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Introduction: In contrast to standard-of-care treatment of newly diagnosed glioblastoma, there is limited consensus on therapy upon disease progression. The role of resection for recurrent glioblastoma remains unclear. This study aimed to identify factors for overall survival (OS) and post-progression survival (PPS) as well as to validate an existing prediction model., Methods: This was a multi-centre retrospective study that reviewed consecutive adult patients from 2006 to 2019 that received a repeat resection for recurrent glioblastoma. The primary endpoint was PPS defined as from the date of second surgery until death., Results: 1032 glioblastoma patients were identified and 190 (18%) underwent resection for recurrence. Patients that had second surgery were more likely to be younger (<70 years) (adjusted OR: 0.3; 95% CI: 0.1-0.6), to have non-eloquent region tumours (aOR: 1.7; 95% CI: 1.1-2.6) and received temozolomide chemoradiotherapy (aOR: 0.2; 95% CI: 0.1-0.4). Resection for recurrent tumour was an independent predictor for OS (aOR: 1.5; 95% CI: 1.3-1.7) (mOS: 16.9 months versus 9.8 months). For patients that previously received temozolomide chemoradiotherapy and subsequent repeat resection (137, 13%), the median PPS was 9.0 months (IQR: 5.0-17.5). Independent PPS predictors for this group were a recurrent tumour volume of >50cc (aOR: 0.6; 95% CI: 0.4-0.9), local recurrence (aOR: 1.7; 95% CI: 1.1-3.3) and 5-ALA fluorescence-guided resection during second surgery (aOR: 1.7; 95% CI: 1.1-2.8). A National Institutes of Health Recurrent Glioblastoma Multiforme Scale score of 0 conferred an mPPS of 10.0 months, a score of 1-2, 9.0 months and a score of 3, 4.0 months (log-rank test, p -value < 0.05)., Conclusion: Surgery for recurrent glioblastoma can be beneficial in selected patients and carries an acceptable morbidity rate. The pattern of recurrence influenced PPS and the NIH Recurrent GBM Scale was a reliable prognostication tool.

In vitro models based on permanent fish liver cell lines have proven to be versatile tools for examining chemical biotransformation and toxicity. However, their in vivo relevance remains uncertain due to their potentially de-differentiated phenotype. Here, we investigate whether a 3D cell culture environment can restore hepatocyte-like properties of the Rainbow trout liver cell line RTL-W1. Utilizing ultralow attachment (ULA) microwell plates, we achieved controlled sizing and extended culture (3 weeks) of spheroidal aggregate cultures (spheroids). RTL-W1 cells within the spheroids remained viable and metabolically active, as confirmed by the CellTiter-Glo 3D assay. Transmission electron microscopy revealed that spheroids exhibit tissue-like arrangements, such as interdigitations, cell-cell junctions, and endo- or exocytic activity at the cell-cell interface. They also displayed ultrastructural characteristics typical of metabolically active cells/hepatocytes, including abundant endoplasmic reticulum (ER), Golgi apparatus, and mitochondria. RT-qPCR analysis showed upregulation of genes involved in xenobiotic and endogenous (lipid) metabolism in 3D cultures over time. Notably, for several genes, especially cyp1a, expression levels were significantly higher in spheroids than in monolayers cultured for the same duration. This was corroborated at the enzyme level by increased Cyp1a-dependent catalytic activity (EROD). Interestingly, increased Cyp1a expression did not lead to heightened susceptibility to benzo[a]pyrene toxicity, which requires bioactivation. However, RTL-W1 3D and 2D cell cultures exhibited differential susceptibility to toxicity from other model chemicals, such as the surfactant SDS and the metal copper (Cu). These findings support the hypothesis that RTL-W1 cells can re-differentiate to a hepatocyte-like phenotype when cultured in a 3D configuration and may exhibit distinct biological responses upon exposure to xenobiotics. Overall, this study advances our understanding of the potential of cell line-derived 3D in vitro models for research and providing more physiologically relevant data for regulatory contexts., 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 Inc. All rights reserved.)

Background: Prophylactic total gastrectomy (PTG) is performed in carriers of CDH1 pathogenic and likely pathogenic (P/LP) variants and is becoming more frequent with broader use of germline genetic testing. There is an unmet need to standardize care and enhance outcomes among patients undergoing surgery for the prevention of gastric cancer., Methods: This was a retrospective analysis of 150 individuals with germline CDH1 P/LP variants who underwent PTG as part of a prospective natural history study from October 2017 to May 2023. All individuals received multidisciplinary, protocolized care before and after total gastrectomy., Results: A total of 150 asymptomatic patients with germline CDH1 P/LP variants underwent PTG with the aid of a multidisciplinary enhanced recovery after surgery (ERAS) pathway. This study demonstrated that acute major morbidity (Clavien-Dindo grade of ≥3) was low (17/150 [11.3%]) and that the most common complication was anastomotic leak (11/150 [7.3%]) in the setting of a comprehensive preoperative and postoperative care pathway. Nearly all gastrectomy specimens (132/150 [88.0%]) harbored occult signet ring cell lesions on final pathology. There were no gastric cancer recurrences or gastric cancer-related deaths during the study period, with a median overall follow-up of 36 months (IQR, 24-48) from gastrectomy., Conclusion: PTG can be performed with low surgical morbidity in a high-volume center. The delivery of patient-centered care by a multidisciplinary team and the application of an ERAS pathway may improve short-term outcomes. However, interventions that can reduce chronic morbidity associated with total gastrectomy warrant further study., (Published by Elsevier Inc.)

Background: Substance use during pregnancy is underreported globally and there is limited data on its prevalence and the availability of supportive services. This study determined population perinatal substance use in British Columbia (BC) by region and examined the availability of clinical and community-based programs., Methods: Using linked provincial health administrative data, we conducted a population-based retrospective cohort study including all BC residents accessing care for substance use (alcohol, opioids, stimulants, sedatives, and cannabis) within 12 months of first perinatal care record to delivery during 2016-2021. We also conducted an environmental scan to identify all programs offering perinatal care and substance use treatment/support in BC as of December 2022 and described program components by region., Results: The population included 12,439 people with perinatal substance use with 13,814 linked livebirths during the study period. The incidence rate of perinatal substance use was nearly eight times higher in rural/remote Northern BC compared to the metropolitan Vancouver Coastal region (1044.2 vs. 131.3 per 100,000 population, respectively). We identified 29 related services (19 wrap-around programs, 8 supportive housing, and only 2 acute care programs). Residents outside of Metro Vancouver accounted for 60 % (N=1745) of people with perinatal substance use; however, these regions represented only 35 % of BC's specialized acute care and supportive housing beds (N=140)., Conclusions: Expanding supports for perinatal substance use - particularly acute care and supportive housing within more rural/remote regions in BC - will be critical to address geographic inequities in access to perinatal care and improve health outcomes for pregnant people who use substances and their infants., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Discordance in perception of disease activity between adolescent patients with lupus and their providers may influence disease outcomes. We found that patients endorsed higher perceptions of disease activity than providers. Discordance was present at all levels of disease activity, particularly in patients with high activity, nephritis, and/or taking corticosteroids or mycophenolate mofetil., Competing Interests: Declaration of Competing Interest K.K.R., K.R., and S.B. are the recipients of grant funding (#2019-10021) from the National Institute on Disability, Independent Living and Rehabilitation Research (NIDILRR). T.B.R. is supported by the Childhood Arthritis and Rheumatology Research Alliance/Arthritis Foundation Career Development Award and the National Institute of Arthritis and Musculoskeletal Skin Diseases (NIAMS) (K23AR080803). The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The Philippines experienced one of the longest restriction periods during the COVID-19 pandemic. This study aimed to provide a developmental profile of 18-25 month-old children and identify factors associated with their development during their early years being born and raised during the pandemic., Methods: The study population was recruited through convenience sampling among families living in proximity to the daycare centers in Cainta, Rizal, Philippines. 116 children qualified to participate and underwent developmental screening using the Early Childhood Care and Development (ECCD) Checklist and their parents were interviewed related to demographic and social factors., Results: The mean score of the children's Overall Development is 106.47 ( SD = 13.43) indicating that children's skills were within the expected range of 80-119. Girls had significantly higher mean scores compared to boys [ M Girl = 111.23, SD Girl = 9.95 vs. M Boy = 101.18, SD Boy = 14.83 t (114) = -4.32 p < 0.001]. Mean scores were highest among children whose mothers completed a high school education ( M High School = 107.76, SD HighSchool = 12.47) compared to those who have some or have completed an elementary education ( M SomeElem = 72.50, SD SomeElem = 6.36 and M Elem = 103.58, SD Elem = 13.86 respectively) [ F (2, 113) = 8.18, p < 0.001]. Unadjusted linear regression shows a modest increase in mean scores as the number of household members increased [ ꞵ = 0.86, (CI: 0.02, 1.70), t -score (1, 113) = 2.03, p = 0.045]., Conclusion: The developmental skills of 18-25 month-old children born and raised during the COVID-19 pandemic in an urban municipality in the Philippines are within average scores. Both hindering and protective demographic factors were identified as associated with the children's developmental evaluation scores. It is important to acknowledge these factors and continue monitoring the children's development and address needs among children who may need further support., 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 Dy, Edillon, Malonzo, Garcia, Dy, Espiritu, Aquino, So, Capulong, Dagal and Sumpaico Tanchanco.)

