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Summary: Rapid gut-brain communication is critical to maintain energy balance and is disrupted in diet-induced obesity. In particular, the role of carbohydrate overconsumption in the regulation of interoceptive circuits in vivo requires further investigation. Here, we report that an obesogenic high-sucrose diet (HSD) selectively blunts silencing of hunger-promoting agouti-related protein (AgRP) neurons following intragastric delivery of glucose, whereas we previously showed that overconsumption of a high-fat diet (HFD) selectively attenuates lipid-induced neural silencing. By contrast, both HSD and HFD reversibly dampen rapid AgRP neuron inhibition following chow presentation and promote intake of more palatable foods. Our findings reveal that excess sugar and fat pathologically modulate feeding circuit activity in both macronutrient-dependent and -independent ways and thus may additively exacerbate obesity.

Low levels of vitamin D in maternal and cord blood have been associated with neonatal sepsis. This study assessed the association of vitamin D metabolites (25(OH)D, 3-epi-25(OH)D 3 , and 24,25(OH) 2 D 3 ) levels in maternal and cord blood with newborn sepsis evaluation in Nigerian mother-infant dyads. Maternal and cord blood from 534 mothers and 536 newborns were processed using liquid chromatography-tandem mass spectrometry. Spearman correlation was used to compare continuous variables, Mann-Whitney for dichotomous variables, and Kruskal-Wallis for two or more groups. High cord percent 3-epi-25(OH)D 3 levels were positively associated with newborn evaluation for sepsis ( p = 0.036), while maternal and cord 25(OH)D and 24,25(OH) 2 D 3 levels were not. Being employed was positively associated with maternal and newborn 3-epi-25(OH)D 3 concentrations ( p = 0.007 and p = 0.005, respectively). The maternal 3-epi-25(OH)D 3 and percent 3-epi-25(OH)D 3 were positively associated with vaginal delivery ( p = 0.013 and p = 0.012, respectively). Having a weight-for-age Z-score ≤ -2 was positively associated with newborn percent 3-epi-25(OH)D 3 levels ( p = 0.004), while a weight-for-length Z-score ≤ -3 was positively associated with maternal and newborn percent 3-epi-25(OH)D 3 levels ( p = 0.044 and p = 0.022, respectively). Our study highlights the need to further investigate the biological role of 3-epi-25(OH)D 3 and its clinical significance in fetal growth and newborn outcome.

This observational study evaluated the impact of a sponsor company-provided Patient Support Program (PSP) on discontinuation of adalimumab in adult Australian patients eligible for Pharmaceutical Benefit Scheme (PBS)-reimbursed adalimumab for Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS), Psoriatic Arthritis (PsA), Crohn's Disease (CD), Ulcerative Colitis (UC), or Hidradenitis Suppurativa (HS). Patients initiating adalimumab between May 2018 and September 2019 were enrolled into two prospective cohorts based on their decision to opt for or decline the PSP (PSP or non-PSP cohorts). In addition, a historical, retrospective Non-PSP cohort was established from the Services Australia 10% PBS dataset by extracting data of patients initiating adalimumab prior to the introduction of adalimumab PSPs and based on adalimumab PBS listing dates (AS: April 2007 to March 2009; PsA/RA: January 2007 to December 2008; CD: January 2009 to December 2010; HS and UC indications not included). Follow-up for all cohorts was 12 months. The primary endpoint was the time to discontinuation, compared between the prospective PSP cohort and the prospective or retrospective Non-PSP cohort. Inverse probability of treatment weighting was used to balance the cohorts. A Cox proportional hazards model indicated no difference in time to discontinuation between the prospective PSP (n = 162) and non-PSP (n = 65) cohorts (HR [95% CI] = 1.256 [0.616-2.563], p = 0.5304). The 12-month adalimumab persistence rates (95% CI) were 78% (69%, 84%) and 82% (67%, 90%), respectively. In contrast, discontinuation was less likely in the prospective PSP (n = 151) compared with the retrospective non-PSP (n = 297) cohort (HR [95% CI] = 0.44 [0.28-0.68], p<0.001). The 12-month persistence rates (95% CI) were 81% (76%, 90%) and 61% (56%, 67%), respectively. Overall, this study suggests that optimal adalimumab persistence can be achieved with either a structured PSP or healthcare support from other sources, but this was not the case more than a decade ago., Competing Interests: There are no patents or products in development associated with this research to declare. A marketed product (HUMIRA® [Adalimumab]) is associated with this research., (Copyright: © 2024 Jones et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Huntington's disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune dysregulation, prominently featuring increased immune activity, plays a significant role in HD pathogenesis. In addition to the central nervous system (CNS), systemic innate immune activation and inflammation are observed in HD patients, exacerbating the effects of the Huntingtin (HTT) gene mutation. Recent attention to sex differences in HD symptom severity underscores the need to consider gender as a biological variable in neurodegenerative disease research. Understanding sex-specific immune responses holds promise for elucidating HD pathophysiology and informing targeted treatment strategies to mitigate cognitive and functional decline. This perspective will highlight the importance of investigating gender influence in HD, particularly focusing on sex-specific immune responses predisposing individuals to disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Risby-Jones, Lee, Woodruff and Fung.)

