abstinence compared with varenicline alone, without compromising safety, but it did not improve biochemically validated abstinence., Trial Registration: anzctr.org.au Identifier: ACTRN12618001792213.

Despite the increasing importance of aldehyde oxidase (AO) in the drug metabolism of clinical candidates, ontogeny data for AO are limited. The objective of our study was to characterize the age-dependent AO content and activity in the human liver cytosolic fraction (HLC) and human hepatocytes (HH). HLC ( n = 121 donors) and HH ( n = 50 donors) were analyzed for (1) AO protein content by quantitative proteomics and (2) enzyme activity using carbazeran as a probe substrate. AO activity showed high technical variability and poor correlation with the content in HLC samples, whereas hepatocyte samples showed a strong correlation between the content and activity. Similarly, AO content and activity showed no significant age-dependent differences in HLC samples, whereas the average AO content and activity in hepatocytes increased significantly (∼20-40-fold) from the neonatal levels (0-28 days). Based on the hepatocyte data, the age at which 50% of the adult AO content is reached (age 50 ) was 3.15 years (0.32-13.97 years, 95% CI). Metabolite profiling of carbazeran revealed age-dependent metabolic switching and the role of non-AO mechanisms (glucuronidation and desmethylation) in carbazeran elimination. The content-activity correlation in hepatocytes improved significantly ( R 2 = 0.95; p < 0.0001) in samples showing <10% contribution of glucuronidation toward the overall metabolism, confirming that AO-mediated oxidation and glucuronidation are the key routes of carbazeran metabolism. Considering the confounding effect of glucuronidation on AO activity, AO content-based ontogeny data are a more direct reflection of developmental changes in protein expression. The comprehensive ontogeny data of AO in HH samples are more reliable than HLC data, which are important for developing robust physiologically based pharmacokinetic models for predicting AO-mediated metabolism in children.

The study aimed to evaluate the feasibility of using QR code-enabled medical bracelets for congenital heart disease (CHD) patients after hospital discharge to ensure quick communication of vital information to other medical personnel in emergency situations. A prospective study was conducted where QR code-enabled medical bracelets were given to families of postoperative pediatric cardiac patients. The QR code linked to a secure medical information sheet detailing the patient's cardiac history. Post-study surveys were completed by providers and families to assess their experiences with the bracelet. Of the 20 participants enrolled, 65% used the QR bracelet when seeking medical care. 55% found the bracelet useful, and 70% rated their experience as either "positive" or "very positive". Additionally, 80% recommended the bracelet for other patients undergoing cardiac procedures. The use of QR code bracelets for postoperative CHD patients has shown high levels of satisfaction from families and providers, potentially reducing medical errors and treatment delays., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Loneliness has increased since the COVID-19 pandemic and negatively impacts mental health. This study examined relationships between loneliness and mental health among adults using a digital mental health platform., Methods: A purposive sample of 919 participants (97% response rate) who were newly enrolled in the platform completed a survey on loneliness, depression, anxiety, well-being, stress, social support, and comorbidities at baseline and 3 months. Platform engagement was tracked during this period. We examined baseline differences between lonely and non-lonely participants; associations between loneliness, mental health symptoms, and comorbidities; and changes in loneliness and mental health through engagement in any form of care., Results: At baseline, 57.8% of the sample were categorized as lonely. Loneliness was associated with younger age, fewer years of education, and the presence of a comorbidity (p values < .05). Baseline loneliness was associated with greater depression, anxiety, and stress and lower well-being and social support (ps < .001). The percentage of lonely participants decreased at follow-up (57.6% to 52.9%, p = .03). Those who improved in loneliness improved in mental health symptoms, well-being, and social support (ps < .001). Lonely participants who engaged in any form of care reported a greater reduction in loneliness than those who did not engage (p = .04)., Conclusions: This study confirms previous findings of the high prevalence of loneliness among adults and risk factors for increased loneliness. Findings highlight the potential of digital platforms to reach lonely individuals and alleviate loneliness through remote mental health support., (© 2023. The Author(s).)

Background: Depression is a common mental health disorder that often starts during adolescence, with potentially important future consequences including 'Not in Education, Employment or Training' (NEET) status., Methods: We took a structured life course modeling approach to examine how depressive symptoms during adolescence might be associated with later NEET status, using a high-quality longitudinal data resource. We considered four plausible life course models: (1) an early adolescent sensitive period model where depressive symptoms in early adolescence are more associated with later NEET status relative to exposure at other stages; (2) a mid adolescent sensitive period model where depressive symptoms during the transition from compulsory education to adult life might be more deleterious regarding NEET status; (3) a late adolescent sensitive period model , meaning that depressive symptoms around the time when most adults have completed their education and started their careers are the most strongly associated with NEET status; and (4) an accumulation of risk model which highlights the importance of chronicity of symptoms., Results: Our analysis sample included participants with full information on NEET status ( N = 3951), and the results supported the accumulation of risk model , showing that the odds of NEET increase by 1.015 (95% CI 1.012-1.019) for an increase of 1 unit in depression at any age between 11 and 24 years., Conclusions: Given the adverse implications of NEET status, our results emphasize the importance of supporting mental health during adolescence and early adulthood, as well as considering specific needs of young people with re-occurring depressed mood.