Vaccine-induced immunoglobulin G (IgG) profiles can vary with respect to the predominant subclasses that characterize the response. Among IgG subclasses, IgG4 is reported to have anti-inflammatory properties, but can also exhibit reduced capacity for virus neutralization and activation of Fc-dependent effector functions. Here, we review evidence that IgG4 subclass responses can be disproportionately increased in response to some types of vaccines targeting an array of diseases, including pertussis, HIV, malaria, and COVID-19. The basis for enhanced IgG4 induction by vaccines is poorly understood but may be associated with platform- or dose regimen-specific differences in antigen exposure and/or cytokine stimulation. The clinical implications of vaccine-induced IgG4 responses remain uncertain, though collective evidence suggests that proportional increases in IgG4 might reduce vaccine antigen-specific immunity. Additional work is needed to determine underlying mechanisms and to elucidate what role IgG4 may play in modifications of vaccine-induced immunity to disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AMM, LMD, HB, MV, MZ, SCC, JSP, and RK are Novavax, Inc. employees and as such receive a salary and may hold Novavax, Inc. stock. LF is a consultant to Novavax, Inc. AWC has received grant funding from NHMRC, MRFF, and NIH., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The frequency of coronary artery disease (CAD) has alarmingly increased in India accounting for the majority of all fatalities. The primary risk factor for CAD, acute myocardial infarction, and stroke is dyslipidemia. CAD risk can be ascertained by the lipid profile as well as atherogenic risk indices. Due to the current scenario of increased CAD prevalence and the established role of dyslipidemia as a risk factor for CAD, this study aimed at identifying the prevalent lipid abnormalities in a tertiary care hospital in Telangana and studying the predictive value of atherogenic indices for assessing CAD risk., Methods: This is a retrospective cross-sectional study. Data pertaining to the subjects from January 2021 to December 2021 was retrieved from the hospital records., Results: Serum triglycerides (TG) were in the higher range for 47 % (n= 235) of total subjects and isolated Low-density lipoprotein (LDL) was higher in 12.6% (n = 63). The overall burden of dyslipidemia was 72.20% (n=361) with 57.6 % (n=208) in males and 42.4% (n=153) in females). The most common dyslipidemia found was Familial Combined Hyperlipidemia in 42.8% (n=214) of individuals. The second most common pattern of dyslipidemia was Primary Familial Hypercholesterolemia which was observed in 25% (n=125) of subjects. Dysbetalipoproteinemia was seen in 24.2% (n=121) of the study subjects. ROC analysis found the Atherogenic Coefficient (AC) to be the most sensitive and specific cardiovascular risk index. 57.8% of the subjects had AC >2.44 and were at the highest risk for developing CAD., Conclusions: The overall burden of dyslipidemia was 72.2%. AC was found to be the most sensitive and specific cardiovascular risk index by ROC curve analysis. Around 57.8% of the subjects had AC >2.44 and were at the highest risk for developing CAD. This study emphasizes the importance of atherogenic indices in the primary prevention and management of CAD, a growing non-communicable disease., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee of All India Institute of Medical Sciences, Bibinagar issued approval AIIMS/BBN/IEC/JAN/2024/398. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Jose et al.)

Idiopathic pulmonary fibrosis (IPF) is characterized by a progressive decline in lung function, worsening quality of life, and high mortality. However, the rate and pattern of progression of IPF are variable. Real-world studies, which include a broader population of patients than clinical trials and collect data over longer periods, have provided important information on the clinical course of IPF and further insights into the efficacy and safety of antifibrotic therapies. They also highlight the worsening of patients' quality of life as lung function is lost, the high frequency of hospitalizations, and the impact of acute exacerbations on mortality in patients with IPF. Data from patient registries and analyses of claims data suggest that antifibrotic therapy is more likely to be used in patients who have worse lung function and that its use is associated with an improvement in life expectancy. The safety profile of antifibrotic therapies in real-world populations is consistent with that observed in clinical trials. Further real-world studies are needed to improve understanding of the course and impact of IPF in specific groups of patients and how the care provided to these patients might be improved.

Background and Aim: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy provides glycemic benefits to individuals with type 2 diabetes (T2D). However, the effects of GLP-1 RA therapy in combination with FreeStyle Libre systems (FSL) are unknown. This study aimed to compare changes in hemoglobin A1c (HbA1c) between people acquiring GLP-1 with FSL (GLP-1+FSL) versus GLP-1 without FSL (GLP-1). Methods: This real-world study used Optum's de-identified Market Clarity Data, a linked electronic health records (EHR)-claims database, and included adults with T2D and HbA1c ≥8% who acquired their first GLP-1 RA medication between 2018 and 2022. GLP-1+FSL subjects acquired their first FSL within ±30 days of their first GLP-1 acquisition. Cohorts were matched 1:5 on baseline insulin therapy, age, sex, baseline HbA1c, and GLP-1 type. Paired changes in HbA1c were compared between unmatched and matched groups at 6 months. Results: The study included 24,724 adults in the unmatched cohort (GLP-1+FSL, n = 478; GLP-1, n = 24,246). The matched cohort included 478 GLP-1+FSL users and 2,390 GLP-1 users: mean age 53.5 ± 11.8 and 53.5 ± 11.3 years, HbA1c 10.25 ± 1.68% and 10.22 ± 1.69%, respectively. HbA1c reduction was greater in the GLP-1+FSL group compared with the GLP-1 group in the unmatched cohort (-2.43% vs. -1.73%, difference 0.70%, P < 0.001, respectively) and in the matched cohort (-2.43% vs. -2.06%, difference 0.37%, P < 0.001). GLP-1+FSL vs. GLP-1 treatment was associated with greater HbA1c reduction in the intensive insulin (-2.32% vs. -1.50%), nonintensive insulin (-2.50% vs. -1.74%), and noninsulin group (-2.46% vs. -1.78%), as well as in patients using semaglutide (-2.73% vs. -1.92%) and dulaglutide (-2.45% vs. -1.71%) GLP-1 RA, all P < 0.001. Conclusions: Adults with suboptimally controlled T2D, initiating GLP-1 RA with FreeStyle Libre, had greater improvement in HbA1c compared with those treated with GLP-1 RA only. These results suggest an additional glycemic benefit of FSL when used with a GLP-1 RA in T2D treatment.

Rationale: Observational studies report a significant protective effect of antifibrotics on mortality among patients with idiopathic pulmonary fibrosis (IPF). Many of these studies, however, were subject to immortal time bias because of the mishandling of delayed antifibrotic initiation. Objectives: To evaluate the antifibrotic effect on mortality among patients with IPF using appropriate statistical methods that avoid immortal time bias. Methods: Using a large administrative database, we identified 10,289 patients with IPF, of whom 2,300 used antifibrotics. Treating delayed antifibrotic initiation as a time-dependent variable, three statistical methods were used to control baseline characteristics and avoid immortal time bias. Stratified analysis was performed for patients who initiated antifibrotics early and those who initiated treatment late. For comparison, methods that mishandle immortal time bias were performed. A simulation study was conducted to demonstrate the performance of these models in a wide range of scenarios. Results: All three statistical methods yielded nonsignificant results for the antifibrotic effect on mortality, with the stratified analysis for patients with early antifibrotic initiation suggesting evidence for reduced mortality risk (for all patients, hazard ratio, 0.89; 95% confidence interval, 0.79-1.01; P  = 0.08; for patients who were 65 years or older, hazard ratio, 0.85; 95% confidence interval, 0.73-0.98; P  = 0.03). Methods that mishandle immortal time bias demonstrated significantly lower mortality risk for antifibrotic users. Bias of these methods was evident in the simulation study, where appropriate methods performed well with little to no bias. Conclusions: Findings in this study did not confirm an association between antifibrotics and mortality, with a stratified analysis showing support for a potential treatment effect with early treatment initiation.