Background: Rapid diagnostic clinics (RDCs) provide a streamlined holistic pathway for patients presenting with non-site specific (NSS) symptoms concerning of malignancy. The current study aimed to: 1) assess the prevalence of anxiety and depression, and 2) identify a combination of patient characteristics and symptoms associated with severe anxiety and depression at Guy's and St Thomas' Foundation Trust (GSTT) RDC in Southeast London. Additionally, we compared standard statistical methods with machine learning algorithms for predicting severe anxiety and depression., Methods: Patients seen at GSTT RDC between June 2019 and January 2023 completed the General Anxiety Disorder Questionnaire (GAD-7) and Patient Health Questionnaire (PHQ-8) questionnaires, at baseline. We used logistic regression (LR) and 2 machine learning (ML) algorithms (random forest (RF), support vector machine (SVM)) to predict risk of severe anxiety and severe depression. The models were constructed using a set of sociodemographic and clinical variables., Results: A total of 1734 patients completed GAD-7 and PHQ-8 questionnaires. Of these, the mean age was 59 years (Standard Deviation: 15.5), and 61.5% (n:1067) were female. Prevalence of severe anxiety (GAD-7 score ≥15) was 13.8% and severe depression (PHQ-8 score≥20) was 9.3%. LR showed that a combination of previous mental health condition (PMH, Adjusted Odds Rario (AOR) 3.28; 95% confidence interval (CI) 2.36-4.56), symptom duration >6 months (AOR 2.20; 95%CI 1.28-3.77), weight loss (AOR 1.88; 95% CI 1.36-2.61), progressive pain (AOR 1.71; 95%CI 1.26-2.32), and fatigue (AOR 1.36; 95%CI 1.01-1.84), was positively associated with severe anxiety. Likewise, a combination PMH condition (AOR 3.95; 95%CI 2.17-5.75), fatigue (AOR 2.11; 95%CI 1.47-3.01), symptom duration >6 months (AOR 1.98; 95%CI 1.06-3.68), weight loss (AOR 1.66; 95%CI 1.13-2.44), and progressive pain (AOR 1.50; 95%CI 1.04-2.16), was positively associated with severe depression. LR and SVM had highest accuracy levels for severe anxiety (LR: 86%, SVM: 85%) and severe depression (SVM: 89%, LR: 86%)., Conclusion: High prevalence of severe anxiety and severe depression was found. PMH, fatigue, weight loss, progressive pain, and symptoms >6 months emerged as combined risk factors for both these psychological comorbidities. RDCs offer an opportunity to alleviate distress in patients with concerning symptoms by expediting diagnostic evaluations., 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 Monroy-Iglesias, Russell, Martin, Fox, Moss, Bruno, Millwaters, Steward, Murtagh, Cargaleiro, Bater, Lavelle, Simpson, Onih, Haire, Reeder, Jones, Smith, Santaolalla, Van Hemelrijck and Dolly.)