Abstract: Rituximab (RTX) and other monoclonal antibodies (mAbs) that bind directly to malignant cells are of great clinical value but are not effective for all patients. A major mechanism of action of RTX is antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells. Prior in vitro studies in our laboratory demonstrated that T cells contribute to maintaining the viability and cytotoxic potential of NK cells activated by anti-CD20-coated target B cells. Here, we conducted studies using a novel mouse model and clinical correlative analysis to assess whether T-cell help contribute to RTX-mediated NK-cell ADCC in the tumor microenvironment (TME) in vivo. A humanized mouse model was developed using Raji lymphoma cells and normal donor peripheral blood mononuclear cells that allows for control of T-cell numbers in the lymphoma TME. In this model, NK-cell viability and CD16 and CD25 expression dropped after RTX in the absence of T cells but increased in the presence of T cells. RTX therapy was more effective when T cells were present and was ineffective when NK cells were depleted. In patients with indolent lymphoma, fine needle aspirates were obtained before and ∼1 week after treatment with a RTX-containing regimen. There was a strong correlation between CD4+ T cells as well as total T cells in the pretherapy TME and an increase in NK-cell CD16 and CD25 expression after RTX. We conclude that T-cell help in the TME enhances RTX-mediated NK-cell viability and ADCC., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

BAK and BAX execute intrinsic apoptosis by permeabilising the mitochondrial outer membrane. Their activity is regulated through interactions with pro-survival BCL-2 family proteins and with non-BCL-2 proteins including the mitochondrial channel protein VDAC2. VDAC2 is important for bringing both BAK and BAX to mitochondria where they execute their apoptotic function. Despite this important function in apoptosis, while interactions with pro-survival family members are well characterised and have culminated in the development of drugs that target these interfaces to induce cancer cell apoptosis, the interaction between BAK and VDAC2 remains largely undefined. Deep scanning mutagenesis coupled with cysteine linkage identified key residues in the interaction between BAK and VDAC2. Obstructive labelling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupted this interaction. Conversely, mutating specific residues in a cytosol-exposed region of VDAC2 stabilised the interaction with BAK and inhibited BAK apoptotic activity. Thus, this VDAC2-BAK interaction site can potentially be targeted to either inhibit BAK-mediated apoptosis in scenarios where excessive apoptosis contributes to disease or to promote BAK-mediated apoptosis for cancer therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yuan 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.)

Background: Ventilator dyssynchrony (VD) can worsen lung injury and is challenging to detect and quantify due to the complex variability in the dyssynchronous breaths. While machine learning (ML) approaches are useful for automating VD detection from the ventilator waveform data, scalable severity quantification and its association with pathogenesis and ventilator mechanics remain challenging., Objective: We develop a systematic framework to quantify pathophysiological features observed in ventilator waveform signals such that they can be used to create feature-based severity stratification of VD breaths., Methods: A mathematical model was developed to represent the pressure and volume waveforms of individual breaths in a feature-based parametric form. Model estimates of respiratory effort strength were used to assess the severity of flow-limited (FL)-VD breaths compared to normal breaths. A total of 93,007 breath waveforms from 13 patients were analyzed., Results: A novel model-defined continuous severity marker was developed and used to estimate breath phenotypes of FL-VD breaths. The phenotypes had a predictive accuracy of over 97% with respect to the previously developed ML-VD identification algorithm. To understand the incidence of FL-VD breaths and their association with the patient state, these phenotypes were further successfully correlated with ventilator-measured parameters and electronic health records., Conclusion: This work provides a computational pipeline to identify and quantify the severity of FL-VD breaths and paves the way for a large-scale study of VD causes and effects. This approach has direct application to clinical practice and in meaningful knowledge extraction from the ventilator waveform data., Competing Interests: Declaration of competing interest None Declared., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Acute respiratory distress syndrome (ARDS) presents a significant clinical challenge, with ventilator-induced lung injury (VILI) being a critical complication arising from life-saving mechanical ventilation. Understanding the spatial and temporal dynamics of VILI can inform therapeutic strategies to mitigate lung damage and improve outcomes., Methods: Histological sections from initially healthy mice and pulmonary lavage-injured mice subjected to a second hit of VILI were segmented with Ilastik to define regions of lung injury. A scale-free network approach was applied to assess the correlation between injury regions, with regions of injury represented as 'nodes' in the network and 'edges' quantifying the degree of correlation between nodes. A simulated time series analysis was conducted to emulate the temporal sequence of injury events., Results: Automated segmentation identified different lung regions in good agreement with manual scoring, achieving a sensitivity of 78% and a specificity of 85% across 'injury' pixels. Overall accuracy across 'injury', 'air', and 'other' pixels was 81%. The size of injured regions followed a power-law distribution, suggesting a 'rich-get-richer' phenomenon in the distribution of lung injury. Network analysis revealed a scale-free distribution of injury correlations, highlighting hubs of injury that could serve as focal points for therapeutic intervention. Simulated time series analysis further supported the concept of secondary injury events following an initial insult, with patterns resembling those observed in seismological studies of aftershocks., Conclusion: The size distribution of injured regions underscores the spatially heterogeneous nature of acute and ventilator-induced lung injury. The application of network theory demonstrates the emergence of injury 'hubs' that are consistent with a 'rich-get-richer' dynamic. Simulated time series analysis demonstrates that the progression of injury events in the lung could follow spatiotemporal patterns similar to the progression of aftershocks in seismology, providing new insights into the mechanisms of injury distribution and propagation. Both phenomena suggest a potential for interventions targeting these injury 'hubs' to reduce the impact of VILI in ARDS management., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gottman and Smith.)