Background: Rheumatoid arthritis (RA) affects roughly 1% of the population and commonly involves the lungs. Of lung involvement in RA, interstitial lung disease (ILD) is well known; however, airways disease in RA is relatively understudied., Research Question: What are the baseline airways abnormalities in a prospective cohort of patients with RA based on pulmonary function testing (PFT) results, high-resolution CT (HRCT) scans, and computational imaging analysis and are there associations between these abnormalities and respiratory symptoms?, Study Design and Methods: In this single-center study, 188 patients with RA without a clinical diagnosis of ILD underwent HRCT imaging and PFT. Radiologists assessed HRCT scans for airway abnormalities. Computational imaging via VIDA Vision software and in-house quantitative CT imaging analysis was applied to 147 HRCT scans to quantify airway abnormalities., Results: Airways obstruction (FEV 1 to FVC ratio < 0.7) was present in 20.7% of patients and was associated with older age, male sex, and higher smoking rate. Radiologists identified airway abnormalities in 61% of patients: 55% had bronchial wall thickening, 12% had bronchiectasis, and 5% had mosaic attenuation. These airways findings were associated with older age; male sex; lower FEV 1 , FVC, and FEV 1 to FVC ratio; and higher rates of rheumatoid factor positivity. Prespecified quantitative CT scan metrics (wall thickening percentage and emphysema percentage) correlated with obstruction in PFT results and more severe respiratory symptoms, including shortness of breath and cough., Interpretation: High rates of airways abnormalities were found in this prospective RA cohort based on 3 methods of detection. Significant associations were identified between quantitative CT scan measures and respiratory symptoms. Airways disease may be an underrecognized extra-articular manifestation of RA and quantitative CT imaging may be a sensitive method to detect the clinical impact on respiratory symptoms., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: M. K. D. and K. D. D. report investigator-initiated grants from Pfizer. M. C. C. accepts consulting fees from Genentech, Teva, Sanofi-Aventis, Merck, Novartis, Arrowhead Pharmaceuticals, Allakos, Amgen, OM Pharma, Pfizer, Pioneering Medicines, and GSK and honoraria from Amgen, AstraZeneca, Genentech, Regeneron, Sanofi-Aventis, and Teva. J. L. L. receives consulting fees from Galapagos, Boehringer Ingelheim, United Therapeutics, Eleven P15, and Bonac. None declare (S. M. M., J. C., D. R., S. K., A. T., T. K., D. H. L., A. A., M. Chen, I. A., L. N., T. J. B., P. S., J. S. L.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The 6-min walk test (6MWT) is a simple test widely used to assess sub-maximal exercise capacity in chronic respiratory diseases. We explored the relationship of 6-min walk distance (6MWD) with measurements of physiological, clinical, radiographic measures in patients with myositis-associated interstitial lung disease (MA-ILD)., Method: We analyzed data from the Abatacept in Myositis Associated Interstitial lung disease (Attack My-ILD) study, a 48-week multicentre randomized trial of patients with anti-synthetase antibodies and active MA-ILD. 6MWD, forced vital capacity (FVC), diffusing capacity (DLCO), high resolution CT, and various physician/patient reported outcome measures were obtained during the trial. Spearman's correlations and repeated-measures analysis with linear mixed-effects models were used to estimate the associations between 6MWD and various physiologic, clinical and radiographic parameters both cross-sectionally and longitudinally., Results: Twenty participants with a median age of 57, 55% male and 85% white were analyzed. Baseline 6MWD did not associate with baseline PFTs. Repeated-measures analysis showed 6MWD over time associated with FVC over time, but not with DLCO. 6MWD over time also correlated with UCSD dyspnea score, Borg scores, as well as global disease activity and muscle strength over time. Emotional role functioning, vitality, general health and physical functioning scores by short form 36 also correlated with 6MWD over time., Conclusions: : Exploratory work in a small cohort of MA-ILD demonstrated 6MWD over time associated with parallel changes in FVC and patient reported outcomes of dyspnea, but not with DLCO. Larger studies are needed to validate the reliability, responsiveness and utility of the 6MWT in MA-ILD., Clinical Trial Registration: ClinicalTrials.gov, NCT03215927., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and continuous glucose monitoring (CGM) improve glycemia in patients with type 2 diabetes (T2D). However, it is unknown whether adding CGM to GLP-1 RA therapy further improves A1c. We evaluated changes in A1c levels 6 months after initiation of FreeStyle Libre (FSL) in adults with sub-optimally controlled T2D already on GLP-1 RA therapy., Methods: This retrospective, observational study used Optum's de-identified Market Clarity Data, a linked electronic health record-claims database to assess changes in A1c after FSL acquisition. Inclusion criteria were T2D diagnosis, ≥ 18 years, baseline A1c ≥ 8%, with the first FSL acquisition between 2018 and 2022. Patients were required to be on GLP-1 RA prior to FSL with at least one GLP-1 RA prescription within 90 days of FSL acquisition. GLP-1 RA initiation was defined as the earliest GLP-1 RA prescription from 2017 onwards. Paired changes in A1c were assessed at 6 months after initial FSL acquisition., Results: The study cohort included 1454 adults with T2D (age 55 ± 10 years, 52% male, 38% with intensive insulin therapy, median 471 days from GLP-1 RA initiation to FSL, and baseline A1c 9.8 ± 1.5%). After FSL acquisition, patients experienced an A1c decrease of 1.5 ± 1.9% (p < 0.001). Patients with a baseline A1c > 10% had the largest reduction (n = 497, - 2.7 ± 2.2%, p < 0.001). Significant improvements were observed in subgroups based on insulin therapy and GLP-1 RA formulation. Those initiating GLP-1 RA therapy > 24 months before FSL acquisition also showed improvements in A1c (n = 478; - 1.3 ± 1.7%, p < 0.001)., Conclusions: In a large, real-world study of adults with T2D, those on prior GLP-1 RA therapy experienced significant A1c improvements after acquiring FSL, irrespective of GLP-1 RA duration, GLP-1 RA formulation, or insulin therapy type. These findings support the use of FSL in adults with T2D treated with GLP-1 RA., (© 2024. The Author(s).)

Evolutionary relationships among parasites of the subfamily Leishmaniinae, which comprises pathogen agents of leishmaniasis, were inferred based on differential protein expression profiles from mass spectrometry-based quantitative data using the PhyloQuant method. Evolutionary distances following identification and quantification of protein and peptide abundances using Proteome Discoverer and MaxQuant software were estimated for 11 species from six Leishmaniinae genera. Results clustered all dixenous species of the genus Leishmania, subgenera L. (Leishmania), L. (Viannia), and L. (Mundinia), sister to the dixenous species of genera Endotrypanum and Porcisia. Placed basal to the assemblage formed by all these parasites were the species of genera Zelonia, Crithidia, and Leptomonas, so far described as monoxenous of insects although eventually reported from humans. Inferences based on protein expression profiles were congruent with currently established phylogeny using DNA sequences. Our results reinforce PhyloQuant as a valuable approach to infer evolutionary relationships within Leishmaniinae, which is comprised of very tightly related trypanosomatids that are just beginning to be phylogenetically unraveled. In addition to evolutionary history, mapping of species-specific protein expression is paramount to understand differences in infection processes, tissue tropisms, potential to jump from insects to vertebrates including humans, and targets for species-specific diagnostic and drug development., (© 2024 Wiley‐VCH GmbH.)

Purpose: We compared the effects of low-volume combined aerobic and resistance high-intensity interval training (C-HIIT), combined moderate-intensity continuous training (C-MICT) and waitlist control (CON) on vascular health after 8-weeks of supervised training, and an additional 10-months of self-directed training, in adults with type 2 diabetes (T2D)., Methods: Sixty-nine low active adults with T2D were randomised to 8-weeks of supervised C-HIIT (3 times/week, 78-min/week), C-MICT (current exercise guidelines, 4 times/week, 210-min/week) or CON. CON underwent usual care for 8-weeks before being re-randomised to C-HIIT or C-MICT. This was followed by 10-months of self-directed training for participants in C-HIIT and C-MICT. Vascular outcomes were evaluated at baseline, 8-weeks, and 12-months., Results: After 8-weeks, supervised C-HIIT significantly improved relative flow-mediated dilation (FMD) compared with CON (mean difference [MD] 0.8% [0.1, 1.4], p = 0.025). Although not significantly different from CON, the magnitude of change in relative FMD following 8-weeks of supervised C-MICT was similar (MD 0.8% [-0.1, 1.7], p = 0.080). There were no differences in haemodynamic indices, carotid-femoral pulse wave velocity (cfPWV), or aortic reservoir pressure between groups at 8-weeks. After 12-months, there was a significant reduction in haemodynamic indices (time effect, p < 0.05) for both C-HIIT and C-MICT, with no between-group difference. The reduction in cfPWV over 12-months was significantly greater in C-MICT than C-HIIT (group × time effect, p = 0.018). There was no difference in FMD over time or between groups at 12-months., Conclusions: Short-term supervised C-HIIT and C-MICT both increased brachial artery FMD compared with CON. Long-term C-HIIT and C-MICT were beneficial for improving haemodynamic indices, but not brachial artery FMD. C-MICT was superior to C-HIIT for improving cfPWV at 12-months., Trial Registration: Australian New Zealand Clinical Trials Registry Identifier ACTRN12615000475549., (© 2024. The Author(s).)

Few studies have examined long-term mortality following traumatic brain injury (TBI) in a military population. This is a secondary analysis of a prospective, longitudinal study that examines long-term mortality (up to 10 years) post-TBI, including analyses of life expectancy, causes of death, and risk factors for death in service members and veterans (SM/V) who survived the acute TBI and inpatient rehabilitation. Among 922 participants in the study, the mortality rate was 8.3% following discharge from inpatient rehabilitation. The mean age of death was 54.5 years, with death occurring on average 3.2 years after injury, and with an average 7-year life expectancy reduction. SM/V with TBI were nearly four times more likely to die compared with the U.S. general population. Leading causes of death were external causes of injury, circulatory disease, and respiratory disorders. Also notable were deaths due to late effects of TBI itself and suicide. Falls were a significant mechanism of injury for those who died. Those who died were also more likely to be older at injury, unemployed, non-active duty status, not currently married, and had longer post-traumatic amnesia, longer rehabilitation stays, worse independence and disability scores at rehabilitation discharge, and a history of mental health issues before injury. These findings indicate that higher disability and less social supportive infrastructure are associated with higher mortality. Our investigation into the vulnerabilities underlying premature mortality and into the major causes of death may help target future prevention, surveillance, and monitoring interventions.