Objective: To determine whether the dietary inflammatory index (DII) scores were associated with knee structural changes and pain over a 10.7-year follow-up., Methods: This study used data from a prospective population-based cohort study (mean age 63 years, 51% female) in which 1,099, 875, 768, and 566 participants completed assessments at baseline, 2.6, 5.1, and 10.7 years, respectively. T1-weighted and T2-weighted magnetic resonance imaging was performed to measure cartilage volume (CV) and bone marrow lesions (BMLs) at baseline and 10.7 years. The Western Ontario and McMaster Universities Osteoarthritis Index pain questionnaire was used to measure knee pain at each visit. Pain trajectories ("minimal pain," "mild pain," and "moderate pain") were previously identified. Baseline energy-adjusted DII (E-DII) scores were calculated. Linear, log-binomial regression, linear mixed-effects modeling, and multi-nominal logistic regression were used for analyses., Results: The mean ± SD E-DII score at baseline was -0.48 ± 1.39. In multivariable analyses, higher E-DII scores were not associated with tibial CV loss or BML size increase except for medial tibial BML size increase. Higher E-DII scores were associated with a higher pain score (β = 0.21; 95% confidence interval [CI] 0.004-0.43) and an increased risk of belonging to the "moderate pain" compared to the "minimal pain" trajectory group (relative risk ratio 1.19; 95% CI 1.02-1.39)., Conclusion: A proinflammatory diet, as indicated by a higher DII score, may be associated with a greater pain score and higher risk of more severe pain trajectory over 10 years. However, inconsistent findings related to structural changes suggest a discordance between the potential impact of diet on structural damage and pain in knee OA., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Ablation of Cyp27b1 eliminates calcitriol but does not disturb fetal mineral homeostasis or skeletal development. However, independent of fetal genotypes, maternal loss of Cyp27b1 altered fetal mineral and hormonal levels compared to offspring of WT dams. We hypothesized that these maternal influences would alter postnatal skeletal development. Cyp27b1 null and WT females were mated to bear only Cyp27b1+/- offspring. Forty-eight hours after birth, pups were cross-fostered to dams of the same or opposite genotype that bore them. Maternal and offspring samples were collected on days 21 (weaning) and 42. Offspring measurements included minerals and hormones, BMC by DXA, ash weight and mineral content, gene expression, 3-point bending tests, and microCT. Maternal lactational behavior was evaluated. Milk was analyzed for nutritional content. At day 21, offspring fostered by nulls, independent of birth dam, had ~20% lower weight, BMC, ash weight, and ash calcium than pups fostered by WT dams. Adjustment for body weight accounted for the lower BMC but not the lower ash weight and ash calcium. Hormones and serum/urine minerals did not differ across offspring groups. Offspring fostered by nulls had shorter femurs and lower cortical thickness, mean polar moment of inertia, cortical area, trabecular bone volume, and trabecular number. Dam lactational behaviors and milk nutritional content did not differ between groups. At day 42, body weight, ash weight, lengths, BMC, and tibial bone strength were no longer different between pups fostered by null vs WT dams. In summary, pups fostered by Cyp27b1 nulls, regardless of birth dam, have proportionately smaller skeletons at 21 d, impaired microstructure, but normal mineral homeostasis. The skeletal effects are largely recovered by day 42 (3 wk after weaning). In conclusion, maternal loss of calcitriol impairs early postnatal cortical bone growth and trabecular bone mass, but affected offspring catch up after weaning., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Climate change majorly impacts biodiversity in diverse regions across the world, including South Asia, a megadiverse area with heterogeneous climatic and vegetation regions. However, climate impacts on bats in this region are not well-studied, and it is unclear whether climate effects will follow patterns predicted in other regions. We address this by assessing projected near-future changes in climatically suitable areas for 110 bat species from South Asia. We used ensemble ecological niche modelling with four algorithms (random forests, artificial neural networks, multivariate adaptive regression splines and maximum entropy) to define climatically suitable areas under current conditions (1970-2000). We then extrapolated near future (2041-2060) suitable areas under four projected scenarios (combining two global climate models and two shared socioeconomic pathways, SSP2: middle-of-the-road and SSP5: fossil-fuelled development). Projected future changes in suitable areas varied across species, with most species predicted to retain most of the current area or lose small amounts. When shifts occurred due to projected climate change, new areas were generally northward of current suitable areas. Suitability hotspots, defined as regions suitable for >30% of species, were generally predicted to become smaller and more fragmented. Overall, climate change in the near future may not lead to dramatic shifts in the distribution of bat species in South Asia, but local hotspots of biodiversity may be lost. Our results offer insight into climate change effects in less studied areas and can inform conservation planning, motivating reappraisals of conservation priorities and strategies for bats in South Asia., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: The growing number of oral anticancer medications represents a significant portion of pharmacy spending and can be costly for patients. Patients taking oral anticancer medications may experience frequent treatment changes following necessary safety and effectiveness monitoring, often resulting in medication waste. Strategies to avoid medication waste could alleviate the financial burden of these costly therapies on the payer and the patient., Objective: To evaluate the impact on waste and cost avoidance of reviewing the amount of medication patients have on hand and the presence of upcoming follow-up (ie, provider visit, laboratory testing, or imaging) before requesting a prescription refill renewal for patients taking oral anticancer medications through an integrated health system specialty pharmacy., Methods: We performed a retrospective review of patients filling oral anticancer medications prescribed by a Vanderbilt University Medical Center provider and dispensed by Vanderbilt Specialty Pharmacy between January 1, 2020, and December 31, 2020. Specialty pharmacists received a system-generated refill renewal request for oral anticancer medications when the final prescription refill was dispensed, prompting the pharmacist to review the patient's medical record for continued therapy appropriateness and to request a new prescription. If the patient had a sufficient supply on hand to last until an upcoming follow-up (ie, provider visit, imaging, or laboratory assessment), the pharmacist postponed the renewal until after the scheduled follow-up. Patients were included in the analysis if the refill renewal request was postponed after review of the amount of medication on hand and the presence of an upcoming follow-up. Medication outcomes (ie, continued, dose changed, held, medication changed to a different oral anticancer medication, or discontinued) resulting from the follow-up were collected. Cost avoidance in US dollars was assigned based on the outcome of follow-up by calculating the price per unit times the number of units that would have been unused or in excess of what was needed if the medication had been dispensed before the scheduled follow-up. The average wholesale price minus 20% (AWP-20%) and wholesale acquisition cost (WAC) were used to report a range of costs avoided over 12 months., Results: The total cost avoidance over 12 months associated with postponing refill renewal requests in a large academic health system with an integrated specialty pharmacy ranged from $549,187.03 using WAC pricing to $751,994.99 using AWP-20% pricing, with a median cost avoidance per fill of $366.04 (WAC) to $1,931.18 (AWP-20%). Refill renewal requests were postponed in 159 instances for 135 unique patients. After follow-up, medications were continued unchanged in only 2% of postponed renewals, 56% of follow-ups resulted in medication discontinuations, 32% in dose changes, 5% in medication changes, and 5% in medication holds., Conclusions: Integrated health system specialty pharmacist postponement of refill requests after review of the amount of medication on hand and upcoming follow-up proved effective in avoiding waste and unnecessary medication costs in patients treated with oral anticancer medications at a large academic health system.