The 2022 mpox virus (MPXV) outbreak was sustained by human-to-human transmission; however, it is currently unclear which factors lead to sustained transmission of MPXV. Here we present Mastomys natalensis as a model for MPXV transmission after intraperitoneal, rectal, vaginal, aerosol and transdermal inoculation with an early 2022 human outbreak isolate (Clade IIb). Virus shedding and tissue replication were route dependent and occurred in the presence of self-resolving localized skin, lung, reproductive tract or rectal lesions. Mucosal inoculation via the rectal, vaginal and aerosol routes led to increased shedding, replication and a pro-inflammatory T cell profile compared with skin inoculation. Contact transmission was higher from rectally inoculated animals. This suggests that transmission might be sustained by increased susceptibility of the anal and genital mucosae for infection and subsequent virus release., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Social decisions are influenced by a person's social preferences. High psychopathy is defined by antisocial behaviour, but the relationship between psychopathy and social preferences remains unclear. In this study, we used a battery of economic games to study social decision-making and social preferences in relation to psychopathy in a sample of 35 male prison inmates, who were arrested for sexual and severe violent offenses (mean age = 39 years). We found no evidence for a relationship between social preferences (measured with the Dictator and Ultimatum Games, Social Value Orientation, and one-shot 2 × 2 games) and psychopathy (measured by the overall Hare Psychopathy Checklist-Revised score and both factors). These results are surprising but also difficult to interpret due to the small sample size. Our results contribute to the ongoing debate about psychopathy and social decision-making by providing crucial data that can be combined with future datasets to reach large sample sizes that can provide a more nuanced understanding about the relationship between psychopathy and social preferences., (© 2024. The Author(s).)

Pre-injured lungs are prone to injury progression in response to mechanical ventilation. Heterogeneous ventilation due to (micro)atelectases imparts injurious strains on open alveoli (known as volutrauma). Hence, recruitment of (micro)atelectases by positive end-expiratory pressure (PEEP) is necessary to interrupt this vicious circle of injury but needs to be balanced against acinar overdistension. In this study, the lung-protective potential of alveolar recruitment was investigated and balanced against overdistension in pre-injured lungs. Mice, treated with empty vector (AdCl) or adenoviral active TGF-β1 (AdTGF-β1) were subjected to lung mechanical measurements during descending PEEP ventilation from 12 to 0 cmH 2 O. At each PEEP level, recruitability tests consisting of two recruitment maneuvers followed by repetitive forced oscillation perturbations to determine tissue elastance (H) and damping (G) were performed. Finally, lungs were fixed by vascular perfusion at end-expiratory airway opening pressures (Pao) of 20, 10, 5 and 2 cmH 2 O after a recruitment maneuver, and processed for design-based stereology to quantify derecruitment and distension. H and G were significantly elevated in AdTGF-β1 compared to AdCl across PEEP levels. H was minimized at PEEP = 5-8 cmH 2 O and increased at lower and higher PEEP in both groups. These findings correlated with increasing septal wall folding (= derecruitment) and reduced density of alveolar number and surface area (= distension), respectively. In AdTGF-β1 exposed mice, 27% of alveoli remained derecruited at Pao = 20 cmH 2 O. A further decrease in Pao down to 2 cmH 2 O showed derecruitment of an additional 1.1 million alveoli (48%), which was linked with an increase in alveolar size heterogeneity at Pao = 2-5 cmH 2 O. In AdCl, decreased Pao resulted in septal folding with virtually no alveolar collapse. In essence, in healthy mice alveoli do not derecruit at low PEEP ventilation. The potential of alveolar recruitability in AdTGF-β1 exposed mice is high. H is optimized at PEEP 5-8 cmH 2 O. Lower PEEP folds and larger PEEP stretches septa which results in higher H and is more pronounced in AdTGF-β1 than in AdCl. The increased alveolar size heterogeneity at Pao = 5 cmH 2 O argues for the use of PEEP = 8 cmH 2 O for lung protective mechanical ventilation in this animal model., (© 2024. Crown.)