Aims: Complete ruptures of the ulnar collateral ligament (UCL) of the thumb are a common injury, yet little is known about their current management in the UK. The objective of this study was to assess the way complete UCL ruptures are managed in the UK., Methods: We carried out a multicentre, survey-based cross-sectional study in 37 UK centres over a 16-month period from June 2022 to September 2023. The survey results were analyzed descriptively., Results: A total of 37 centres participated, of which nine were tertiary referral hand centres and 28 were district general hospitals. There was a total of 112 respondents (69 surgeons and 43 hand therapists). The strongest influence on the decision to offer surgery was the lack of a firm 'endpoint' to stressing the metacarpophalangeal joint (MCPJ) in either full extension or with the MCPJ in 30° of flexion. There was variability in whether additional imaging was used in managing acute UCL injuries, with 46% routinely using additional imaging while 54% did not. The use of a bone anchor was by far the most common surgical option for reconstructing an acute ligament avulsion (97%, n = 67) with a transosseous suture used by 3% (n = 2). The most common duration of immobilization for those managed conservatively was six weeks (58%, n = 65) and four weeks (30%, n = 34). Most surgeons (87%, n = 60) and hand therapists (95%, n = 41) would consider randomizing patients with complete UCL ruptures in a future clinical trial., Conclusion: The management of complete UCL ruptures in the UK is highly variable in certain areas, and there is a willingness for clinical trials on this subject., Competing Interests: B. J. F. Dean and M.Mikhail report a British Society for Surgery of the Hand (BSSH) pump priming grant for this study. B. J. F. Dean also reports a British Medical Association Doris Hillier grant which was unrelated to this study. B. J. F. Dean is also a member of the BSSH research committee. D. J. Beard holds a Senior Investigator grant from the National Institute for Health and Care Research, unrelated to this study. M. Mikhail reports a BSSH grant to the ULCTEAR steering group for this study, allocated under his name. N. Riley reports consulting fees from Acumend, Arthrex, and Meshworks, unrelated to this study., (© 2024 Mikhail et al.)

Objectives: Alexithymia an emotional processing deficit that interferes with a person's ability to recognize, express, and differentiate emotional states. Study objectives were to (1) determine rates of elevated alexithymia among people with moderate-to-severe traumatic brain injury (TBI) 1-year post-injury, (2) identify demographic and injury-related variables associated with high versus low-average levels of alexithymia, and (3) examine associations among alexithymia with other aspects of emotional functioning and life satisfaction., Setting: Data were collected during follow-up interviews across four TBI Model System (TBIMS) centers., Participants: The sample consisted of 196 participants with moderate-to-severe TBI enrolled in the TBIMS. They were predominately male (77%), White (69%), and had no history of pre-injury mental health treatment (66.3%)., Design: Cross-sectional survey data were obtained at study enrollment and 1-year post-injury., Main Measures: Toronto Alexithymia Scale-20 (TAS-20) as well as measures of anger, aggression, hostility, emotional dysregulation, post-traumatic stress, anxiety, depression, resilience and life satisfaction. Sociodemographic information, behavioral health history and injury-related variables were also included., Results: High levels of alexithymia (TAS-20 score > 1.5 standard deviation above the normative mean) were observed for 14.3%. Compared to individuals with low/average levels of alexithymia, the high alexithymia group tended to have lower levels of education. At 1-year follow-up, high TAS-20 scores were strongly associated with emotional dysregulation and post-traumatic stress; moderately associated with anger, hostility, depression, anxiety, lower resilience and lower satisfaction with life; and weakly associated with aggression., Conclusion: These findings provide further evidence that alexithymia is associated with poor emotional functioning and life satisfaction after TBI. Longitudinal studies are needed to determine if alexithymia is a risk factor that precipitates and predicts worse emotional outcomes in the TBI population. This line of work is important for informing treatment targets that could prevent or reduce of psychological distress after TBI., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To characterize the traumatic brain injury profile and its associated risk factors in homeless individuals in Santa Clara County, CA., Design: Observational cohort study SETTING: : Two homeless shelter health clinics in Santa Clara County, CA PARTICIPANTS: Currently or recently homeless individuals seeking health care at two homeless shelter health clinics between August 2013 and May 2014., Interventions: Not applicable MAIN OUTCOME MEASURES: Demographics, traumatic brain injury incidence and characteristics RESULTS: Findings indicate that TBI history in the homeless population is higher (79.7%) than the general population (12%). Almost half of the population (49.2%) reported that their TBI occurred before the age of 18. 68.2% of participants reported sustaining a TBI with loss of consciousness. TBI due to violence (60%) was lower in this cohort compared to other homeless cohorts but was the main cause of injury regardless of age. Alcoholism was a risk factor for having more TBIs. No differences in TBI profile were found between genders., Conclusion: Our findings underscore the need for more research on the lifetime risk factors associated with TBI to prevent and reduce the number of brain injuries in homeless populations., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Comprehensive stroke centres across England have developed investment proposals, showing the estimated increases in mechanical thrombectomy (MT) treatment volume that would justify extending the standard hours to a 24/7 service provision. These investment proposals have been developed taking a financial accounting perspective, that is by considering the financial revenues from tariff income. However, given the pressure put on local health authorities to provide value for money services, an affordability question emerges. That is, at what additional MT treatment volume the additional treatment costs are offset by the additional health economic benefits, that is quality-adjusted life years (QALYs) and societal cost savings, generated by administering MT compared to standard care., Methods: A break-even analysis was conducted to identify the additional MT treatment volume required. The incremental hospital-related costs associated with the 24/7 MT extension were estimated using information and parameters from four relevant business cases. The additional societal cost savings and health benefits were estimated by adapting a previously developed Markov chain-based model., Results: The additional hospital-related annual costs for extending MT to a 24/7 service were estimated at a mean of £3,756,818 (range £1,847,387 to £5,092,788). On average, 750 (range 246 to 1,571) additional eligible stroke patients are required to be treated with MT yearly for the proposed 24/7 service extension to be affordable from a health economic perspective. Overall, the additional facility and equipment costs associated with the 24/7 extension would affect this estimate by 20%., Conclusions: These findings support the ongoing debate regarding the optimal levels of MT treatment required for a 24/7 extension and respective changes in hospital organisational activities. They also highlight a need for a regional-level coordination between local authorities and hospital administrations to ensure equity provision in that stroke patients can benefit from MT and that the optimal MT treatment volume is reached. Future studies should contemplate reproducing the presented analysis for different health service provision settings and decision making contexts., (© 2024. The Author(s).)

Objective: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation., Results: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

Objective: To examine the unique contribution of alexithymia at 1 year after traumatic brain injury (TBI) to the prospective prediction of emotional and social health outcomes at 2 years after injury., Design: Multicenter, longitudinal cohort study., Setting: Data were collected during year 1 and year 2 postinjury follow-up interviews across 4 TBI Model System centers., Participants: Persons with TBI (N=175; 134 men and 41 women) who had English fluency and were capable of providing self-reported data., Interventions: Not applicable., Main Outcome Measures: Primary independent variable was the Toronto Alexithymia Scale-20. Outcome measures included the Interpersonal Reactivity Index, National Institute of Health Toolbox Emotion Battery Anger, Difficulty with Emotion Regulation Scale, Connor-Davidson Resilience Scale, Posttraumatic Stress Disorder Checklist - Civilian, Satisfaction with Life Scale, General Anxiety Disorder-7, Patient Health Questionnaire 9, suicidal ideation, and problematic substance use., Results: Simple adjusted models demonstrated that after controlling for the specific outcome at year 1, Toronto Alexithymia Scale-20 scores significantly predicted year 2 scores for perspective-taking, physical aggression, emotional dysregulation, resilience, anxiety, depression, and suicidal ideation. All of these predictive findings except for physical aggression were maintained in the fully adjusted models that also controlled for age, sex, education level, number of prior TBIs, and motor and cognitive functioning., Conclusions: Compared with those with lower alexithymia scores, persons with TBI who had higher alexithymia scores at 1 year after injury reported poorer emotional health at 2 years after TBI, even after controlling for year 1 outcome scores, sociodemographic characteristics, and injury-related factors. These results support the need to assess for elevated alexithymia and to provide interventions targeting alexithymia early in the TBI recovery process., (Copyright © 2024 American Congress of Rehabilitation Medicine. All rights reserved.)

Objective: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation., Results: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

Objective: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs)., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations., Results: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

Objective: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs)., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations., Results: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