Circulating tumor DNA (ctDNA) holds promise as a biomarker for predicting clinical responses to therapy in solid tumors, and multiple ctDNA assays are in development. However, the heterogeneity in ctDNA levels prior to treatment (baseline) across different cancer types and stages and across ctDNA assays has not been widely studied. Friends of Cancer Research formed a collaboration across multiple commercial ctDNA assay developers to assess baseline ctDNA levels across five cancer types in early- and late-stage disease. This retrospective study included eight commercial ctDNA assay developers providing summary-level de-identified data for patients with non-small cell lung cancer (NSCLC), bladder, breast, prostate, and head and neck squamous cell carcinoma following a common analysis protocol. Baseline ctDNA levels across late-stage cancer types were similarly detected, highlighting the potential use of ctDNA as a biomarker in these cancer types. Variability was observed in ctDNA levels across assays in early-stage NSCLC, indicative of the contribution of assay analytical performance and methodology on variability. We identified key data elements, including assay characteristics and clinicopathological metadata, that need to be standardized for future meta-analyses across multiple assays. This work facilitates evidence generation opportunities to support the use of ctDNA as a biomarker for clinical response.

The initiation of abstinence after chronic drug self-administration is stressful. Cocaine-seeking behavior on the first day of the absence of the expected drug (Extinction Day 1, ED1) is reduced by blocking 5-HT signaling in dorsal hippocampal cornu ammonis 1 (CA1) in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior and that dorsal raphe (DR) serotonin (5-HT) input to CA1 may be involved. We inhibited 5-HT 1A/1B receptors (WAY-100635 plus GR-127935), or DR input (chemogenetics), in CA1 on ED1 to test the role of this pathway on cocaine-seeking persistence 2 weeks later. We also inhibited 5-HT 1A or 5-HT 1B receptors in CA1 during conditioned place preference (CPP) for cocaine, to examine mechanisms involved in the persistent effects of ED1 manipulations. Inhibition of DR inputs, or 5-HT 1A/1B signaling, in CA1 decreased drug seeking on ED1 and decreased cocaine seeking 2 weeks later revealing that 5-HT signaling in CA1 during ED1 contributes to persistent drug seeking during abstinence. In addition, 5-HT 1B antagonism alone transiently decreased drug-associated memory performance when given prior to a CPP test, whereas similar antagonism of 5-HT 1A alone had no such effect but blocked CPP retrieval on a test 24 h later. These CPP findings are consistent with prior work showing that DR inputs to CA1 augment recall of the drug-associated context and drug seeking via 5-HT 1B receptors and prevent consolidation of the updated nondrug context via 5-HT 1A receptors. Thus, treatments that modulate 5-HT-dependent memory mechanisms in CA1 during initial abstinence may facilitate later maintenance of abstinence., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Purpose: Hip osteoarthritis (OA) is a major cause of pain and disability worldwide. Lack of effective therapies may reflect poor knowledge on its aetiology and risk factors, and result in the management of end-stage hip OA with costly joint replacement. The Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) consortium was established to pool and harmonise individual participant data from prospective cohort studies. The consortium aims to better understand determinants and risk factors for the development and progression of hip OA, to optimise and automate methods for (imaging) analysis, and to develop a personalised prediction model for hip OA., Participants: World COACH aimed to include participants of prospective cohort studies with ≥200 participants, that have hip imaging data available from at least 2 time points at least 4 years apart. All individual participant data, including clinical data, imaging (data), biochemical markers, questionnaires and genetic data, were collected and pooled into a single, individual-level database., Findings to Date: World COACH currently consists of 9 cohorts, with 38 021 participants aged 18-80 years at baseline. Overall, 71% of the participants were women and mean baseline age was 65.3±8.6 years. Over 34 000 participants had baseline pelvic radiographs available, and over 22 000 had an additional pelvic radiograph after 8-12 years of follow-up. Even longer radiographic follow-up (15-25 years) is available for over 6000 of these participants., Future Plans: The World COACH consortium offers unique opportunities for studies on the relationship between determinants/risk factors and the development or progression of hip OA, by using harmonised data on clinical findings, imaging, biomarkers, genetics and lifestyle. This provides a unique opportunity to develop a personalised hip OA risk prediction model and to optimise methods for imaging analysis of the hip., Competing Interests: Competing interests: GJ reports personal fees from Novartis outside the submitted work. SBZ reports consulting fees from Pfizer Infirst Healthcare and personal fees for being a Deputy Editor for Osteoarthritis and Cartilage outside the submitted work. CL and TC report a patent for an image processing apparatus and method for fitting a deformable shape model to an image using random forest regression voting. CL reports licensing royalties for this patent from Optasia Medical outside the submitted work. AN is an associate editor for Osteoarthritis and Cartilage and is on the OARSI Board of Directors outside the submitted work. AM is on the Editorial Board for the British Journal of Sports Medicine and the Journal of Science and Medicine in Sport outside the submitted work. HW reports being a minority shareholder of Uplanner BV and Replasia BV outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolves the infection and restores mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlates with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, restores mammary tissue normal homeostasis, thus providing evidence for a link between the systemic host response during UTI and mammary gland alterations., (© 2024. The Author(s).)