Background: The Gender, Age and Physiology (GAP) model is a simple mortality prediction tool in patients with idiopathic pulmonary fibrosis that uses demographic and physiological variables available at initial evaluation. White blood cell variables may have associations with idiopathic pulmonary fibrosis outcomes. We evaluated whether incorporating blood cell counts in modified GAP (cGAP) models would improve outcome prediction in patients with idiopathic pulmonary fibrosis., Patients and Methods: This retrospective analysis included pooled data from phase 3 randomised trials of pirfenidone in idiopathic pulmonary fibrosis (ASCEND, CAPACITY 004, CAPACITY 006). Study outcomes (disease progression, all-cause mortality, all-cause hospitalisation, respiratory-related hospitalisation) were evaluated during the initial 1-year period. Shared frailty models were used to evaluate associations between continuous and categorical baseline white and red blood cell parameters and study outcomes in a bivariate context, and to evaluate the impact of adding continuous monocyte count (cGAP1) or white and red blood cell parameters (cGAP2) to traditional GAP variables in a multivariable context based on C-statistics changes., Results: Data were pooled from 1247 patients (pirfenidone, n=623; placebo, n=624). Significant associations (bivariate analyses) were idiopathic pulmonary fibrosis progression with neutrophil and eosinophil counts; all-cause mortality with monocyte and neutrophil counts; all-cause hospitalisation with monocyte count, neutrophil count and haemoglobin level; and respiratory-related hospitalisation with monocyte count, neutrophil count and haemoglobin level. In multivariate analyses, C-statistics were highest for the cGAP2 model for each of the outcomes., Conclusion: Modified GAP models incorporating monocyte counts alone or plus other white and red blood cell variables may be useful to improve prediction of outcomes in patients with idiopathic pulmonary fibrosis., Competing Interests: Conflict of interest: M. Kreuter has received fees for speaking and/or organising education from AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, ERS, F. Hoffmann-La Roche, Ltd., GlaxoSmithKline and Novartis; has received fees for consulting from Boehringer Ingelheim, F. Hoffmann-La Roche, Ltd., Galapagos, GlaxoSmithKline and InterMune; and has received research funding, including institutional funding, from Boehringer Ingelheim, BMBF, DFG, the German Center for Lung Research (DZL), F. Hoffmann-La Roche, Ltd., Dietmar Hopp Stiftung, InterMune, Lilly, Lungenfibrose e.V., medac Pharma, Olympus, UKGM and WATL. Conflict of interest: J.S Lee has received grants from the National Institutes of Health, Boehringer Ingelheim and Pliant, and received consulting fees from Blade, Boehringer Ingelheim, United Therapeutics, Eleven P15 and Avalyn, all outside the submitted work. Conflict of interest: A. Tzouvelekis has received fees for speaking and/or organising education from AstraZeneca, Menarini, Boehringer Ingelheim, Chiesi, F. Hoffmann-La Roche, Ltd., GlaxoSmithKline and Elpen; has received fees for consulting from Boehringer Ingelheim, Pfizer, Gilead, F. Hoffmann-La Roche, Ltd. and GlaxoSmithKline; and has received research funding, including institutional funding, from Boehringer Ingelheim, Chiesi, F. Hoffmann-La Roche, Ltd., GlaxoSmithKline and AstraZeneca. Conflict of interest: J.M. Oldham has received fees for consulting from Boehringer Ingelheim, F. Hoffmann-La Roche, Ltd., Genentech, Gatehouse Bio, AmMax Bio and Lupin Pharmaceuticals; and research funding, including institutional funding, from Boehringer Ingelheim and the National Institutes of Health. Conflict of interest: P.L. Molyneaux has, via his institution, received industry–academic funding from AstraZeneca, Boehringer Ingelheim and Galapagos; and has received consultancy or speakers’ fees from F. Hoffmann-La Roche, Ltd, Boehringer Ingelheim, Trevi, Vicore, GlaxoSmithKline R&D, Qurate and AstraZeneca; and is an associate editor of this journal. Conflict of interest: D. Weycker and M. Atwood are employees of Avalere Health (formerly Policy Analysis Inc.). Conflict of interest: K. Samara is an employee of F. Hoffmann-La Roche, Ltd. Conflict of interest: K-U. Kirchgässler is a former employee and shareholder of F. Hoffmann-La Roche, Ltd. Conflict of interest: T.M. Maher has, via his institution, received industry–academic funding from AstraZeneca and GlaxoSmithKline R&D; and has received consultancy or speakers’ fees from AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Fibrogen, Galapagos, GlaxoSmithKline R&D, IQVIA, Pliant, F. Hoffmann-La Roche, Ltd, Trevi and Veracyte., (Copyright ©The authors 2024.)

Background: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone or as a bivalent preparation with the prototype vaccine (NVX-CoV2373) to assess antibody responses to SARS-CoV-2., Methods: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or the bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed., Results: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated a superior neutralizing antibody response to BA.1 vs NVX-CoV2373 (n = 274) at day 14 (geometric mean titer ratio, 1.6; 95% CI, 1.33-2.03). Seroresponse rates were 73.4% (91/124; 95% CI, 64.7-80.9) for NVX-CoV2515 vs 50.9% (59/116; 95% CI, 41.4-60.3) for NVX-CoV2373. All formulations were similarly well tolerated., Conclusions: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant as compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373., Clinical Trials Registration: ClinicalTrials.gov (NCT05372588)., Competing Interests: Potential conflicts of interest. C. B., E. J. R., W. W., J. S. P., S. C.-C., M. Z., R. K., N. P., A. B., A. M., J. S., G. S., I. C., G. M. G., R. W., and R. M. M. are current or former Novavax employees and as such receive or received a salary for their work and may hold Novavax stock. O. C. and T. M. P. act as investigators at Novatrials on clinical trials and have not received personal financial payment from Novavax. A. M. N. acts as an investigator at AusTrials on clinical trials of COVID-19 and other vaccines sponsored by vaccine manufacturers, including Pfizer, GlaxoSmithKline, Novavax, Seqirus, and Moderna. He receives no personal financial payment for this work. K. C. acts as an investigator at Emeritus Research and has not received any personal financial payment from Novavax. R. M. acts as an investigator at Paratus Clinical Research and has not received any personal financial payment from Novavax. M. B. has received payment or honoraria as well as support for meeting attendance and/or travel from Gilead Sciences and ViiV Healthcare and has received research funding from Gilead Sciences, ViiV Healthcare, GlaxoSmithKline, Merck & Co, Eli Lilly, Amgen, Pfizer, Bristol-Myers Squibb, Novartis, and Sanofi. He has also participated on a data safety monitoring board or advisory board for Gilead Sciences, ViiV Healthcare, and Cymra. 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: While the amygdala receives early tau deposition in Alzheimer's disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms., Methods: We examined 598 individuals (347 amyloid positive [58% female], 251 amyloid negative [62% female] subset in tau positron emission tomography and functional magnetic resonance imaging cohorts) from the A4 (Anti-Amyloid Treatment in Asymptomatic AD) Study. In the tau positron emission tomography cohort, we used amygdalar segmentations to examine representative nuclei from 3 functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the functional magnetic resonance imaging cohort. Finally, we conducted exploratory post hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores., Results: Amyloid-positive individuals demonstrated increased tau binding in the medial and lateral amygdala, and tau binding in these regions was associated with mood symptoms. Across amygdalar divisions, amyloid-positive individuals had relatively higher regional connectivity from the amygdala to other temporal regions, the insula, and the orbitofrontal cortex, but medial amygdala to retrosplenial cortex connectivity was lower. Medial amygdala to retrosplenial connectivity was negatively associated with anxiety symptoms, as was retrosplenial tau., Conclusions: Our findings suggest that preclinical tau deposition in the amygdala and associated changes in functional connectivity may be related to early mood symptoms in AD., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD., Competing Interests: Declaration of interests In disclosures unrelated to this work: M.K. received research funding from GlaxoSmithKline. T.J.D. received research support from Bayer and Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech, all unrelated to this study. L.K.D. received research grants from the Brazilian Ministry of Health (PROADI-SUS), Boehringer Ingelheim, and Bristol-Myers-Squibb. J.S.L. received grants from the NIH and Boehringer Ingelheim, an unrestricted research gift from Pliant, and consulting fees from Blade, Boehringer Ingelheim, United Therapeutics, Astra Zenca, and Eleven P15, all outside the submitted work. J.S.L. serves on the DSMB for UT, Avalyn and is an advisor for the Pulmonary Fibrosis Foundation, all outside the submitted work. L.K.D. received consulting fees from Boehringer Ingelheim, Roche, and Bristol-Myers-Squibb. J.A.S. has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers-Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, and ReCor unrelated to this work. C.M.H. serves in a scientific advisory role for the following companies: Lung Therapeutics, Lassen Therapeutics, Rubedo Life Sciences, and Structure Therapeutics. C.M.H. also consults for the Three Lakes Foundation. C.M.H. receives research funding from Kyowa Kirin Co, Ltd. B.B.M. is a grant review consultant for Boehringer-Ingelheim, the Pulmonary Fibrosis Foundation and the National Scleroderma Foundation. W.M.O. has received consulting fees from Nikang Therapeutics on a topic unrelated to the present manuscript. E.Y.K. receives research funding in fILD from Bayer AG, Roche Pharma Research and Early Development, and 10X Genomics. E.Y.K. has a PCT patent application (US2022/075673) concerning a method to treat fibrosis that is not mentioned in this manuscript. E.Y.K. has a financial interest in Novartis AG unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Despite the highest levels of evidence on cardiac rehabilitation (CR) effectiveness, its translation into practice is compromised by low participation., Aim: This study aimed to investigate CR utilisation and effectiveness in South Australia., Methods: This retrospective cohort study used data linkage of clinical and administrative databases from 2016 to 2021 to assess the association between CR utilisation (no CR received, commenced without completing, or completed) and the composite primary outcome (mortality/cardiovascular re-admissions within 12 months after discharge). Cox survival models were adjusted for sociodemographic and clinical data and applied to a population balanced by inverse probability weighting. Associations with non-completion were assessed by logistic regression., Results: Among 84,064 eligible participants, 74,189 did not receive CR, with 26,833 of the 84,064 (31.9%) participants referred. Of these, 9,875 (36.8%) commenced CR, and 7,681 of the 9,875 (77.8%) completed CR. Median waiting time from discharge to commencement was 40 days (interquartile range, 23-79 days). Female sex (odds ratio [OR] 1.12; 95% CI 1.01-1.24; p=0.024), depression (OR 1.17; 95% CI 1.05-1.30; p=0.002), and waiting time >28 days (OR 1.15; 95% CI 1.05-1.26; p=0.005) were associated with higher odds of non-completion, whereas enrolment in a telehealth program (OR 0.35; 95% CI 0.31-0.40; p<0.001) was associated with lower odds of non-completion. Completing CR (hazard ratio [HR] 0.62; 95% CI 0.58-0.66; p<0.001) was associated with a lower risk of 12-month mortality/cardiovascular re-admissions. Commencing without completing was also associated with decreased risk (HR 0.81; 95% CI 0.73-0.90; p<0.001), but the effect was lower than for those completing CR (p<0.001)., Conclusions: Cardiac rehabilitation (CR) attendance is associated with lower all-cause mortality/cardiovascular re-admissions, with CR completion leading to additional benefits. Quality improvement initiatives should include promoting referral, women's participation, access to telehealth, and reduction of waiting times to increase completion., 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.)

Na V 1.7 plays a crucial role in inducing and conducting action potentials in pain-transducing sensory nociceptor fibres, suggesting that Na V 1.7 blockers could be effective non-opioid analgesics. While SCN9A is expressed in both sensory and autonomic neurons, its functional role in the autonomic system remains less established. Our single neuron rt-PCR analysis revealed that 82% of sympathetic neurons isolated from guinea-pig stellate ganglia expressed Na V 1.7 mRNA, with Na V 1.3 being the only other tetrodotoxin-sensitive channel expressed in approximately 50% of neurons. We investigated the role of Na V 1.7 in conducting action potentials in postganglionic sympathetic nerves and in the sympathetic adrenergic contractions of blood vessels using selective Na V 1.7 inhibitors. Two highly selective Na V 1.7 blockers, GNE8493 and PF 05089771, significantly inhibited postganglionic compound action potentials by approximately 70% (P < 0.01), with residual activity being blocked by the Na V 1.3 inhibitor, ICA 121431. Electrical field stimulation (EFS) induced rapid contractions in guinea-pig isolated aorta, pulmonary arteries, and human isolated pulmonary arteries via stimulation of intrinsic nerves, which were inhibited by prazosin or the Na V 1 blocker tetrodotoxin. Our results demonstrated that blocking Na V 1.7 with GNE8493, PF 05089771, or ST2262 abolished or strongly inhibited sympathetic adrenergic responses in guinea-pigs and human vascular smooth muscle. These findings support the hypothesis that pharmacologically inhibiting Na V 1.7 could potentially reduce sympathetic and parasympathetic function in specific vascular beds and airways. KEY POINTS: 82% of sympathetic neurons isolated from the stellate ganglion predominantly express Na V 1.7 mRNA. Na V 1.7 blockers inhibit action potential conduction in postganglionic sympathetic nerves. Na V 1.7 blockade substantially inhibits sympathetic nerve-mediated adrenergic contractions in human and guinea-pig blood vessels. Pharmacologically blocking Na V 1.7 profoundly affects sympathetic and parasympathetic responses in addition to sensory fibres, prompting exploration into the broader physiological consequences of Na V 1.7 mutations on autonomic nerve activity., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Background and Objectives: Noninvasive and accurate biomarkers of neurologic Wilson disease (NWD), a rare inherited disorder, could reduce diagnostic error or delay. Excessive subcortical metal deposition seen on susceptibility imaging has suggested a characteristic pattern in NWD. With submillimeter spatial resolution and increased contrast, 7T susceptibility-weighted imaging (SWI) may enable better visualization of metal deposition in NWD. In this study, we sought to identify a distinctive metal deposition pattern in NWD using 7T SWI and investigate its diagnostic value and underlying pathophysiologic mechanism., Methods: Patients with WD, healthy participants with monoallelic ATP7B variant(s) on a single chromosome, and health controls (HCs) were recruited. NWD and non-NWD (nNWD) were defined according to the presence or absence of neurologic symptoms during investigation. Patients with other diseases with comparable clinical or imaging manifestations, including early-onset Parkinson disease (EOPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and neurodegeneration with brain iron accumulation (NBIA), were additionally recruited and assessed for exploratory comparative analysis. All participants underwent 7T T1, T2, and high-resolution SWI scanning. Quantitative susceptibility mapping and principal component analysis were performed to illustrate metal distribution., Results: We identified a linear signal intensity change consisting of a hyperintense strip at the lateral border of the globus pallidus in patients with NWD. We termed this feature "hyperintense globus pallidus rim sign." This feature was detected in 38 of 41 patients with NWD and was negative in all 31 nNWD patients, 15 patients with EOPD, 30 patients with MSA, 15 patients with PSP, and 12 patients with NBIA; 22 monoallelic ATP7B variant carriers; and 41 HC. Its sensitivity to differentiate between NWD and HC was 92.7%, and specificity was 100%. Severity of the hyperintense globus pallidus rim sign measured by a semiquantitative scale was positively correlated with neurologic severity (ρ = 0.682, 95% CI 0.467-0.821, p < 0.001). Patients with NWD showed increased susceptibility in the lenticular nucleus with high regional weights in the lateral globus pallidus and medial putamen., Discussion: The hyperintense globus pallidus rim sign showed high sensitivity and excellent specificity for diagnosis and differential diagnosis of NWD. It is related to a special metal deposition pattern in the lenticular nucleus in NWD and can be considered as a novel neuroimaging biomarker of NWD., Classification of Evidence: The study provides Class II evidence that the hyperintense globus pallidus rim sign on 7T SWI MRI can accurately diagnose neurologic WD.

Background: Health systems have a dual imperative to take action on climate change. First, they must develop climate resilient health services in response to the direct and indirect impacts of climate change on health. Second, they must reduce their own carbon footprint since health systems are a significant contributor to global greenhouse gas emissions., Methods: An environmentally-extended multi-region input-output analysis was carried out, incorporating National Accounts data for Australia and annual expenditure data from WA Health for financial year 2019-20. Expenditure data were categorised to one of 344 economic sectors and by location of the provider of goods or services purchased., Findings: WA Health contributes 8% of WA's total carbon footprint, driven by expenditure on chemicals (23.8% of total), transport (20.2% of total), and electricity supply (19.7% of total). These 3 sectors represent 63.7% of WA Health's carbon footprint, but only 10.8% of its total expenditure., Interpretation: Reducing emissions related to health service provision in WA will require a holistic approach that leverages carbon footprinting insights and integrates them into organisational decision-making across all health programs. The high carbon-intensity of the transport and chemicals sectors supports previous research calling for a reduction in unnecessary pathology testing and the transition to delivery of non-urgent health care via sustainable models of telehealth. The impact of WA's size and location presents challenges, with a predominantly non-renewable energy supply and reliance on transport and supply chains from other states adding significantly to emissions., Funding: The study received funding from the Australian Research Council, The University of Sydney, and the WA Department of Health. The full list of funding information can be found in Acknowledgements., Competing Interests: The authors declare no conflicts of interest. The author's views are their own and not necessarily those of the Western Australian State Government or WA Department of Health., (© 2024 The Author(s).)

Objectives: This study aims to analyze the cost of patient care among ORL-HNS patients admitted in a tertiary, teaching government hospital in a low- to middle-income country., Methods: This is a prevalence-based, prospective, bottom-up, cost-of-illness analysis among patients of the Department of Otorhinolaryngology-Head and Neck Surgery in a tertiary training government hospital admitted from July 2021 to March 2022. The value assessment method used is the human capital approach. The societal perspective is used for analysis to estimate and reflect payer (insurance providers) and patient perspectives., Results: A total of one hundred fifty seven (157) patients were admitted for elective surgery under the service of ORL-HNS consisting of 75 females and 82 males. The average total overall cost was $3,851.10 (Php 199, 870.50 ± 164, 725.60). The total direct health care cost for all patients within the study period amounted to $3,712.18 (Php 192, 662.22 ± 159, 548.60) while the direct non-health care cost was $58.60. The workforce cost (58.5%) and medication cost (18.8%) comprised the majority of in-patient expenses with a mean cost of $2,221.36 (Php 37,083.66) and $714.51 (Php 44,363.14), respectively. In this study, an average of $80.29 was lost due to illness and hospitalization (± $81.74). The total PHIC coverage pays a range from zero to 67.5% with an average coverage of only 17%., Conclusion: Our analysis has shown that workforce and medication expenses are the main cost drivers for the direct healthcare costs among Otolaryngology patients admitted for elective procedures. Stakeholders, such as the otolaryngologists and hospitals should coordinate closely to create a more encompassing coverage of Philhealth to prevent patients from suffering from financial crises due to their illness., Competing Interests: All authors declared no conflicts of interest., (© 2024 Acta Medica Philippina.)

The evaluation of coronavirus disease 2019 (COVID-19) vaccine immunogenicity remains essential as the severe acute respiratory syncytial virus 2 (SARS-CoV-2) pandemic continues to evolve and as additional variants emerge. Neutralizing antibodies are a known correlate of protection for SARS-CoV-2 vaccines. A pseudovirus neutralization (PNT) assay was developed and validated at Novavax Clinical Immunology Laboratories to allow for the detection of neutralizing antibodies in vaccine clinical trial sera. The PNT assay was precise, accurate, linear, and specific in measuring SARS-CoV-2 neutralization titers in human serum for ancestral strain and the Omicron subvariants BA.5 and XBB.1.5, with an overall geometric coefficient of variation of ≤43.4%, a percent relative bias within the expected range of -60% to 150%, and a linearity value of R 2 > 0.98 for all three strains. This pseudovirus assay will be useful for the analysis of vaccine clinical trial samples to assess vaccine immunogenicity. Future work will focus on modifying the assay for emerging variants, including XBB.1.16, EG.5.1, BA.2.86, and any other variants that emerge in the ongoing pandemic.