Objective: To analyse the effectiveness of rapid diagnostic clinics (RDCs) as an alternative pathway for patients with concerning symptoms and a faecal immunochemical test (FIT) result <10. Our primary endpoint was rate of colorectal cancer (CRC) detection. Second endpoints were rates of other cancers and gastrointestinal (GI) serious benign conditions. Finally, we analysed the specific pathway followed by FIT <10 patients with cancer at Guy's and St Thomas NHS Foundation Trust (GSTT) RDC., Design: A retrospective and prospective cohort study., Setting: GSTT RDC, one of England's largest single-centre RDCs. Sociodemographic and clinical characteristics of FIT <10 patients were analysed descriptively., Participants: Patients with an FIT result <10, seen at GSTT RDC between 1 January 2020 and 5 May 2023., Results: A total of 1299 patients with an FIT<10 were seen at GSTT RDC between January 2020 and May 2023. Of these, 66% (n=861) reported weight loss, 62% (n=805) pain, 37% (n=481) fatigue, 34% (n=444) were anaemic and 23% (n=301) had nausea and vomiting. Among these patients, 7% (n=88) received a cancer diagnosis, 36% (n=462) were identified as having a serious benign condition. Within the patients with cancer, 9% (n=8) were diagnosed with CRC. Among patients with serious benign conditions, 7% (n=31) were referred to colorectal, hepatopancreatobiliary, or upper GI specialists., Conclusion: This study demonstrates the effectiveness of RDCs as an alternate pathway for FIT <10 patients with ongoing clinical concerns. These results contribute to enhancing patient care and optimising resource allocation within the healthcare system., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Meiosis is the specialized cellular program that underlies gamete formation for sexual reproduction. It is therefore not only interesting but also a fundamentally important subject for investigation. An especially attractive feature of this program is that many of the processes of special interest involve organized chromosomes, thus providing the possibility to see chromosomes "in action". Analysis of meiosis has also proven to be useful in discovering and understanding processes that are universal to all chromosomal programs. Here we provide an overview of the different historical moments when the gap between observation and understanding of mechanisms and/or roles for the new discovered molecules was bridged. This review reflects also the synergy of thinking and discussion among our three laboratories during the past several decades., (© 2024. The Author(s).)