Background: While the amygdala receives early tau deposition in Alzheimer's disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms., Methods: We examined n=598 individuals (n=347 amyloid-positive (58% female), n=251 amyloid-negative (62% female); subset into tau PET and fMRI cohorts) from the A4 Study. In our tau PET cohort, we used amygdalar segmentations to examine representative nuclei from three functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the fMRI cohort. Finally, we conducted exploratory post-hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores., Results: Amyloid-positive individuals demonstrated increased tau binding in medial and lateral amygdala ( F (4,442)=14.61, p =0.00045; F( 4,442)=5.83, p =0.024, respectively). Across amygdalar divisions, amyloid-positive individuals had relatively increased regional connectivity from amygdala to other temporal regions, insula, and orbitofrontal cortex. There was an interaction by amyloid group between tau binding in the medial and lateral amygdala and anxiety. Medial amygdala to retrosplenial connectivity negatively correlated with anxiety symptoms (r s =-0.103, p =0.015)., Conclusions: Our findings suggest that preclinical tau deposition in the amygdala may result in meaningful changes in functional connectivity which may predispose patients to mood symptoms., Competing Interests: DISCLOSURES WX is currently employed in a fellowship role at Unlearn. AI Inc. JL, ST, BFT, SW, CH, TT, SN, CZ, YZ, AP, EB, and CF have no conflicts of interest or financial interests to declare.

Importance: Persistent symptoms and disability following SARS-CoV-2 infection, known as post-COVID-19 condition or "long COVID," are frequently reported and pose a substantial personal and societal burden., Objective: To determine time to recovery following SARS-CoV-2 infection and identify factors associated with recovery by 90 days., Design, Setting, and Participants: For this prospective cohort study, standardized ascertainment of SARS-CoV-2 infection was conducted starting in April 1, 2020, across 14 ongoing National Institutes of Health-funded cohorts that have enrolled and followed participants since 1971. This report includes data collected through February 28, 2023, on adults aged 18 years or older with self-reported SARS-CoV-2 infection., Exposure: Preinfection health conditions and lifestyle factors assessed before and during the pandemic via prepandemic examinations and pandemic-era questionnaires., Main Outcomes and Measures: Probability of nonrecovery by 90 days and restricted mean recovery times were estimated using Kaplan-Meier curves, and Cox proportional hazards regression was performed to assess multivariable-adjusted associations with recovery by 90 days., Results: Of 4708 participants with self-reported SARS-CoV-2 infection (mean [SD] age, 61.3 [13.8] years; 2952 women [62.7%]), an estimated 22.5% (95% CI, 21.2%-23.7%) did not recover by 90 days post infection. Median (IQR) time to recovery was 20 (8-75) days. By 90 days post infection, there were significant differences in restricted mean recovery time according to sociodemographic, clinical, and lifestyle characteristics, particularly by acute infection severity (outpatient vs critical hospitalization, 32.9 days [95% CI, 31.9-33.9 days] vs 57.6 days [95% CI, 51.9-63.3 days]; log-rank P < .001). Recovery by 90 days post infection was associated with vaccination prior to infection (hazard ratio [HR], 1.30; 95% CI, 1.11-1.51) and infection during the sixth (Omicron variant) vs first wave (HR, 1.25; 95% CI, 1.06-1.49). These associations were mediated by reduced severity of acute infection (33.4% and 17.6%, respectively). Recovery was unfavorably associated with female sex (HR, 0.85; 95% CI, 0.79-0.92) and prepandemic clinical cardiovascular disease (HR, 0.84; 95% CI, 0.71-0.99). No significant multivariable-adjusted associations were observed for age, educational attainment, smoking history, obesity, diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease, or elevated depressive symptoms. Results were similar for reinfections., Conclusions and Relevance: In this cohort study, more than 1 in 5 adults did not recover within 3 months of SARS-CoV-2 infection. Recovery within 3 months was less likely in women and those with preexisting cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave.

As variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, assessment of vaccine immunogenicity remains a critical factor to support continued vaccination. To this end, an in vitro microneutralization (MN50) assay was validated to quantitate SARS-CoV-2 neutralizing antibodies against prototype and variant strains (Beta, Delta, Omicron BA.1, Omicron BA.5, and XBB.1.5) in human serum. For the prototype strain, the MN50 assay met acceptance criteria for inter-/intra-assay precision, specificity, linearity, and selectivity. The assay was robust against changes to virus/serum incubation time, cell seeding density, virus content per well, cell passage number, and serum interference. Analyte in serum samples was stable up to five freeze/thaw cycles and for up to 12 months of storage at -80 ± 10 °C. Similar results were observed for the variant-adapted MN50 assays. The conversion factor to convert assay result units to WHO international standard units (IU/mL) was determined to be 0.62 for the prototype strain. This MN50 assay will be useful for vaccine immunogenicity analyses in clinical trial samples, enabling assessment of vaccine immunogenicity for ancestral and variant strains as variant-adapted vaccines are developed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All the authors that are employees of Novavax, Inc. are stockholders of Novavax, Inc., (Copyright © 2024. Published by Elsevier B.V.)

Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for RA-ILD is not yet well defined. Reliable prognostic indicators are largely byproducts of prior ILD progression, including low or decreasing forced vital capacity and extensive or worsening fibrosis on imaging. In the absence of validated tools to predict treatment response, decisions about whether to initiate or augment treatment are instead based on clinical judgment. In general, treatment should be initiated in patients who are symptomatic, progressing, or at high risk of poor outcomes. Retrospective data suggest that mycophenolate mofetil, azathioprine, and rituximab are likely effective therapies for RA-ILD. Abatacept is also emerging as a potential first-line treatment option for patients with RA-ILD. Further, recent data demonstrate that immunosuppression may be beneficial even in patients with a usual interstitial pneumonia (UIP) pattern on imaging, suggesting that immunosuppression should be considered irrespective of imaging pattern. Recent randomized controlled trials have shown that antifibrotic medications, such as nintedanib and likely pirfenidone, slow forced vital capacity decline in RA-ILD. Consideration can be given to antifibrotic initiation in patients progressing despite immunosuppression, particularly in patients with a UIP pattern. Future research directions include developing tools to predict which patients will remain stable from patients who will progress, discriminating patients who will respond to treatment from nonresponders, and developing algorithms for starting immunosuppression, antifibrotics, or both as first-line therapies., Competing Interests: J.V.P. reports no conflicts. J.S.L. reports receiving grants from the NIH and Boehringer Ingelheim, an unrestricted research gift from Pliant, and consulting fees from Blade, Boehringer Ingelheim, United Therapeutics, AstraZeneca, and Eleven P15, outside the submitted work. J.S.L. is/has been on the DSMB for United Therapeutics and Avalyn and is an advisor for the Pulmonary Fibrosis Foundation, outside the submitted work., (Thieme. All rights reserved.)

Background: SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose., Methods: In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 μg SARS-CoV-2 recombinant spike protein and 50 μg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 μg of NVX-CoV2373 plus 2·5 μg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588., Findings: Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated., Interpretation: All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence., Funding: Novavax., Competing Interests: Declaration of interests CB, WW, JSP, SC-C, MZ, RK, NP, AM, JS, GS, IC, RW, and RMM are current Novavax employees and as such receive a work salary and hold Novavax stock. GMG is a former employee and current consultant for Novavax and holds Novavax stock. OC and TMP act as investigators at Novatrials on clinical trials. AMN acts as an investigator at AusTrials on clinical trials of COVID-19 and other vaccines sponsored by vaccine manufacturers, including Pfizer, GlaxoSmithKline, Novavax, Seqirus, and Moderna; he receives no personal financial payment for this work. KC acts as an investigator at Emeritus Research. RM acts as an investigator at Paratus Clinical Research. OC, TMP, KC, and RM have not received any personal financial payment from Novavax. MB has received payment or honoraria as well as support for meeting attendance or travel, or both, from Gilead Sciences and ViiV Healthcare, and his institution has received research funding from Gilead Sciences, ViiV Healthcare, GlaxoSmithKline, Merck & Co, Eli Lilly, Amgen, Pfizer, Bristol-Myers Squibb, Novartis, Biotron, Cymra, and Eyegene; his institution has received payment for his participation on a data safety monitoring board for Eyegene and Cymra, whereas he has received payment for advisory board attendance for Gilead Sciences and ViiV Healthcare. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To investigate cardiac rehabilitation utilisation and effectiveness, factors, needs and barriers associated with non-completion., Design: We used the mixed-methods design with concurrent triangulation of a retrospective cohort and a qualitative study., Setting: Economically disadvantaged areas in rural Australia., Participants: Patients (≥18 years) referred to cardiac rehabilitation through a central referral system and living in rural areas of low socioeconomic status., Main Measures: A Cox survival model balanced by inverse probability weighting was used to assess the association between cardiac rehabilitation utilization and 12-month mortality/cardiovascular readmissions. Associations with non-completion were tested by logistic regression. Barriers and needs to cardiac rehabilitation completion were investigated through a thematic analysis of semi-structured interviews and focus groups (n = 28)., Results: Among 16,159 eligible separations, 44.3% were referred, and 11.2% completed cardiac rehabilitation. Completing programme (HR 0.65; 95%CI 0.57-0.74; p < 0.001) led to a lower risk of cardiovascular readmission/death. Living alone (OR 1.38; 95%CI 1.00-1.89; p = 0.048), having diabetes (OR 1.48; 95%CI 1.02-2.13; p = 0.037), or having depression (OR 1.54; 95%CI 1.14-2.08; p = 0.005), were associated with a higher risk of non-completion whereas enrolment in a telehealth programme was associated with a lower risk of non-completion (OR 0.26; 95%CI 0.18-0.38; p < 0.001). Themes related to logistic issues, social support, transition of care challenges, lack of care integration, and of person-centeredness emerged as barriers to completion., Conclusions: Cardiac rehabilitation completion was low but effective in reducing mortality/cardiovascular readmissions. Understanding and addressing barriers and needs through mixed methods can help tailor cardiac rehabilitation programmes to vulnerable populations and improve completion and outcomes.

Background: Idiopathic interstitial pneumonias (IIPs) such as idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF), present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF)., Methods: Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared to controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles which were then analyzed to predict survival outcomes and investigate associated pathways., Results: Proteomic profiling successfully differentiated IIP from controls. k -means clustering, based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology (GAP) index (C-index 0.794 vs. 0.709). The cluster with the worst prognosis featured decreased inflammatory signaling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B cell-mediated immunity., Conclusions: The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalized treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.

Background: Iron deposition plays a crucial role in the pathophysiology of Parkinson's disease (PD), yet the distribution pattern of iron deposition in the subcortical nuclei has been inconsistent across previous studies. We aimed to assess the difference patterns of iron deposition detected by quantitative iron-sensitive magnetic resonance imaging (MRI) between patients with PD and patients with atypical parkinsonian syndromes (APSs), and between patients with PD and healthy controls (HCs)., Methods: A systematic literature search was conducted on PubMed, Embase, and Web of Science databases to identify studies investigating the iron content in PD patients using the iron-sensitive MRI techniques (R2* and quantitative susceptibility mapping [QSM]), up until May 1, 2023. The quality assessment of case-control and cohort studies was performed using the Newcastle-Ottawa Scale, whereas diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Standardized mean differences and summary estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for iron content, using a random effects model. We also conducted the subgroup-analysis based on the MRI sequence and meta-regression., Results: Seventy-seven studies with 3192 PD, 209 multiple system atrophy (MSA), 174 progressive supranuclear palsy (PSP), and 2447 HCs were included. Elevated iron content in substantia nigra (SN) pars reticulata (P <0.001) and compacta (P <0.001), SN (P <0.001), red nucleus (RN, P <0.001), globus pallidus (P <0.001), putamen (PUT, P = 0.009), and thalamus (P = 0.046) were found in PD patients compared with HCs. PD patients showed lower iron content in PUT (P <0.001), RN (P = 0.003), SN (P = 0.017), and caudate nucleus (P = 0.027) than MSA patients, and lower iron content in RN (P = 0.001), PUT (P <0.001), globus pallidus (P = 0.004), SN (P = 0.015), and caudate nucleus (P = 0.001) than PSP patients. The highest diagnostic accuracy distinguishing PD from HCs was observed in SN (AUC: 0.85), and that distinguishing PD from MSA was found in PUT (AUC: 0.90). In addition, the best diagnostic performance was achieved in the RN for distinguishing PD from PSP (AUC: 0.84)., Conclusion: Quantitative iron-sensitive MRI could quantitatively detect the iron content of subcortical nuclei in PD and APSs, while it may be insufficient to accurately diagnose PD. Future studies are needed to explore the role of multimodal MRI in the diagnosis of PD., Registrision: PROSPERO; CRD42022344413., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Background: Gamma hydroxybutyrate (GHB) is used illicitly for its sedative hypnotic effects, and those who take it regularly are at risk of developing a substance use disorder. Withdrawal from GHB can include severe symptoms that may require medical management. For GHB use and withdrawal during pregnancy, there are no evidence- or practice-based guidelines to follow, and there is only minimal research literature., Case Summary: We present the case of a 32-year-old woman, G1P0 at 29 weeks and 6 days of gestation, admitted to the perinatal unit at a tertiary hospital for GHB withdrawal management and stabilization. GHB withdrawal was managed with a combination of baclofen and diazepam. We report the dosing and tapering of these medications throughout her 14-day admission. Withdrawal symptoms were well managed with this medication protocol, and she did not experience any features of complicated withdrawal. The patient later presented to hospital in preterm labor and precipitously delivered a healthy, preterm infant male at 34 weeks and 5 days of gestation. At 7 months postpartum, the patient continued to engage with perinatal addiction service, reported no use of GHB since her admission, and was parenting her healthy son., Clinical Significance: There is a paucity of guidelines for managing GHB withdrawal in pregnancy. This case demonstrates good clinical outcomes administering a short-term combination of diazepam and baclofen during the third trimester of pregnancy. This case helps to fill a gap in the literature and may inform future research or clinical decision-making in similar situations., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Objectives: The aim of the current study was to investigate the impact of individualised versus standardised combined endurance and resistance training on the fitness-fatness index in physically inactive adults., Design: Randomised controlled trial., Methods: Fifty-four participants aged 21-55 years were randomised into three groups; 1) non-exercise control (n = 18), 2) standardised moderate-intensity continuous training (n = 18), or 3) individualised moderate-intensity continuous training + high-intensity interval training (n = 18). The fitness-fatness index was calculated by dividing cardiorespiratory fitness (expressed as metabolic equivalents) by the waist-to-height ratio. Participants were classified as likely responders to the intervention if a change of ≥1 fitness-fatness index unit was achieved., Results: The individualised group showed the greatest fitness-fatness index improvement (between group difference p < 0.001), with 100 % of this group classified as likely responders, compared to the standardised (68 %) and non-exercise control (0 %) groups., Conclusions: An individualised, threshold-based exercise programme may produce more favourable changes in the fitness-fatness index than a standardised exercise programme., Competing Interests: Declaration of interest statement The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

When contracting muscles are freely perfused, the acid-sensing ion channel 3 (ASIC3) on group IV afferents plays a minor role in evoking the exercise pressor reflex. We recently showed in isolated dorsal root ganglion neurons innervating the gastrocnemius muscles that two mu opioid receptor agonists, namely endomorphin 2 and oxycodone, potentiated the sustained inward ASIC3 current evoked by acidic solutions. This in vitro finding prompted us to determine whether endomorphin 2 and oxycodone, when infused into the arterial supply of freely perfused contracting hindlimb muscles, potentiated the exercise pressor reflex. We found that infusion of endomorphin 2 and naloxone in decerebrated rats potentiated the pressor responses to contraction of the triceps surae muscles. The endomorphin 2-induced potentiation of the pressor responses to contraction was prevented by infusion of APETx2, an ASIC3 antagonist. Specifically, the peak pressor response to contraction averaged 19.3 ± 5.6 mmHg for control ( n = 10), 27.2 ± 8.1 mmHg after naloxone and endomorphin 2 infusion ( n = 10), and 20 ± 8 mmHg after APETx2 and endomorphin 2 infusion ( n = 10). Infusion of endomorphin 2 and naloxone did not potentiate the pressor responses to contraction in ASIC3 knockout rats ( n = 6). Partly similar findings were observed when oxycodone was substituted for endomorphin 2. Oxycodone infusion significantly increased the exercise pressor reflex over its control level, but subsequent APETx2 infusion failed to restore the increase to its control level ( n = 9). The peak pressor response averaged 23.1 ± 8.6 mmHg for control ( n = 9), 33.2 ± 11 mmHg after naloxone and oxycodone were infused ( n = 9), and 27 ± 8.6 mmHg after APETx2 and oxycodone were infused ( n = 9). Our data suggest that after opioid receptor blockade, ASIC3 stimulation by the endogenous mu opioid, endomorphin 2, potentiated the exercise pressor reflex. NEW & NOTEWORTHY This paper provides the first in vivo evidence that endomorphin 2, an endogenous opioid peptide, can paradoxically increase the magnitude of the exercise pressor reflex by an ASIC3-dependent mechanism even when the contracting muscles are freely perfused.

Aims: Parkinsonian tremor (PT) is regulated by numerous neurophysiological components across multiple temporospatial scales. The dynamics of tremor fluctuation are thus highly complex. This study aimed to explore the effects of different medications on tremor complexity, and how the underlying factors contribute to such tremor complexity., Methods: In this study, 66 participants received a 2-mg dose of benzhexol or a pre-determined dose of levodopa at two study visits in a randomized order. Before and after taking the medications, tremor fluctuation was recorded using surface electromyography electrodes and accelerometers in resting, posture, and weighting conditions with and without a concurrent cognitive task. Tremor complexity was quantified using multiscale entropy., Results: Tremor complexity in resting (p = 0.002) and postural condition (p < 0.0001) was lower when participants were performing a cognitive task compared to a task-free condition. After taking levodopa and benzhexol, participants had increased (p = 0.02-0.03) and decreased (p = 0.03) tremor complexity compared to pre-medication state, respectively. Tremor complexity and its changes as induced by medications were significantly correlated with clinical ratings and their changes (β = -0.23 to -0.39; p = 0.002-0.04), respectively., Conclusion: Tremor complexity may be a promising marker to capture the pathophysiology underlying the development of PT, aiding the characterization of the effects medications have on PT regulation., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)