Background and Aim: Long Covid is often stigmatised, particularly in people who are disadvantaged within society. This may prevent them from seeking help and could lead to widening health inequalities. This coproduced study with a Community Advisory Board (CAB) of people with Long Covid aimed to understand healthcare and wider barriers and stigma experienced by people with probable Long Covid., Methods: An active case finding approach was employed to find adults with probable, but not yet clinically diagnosed, Long Covid in two localities in London (Camden and Merton) and Derbyshire, England. Interviews explored the barriers to care and the stigma faced by participants and were analysed thematically. This study forms part of the STIMULATE-ICP Collaboration., Findings: Twenty-three interviews were completed. Participants reported limited awareness of what Long Covid is and the available pathways to management. There was considerable self-doubt among participants, sometimes reinforced by interactions with healthcare professionals (HCPs). Participants questioned their deservedness in seeking healthcare support for their symptoms. Hesitancy to engage with healthcare services was motivated by fear of needing more investigation and concerns regarding judgement about the ability to carry out caregiving responsibilities. It was also motivated by the complexity of the clinical presentation and fear of all symptoms being attributed to poor mental health. Participants also reported trying to avoid overburdening the health system. These difficulties were compounded by experiences of stigma and discrimination. The emerging themes reaffirmed a framework of epistemic injustice in relation to Long Covid, where creating, interpreting and conveying knowledge has varied credibility based on the teller's identity characteristics and/or the level of their interpretive resources., Conclusion: We have codeveloped recommendations based on the findings. These include early signposting to services, dedicating protected time to listening to people with Long Covid, providing a holistic approach in care pathways, and working to mitigate stigma. Regardless of the diagnosis, people experiencing new symptoms must be encouraged to seek timely medical help. Clear public health messaging is needed among communities already disadvantaged by epistemic injustice to raise awareness of Long Covid, and to share stories that encourage seeking care and to illustrate the adverse effects of stigma., Patient or Public Contribution: This study was coproduced with a CAB made up of 23 members including HCPs, people with lived experience of Long Covid and other stakeholders., (© 2024 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence., (© 2024. The Author(s).)

Purpose: Refixation of acute anterior cruciate ligament (ACL) tears represents an increasingly popular treatment option. Systematic evaluations of various suture technique parameters are still pending. We therefore aimed to evaluate the mechanical pull-out outcomes of various suture methods for optimization of ACL refixation., Methods: Sixty fresh knees from mature domestic pigs were dissected and the femoral attachment of the ACL was peeled off. The 60 knees were divided in 10 groups and sutured as follows: (A) one suture (1, 2, 4 and 6 passes), (B) two sutures (2, 4 and 6 passes each; sutures knotted together as a loop) and (C) two sutures (2, 4 and 6 passes each, sutures knotted separately). The pull-out test was conducted using a validated electrodynamic testing machine. First occurrence of failure, maximum pull-out load and stiffness were measured. Suture failure was defined as pull-out of the ACL., Results: Two-point fixation, using two sutures, with at least two passes, showed the most favourable biomechanical stability. The maximum pull-out load was significantly higher with two sutures (529.5 N) used compared to one (310.4 N), p  < 0.001. No significant differences were found for maximum pull-out loads between two-point fixation versus one-point fixation but stiffness was significantly higher with two-point fixation (107.4 N/mm vs. 79.4 N/mm, p  < 0.001). More passes resulted in higher maximum pull-out loads., Conclusion: The results suggest using two independent sutures, refixed separately and at least two suture passes, is appropriate for ACL refixation. More suture passes provide additional strength but are technically challenging to achieve during surgery., Level of Evidence: Level IV., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Purpose: Tear fluid is a complex and dynamic biological fluid that plays essential roles in maintaining ocular homeostasis and protecting against the external environment. Owing to the small sample volume, studying the tear proteome is challenging. However, advances in high-resolution mass spectrometry have expanded tear proteome profiling, revealing >500 unique proteins. Tears are emerging as a noninvasive source of biomarkers for both ocular and systemic diseases; nevertheless, intraday variability of proteins in tear fluid remains questionable. This study investigates intraday variations in the tear fluid proteome to identify stable proteins that could act as candidate biomarkers., Methods: Tear samples from 15 individuals at four time points (10 am, 12 pm, 2 pm, and 4 pm) were analyzed using mass spectrometry to evaluate protein variation during these intervals. Technical variation was assessed by analyzing pooled samples and was subtracted from the total variation to isolate biological variability., Results: Owing to high technical variation, low-abundant proteins were filtered, and only 115 proteins met the criteria for further analysis. These criteria include being detected at all four time points in at least eight subjects, having a mean peptide-spectrum match count greater than 5, and having a technical variation less than 0.10. Lactotransferrin, lipocalin-1, and several immunoglobulins were among the 51 stable proteins (mean biological coefficient of variation < 0.10). Additionally, 43 proteins displayed significant slopes across the 4 time points, with 17 increasing and 26 decreasing over time., Conclusions: These findings contribute to the understanding of tear fluid dynamics and further expand our knowledge of the tear proteome.

This study demonstrates that changes in mindfulness predict subsequent changes in well-being in a data set including individuals who recently engaged in psychedelic use., (©Grant Jones, Felipe Herrmann, Adam Bear, Robin Carhart-Harris, Hannes Kettner. Originally published in JMIR Formative Research (https://formative.jmir.org), 04.03.2024.)

Introduction : The BIOFIRE Joint Infection (JI) Panel is a diagnostic tool that uses multiplex-PCR testing to detect microorganisms in synovial fluid specimens from patients suspected of having septic arthritis (SA) on native joints or prosthetic joint infections (PJIs). Methods : A study was conducted across 34 clinical sites in 19 European and Middle Eastern countries from March 2021 to June 2022 to assess the effectiveness of the BIOFIRE JI Panel. Results : A total of 1527 samples were collected from patients suspected of SA or PJI, with an overall agreement of 88.4 % and 85 % respectively between the JI Panel and synovial fluid cultures (SFCs). The JI Panel detected more positive samples and microorganisms than SFC, with a notable difference on Staphylococcus aureus , Streptococcus species, Enterococcus faecalis , Kingella kingae , Neisseria gonorrhoeae , and anaerobic bacteria. The study found that the BIOFIRE JI Panel has a high utility in the real-world clinical setting for suspected SA and PJI, providing diagnostic results in approximately 1 h. The user experience was positive, implying a potential benefit of rapidity of results' turnover in optimising patient management strategies. Conclusion : The study suggests that the BIOFIRE JI Panel could potentially optimise patient management and antimicrobial therapy, thus highlighting its importance in the clinical setting., Competing Interests: At least one of the (co-)authors is a member of the editorial board of Journal of Bone and Joint Infection. The peer-review process was guided by an independent editor, and the authors also have no other competing interests to declare., (Copyright: © 2024 Stéphanie Pascual et al.)

Background: Severe mental ill health (SMI) includes schizophrenia, bipolar disorder and schizoaffective disorder and is associated with premature deaths when compared to people without SMI. Over 70% of those deaths are attributed to preventable health conditions, which have the potential to be positively affected by the adoption of healthy behaviours, such as physical activity. People with SMI are generally less active than those without and face unique barriers to being physically active. Physical activity interventions for those with SMI demonstrate promise, however, there are important questions remaining about the potential feasibility and acceptability of a physical activity intervention embedded within existing NHS pathways., Method: This is a two-arm multi-site randomised controlled feasibility trial, assessing the feasibility and acceptability of a co-produced physical activity intervention for a full-scale trial across geographically dispersed NHS mental health trusts in England. Participants will be randomly allocated via block, 1:1 randomisation, into either the intervention arm or the usual care arm. The usual care arm will continue to receive usual care throughout the trial, whilst the intervention arm will receive usual care plus the offer of a weekly, 18-week, physical activity intervention comprising walking and indoor activity sessions and community taster sessions. Another main component of the intervention includes one-to-one support. The primary outcome is to investigate the feasibility and acceptability of the intervention and to scale it up to a full-scale trial, using a short proforma provided to all intervention participants at follow-up, qualitative interviews with approximately 15 intervention participants and 5 interventions delivery staff, and data on intervention uptake, attendance, and attrition. Usual care data will also include recruitment and follow-up retention. Secondary outcome measures include physical activity and sedentary behaviours, body mass index, depression, anxiety, health-related quality of life, healthcare resource use, and adverse events. Outcome measures will be taken at baseline, three, and six-months post randomisation., Discussion: This study will determine if the physical activity intervention is feasible and acceptable to both participants receiving the intervention and NHS staff who deliver it. Results will inform the design of a larger randomised controlled trial assessing the clinical and cost effectiveness of the intervention., Trial Registration: ISRCTN: ISRCTN83877229. Registered on 09.09.2022., (© 2024. The Author(s).)

Animal size, a trait sensitive to spatial and temporal variables, is a key element in ecological and evolutionary dynamics. In the context of climate change, there is evidence that some bat species are increasing their body size via phenotypic responses to higher temperatures at maternity roosts. To test the generality of this response, we conducted a >20-year study examining body size changes in 15 bat species in Italy, analysing data from 4393 individual bats captured since 1995. In addition to examining the temporal effect, we considered the potential influence of sexual dimorphism and, where relevant, included latitude and altitude as potential drivers of body size change. Contrary to initial predictions of a widespread increase in size, our findings challenge this assumption, revealing a nuanced interplay of factors contributing to the complexity of bat body size dynamics. Specifically, only three species ( Myotis daubentonii , Nyctalus leisleri , and Pipistrellus pygmaeus ) out of the 15 exhibited a discernible increase in body size over the studied period, prompting a reassessment of bats as reliable indicators of climate change based on alterations in body size. Our investigation into influencing factors highlighted the significance of temperature-related variables, with latitude and altitude emerging as crucial drivers. In some cases, this mirrored patterns consistent with Bergmann's rule, revealing larger bats recorded at progressively higher latitudes ( Plecotus auritus , Myotis mystacinus , and Miniopterus schreibersii ) or altitudes ( Pipistrellus kuhlii ). We also observed a clear sexual dimorphism effect in most species, with females consistently larger than males. The observed increase in size over time in three species suggests the occurrence of phenotypic plasticity, raising questions about potential long-term selective pressures on larger individuals. The unresolved question of whether temperature-related changes in body size reflect microevolutionary processes or phenotypic plastic responses adds further complexity to our understanding of body size patterns in bats over time and space., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

The aqueous humor (AH) is a low-viscosity biofluid that continuously circulates from the posterior chamber to the anterior chamber of the eye. Recent advances in high-resolution mass-spectrometry workflows have facilitated the study of proteomic content in small-volume biofluids like AH, highlighting the potential clinical implications of the AH proteome. Nevertheless, in-depth investigations into the role of AH proteins in ocular diseases have encountered challenges due to limited accessibility to these workflows, difficulties in large-scale AH sample collection and the absence of a reference AH proteomic database. In response to these obstacles, and to promote further research on the involvement of AH proteins in ocular physiology and pathology, we have developed the web-based Aqueous Humor Proteomics Database (AHP DB). The current version of AHP DB contains proteomic data from 307 human AH samples, which were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The database offers comprehensive information on 1683 proteins identified in the AH samples. Furthermore, relevant clinical data are provided for each analyzed sample. Researchers also have the option to download these datasets individually for offline use, rendering it a valuable resource for the scientific community. Database URL: https://ahp.augusta.edu/., (© The Author(s) 2024. Published by Oxford University Press.)

Background: ChatGPT (Open AI) is a state-of-the-art large language model that uses artificial intelligence (AI) to address questions across diverse topics. The American Society of Clinical Oncology Self-Evaluation Program (ASCO-SEP) created a comprehensive educational program to help physicians keep up to date with the many rapid advances in the field. The question bank consists of multiple choice questions addressing the many facets of cancer care, including diagnosis, treatment, and supportive care. As ChatGPT applications rapidly expand, it becomes vital to ascertain if the knowledge of ChatGPT-3.5 matches the established standards that oncologists are recommended to follow., Objective: This study aims to evaluate whether ChatGPT-3.5's knowledge aligns with the established benchmarks that oncologists are expected to adhere to. This will furnish us with a deeper understanding of the potential applications of this tool as a support for clinical decision-making., Methods: We conducted a systematic assessment of the performance of ChatGPT-3.5 on the ASCO-SEP, the leading educational and assessment tool for medical oncologists in training and practice. Over 1000 multiple choice questions covering the spectrum of cancer care were extracted. Questions were categorized by cancer type or discipline, with subcategorization as treatment, diagnosis, or other. Answers were scored as correct if ChatGPT-3.5 selected the answer as defined by ASCO-SEP., Results: Overall, ChatGPT-3.5 achieved a score of 56.1% (583/1040) for the correct answers provided. The program demonstrated varying levels of accuracy across cancer types or disciplines. The highest accuracy was observed in questions related to developmental therapeutics (8/10; 80% correct), while the lowest accuracy was observed in questions related to gastrointestinal cancer (102/209; 48.8% correct). There was no significant difference in the program's performance across the predefined subcategories of diagnosis, treatment, and other (P=.16, which is greater than .05)., Conclusions: This study evaluated ChatGPT-3.5's oncology knowledge using the ASCO-SEP, aiming to address uncertainties regarding AI tools like ChatGPT in clinical decision-making. Our findings suggest that while ChatGPT-3.5 offers a hopeful outlook for AI in oncology, its present performance in ASCO-SEP tests necessitates further refinement to reach the requisite competency levels. Future assessments could explore ChatGPT's clinical decision support capabilities with real-world clinical scenarios, its ease of integration into medical workflows, and its potential to foster interdisciplinary collaboration and patient engagement in health care settings., (©Roupen Odabashian, Donald Bastin, Georden Jones, Maria Manzoor, Sina Tangestaniapour, Malke Assad, Sunita Lakhani, Maritsa Odabashian, Sharon McGee. Originally published in JMIR AI (https://ai.jmir.org), 12.01.2024.)

Myelin is essential for rapid nerve signaling and is increasingly found to play important roles in learning and in diverse diseases of the CNS. Morphological parameters of myelin such as sheath length are thought to precisely tune conduction velocity, but the mechanisms controlling sheath morphology are poorly understood. Local calcium signaling has been observed in nascent myelin sheaths and can be modulated by neuronal activity. However, the role of calcium signaling in sheath formation remains incompletely understood. Here, we use genetic tools to attenuate oligodendrocyte calcium signaling during myelination in the developing mouse CNS. Surprisingly, genetic calcium attenuation does not grossly affect the number of myelinated axons or myelin thickness. Instead, calcium attenuation causes myelination defects resulting in shorter, dysmorphic sheaths. Mechanistically, calcium attenuation reduces actin filaments in oligodendrocytes, and an intact actin cytoskeleton is necessary and sufficient to achieve accurate myelin morphology. Together, our work reveals a cellular mechanism required for accurate CNS myelin formation and may provide mechanistic insight into how oligodendrocytes respond to neuronal activity to sculpt and refine myelin sheaths., (© 2024. The Author(s).)