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Context: It is hypothesized that gut dysbiosis, a typical feature of patients with autism spectrum disorder (ASD), could be involved in the origin of this neurodevelopmental disorder. Therefore, the use of probiotics to restore gastrointestinal (GI) equilibrium might be a promising therapeutic strategy due to its capacity to balance the gut-brain axis and behavioral responses., Objective: To summarize current knowledge on the use of probiotics to treat core clinical ASD symptoms and concomitant GI signs, compare the design of published studies with those of ongoing trials, assess the near future of this field, and provide recommendations for improving novel studies., Data Sources: The literature search was conducted in February 2020 and updated in March 2021, using a broad range of bibliographic and clinical trial-specific databases., Data Extraction: Data were extracted using a standardized form, and articles reporting on 28 clinical studies (already published or still ongoing) were included. The risk of bias in clinical studies was evaluated using the Cochrane Collaboration Risk of Bias Assessment tool for randomized trials and the Risk of Bias in Nonrandomized Studies-Interventions tool for nonrandomized trials., Results: The results suggest that probiotics improve ASD-like social deficits, GI symptoms, and gut microbiota profile. However, inconsistencies among studies and their methodological limitations make it difficult to draw any conclusions regarding the efficacy of probiotics in ASD. This review provides specific suggestions for future research to improve the quality of the studies., Conclusions: Although ongoing studies have improved designs, the available knowledge does not permit solid conclusions to be made regarding the efficacy of probiotics in ameliorating the symptoms (psychiatric and/or GI) associated with ASD. Thus, more high-quality research and new approaches are needed to design effective probiotic strategies for ASD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is rising in prevalence and is associated with better survival than HPV-negative OPSCC. In surgically treated HPV-negative OPSCCs, adverse pathologic features such as positive surgical margins, extra-nodal extension (ENE) and perineural invasion are well described to portend worse clinical outcomes. These adverse pathological features, however, are not validated prognostic markers among surgically treated HPV-positive OPSCCs. To that end, we pooled all available evidence to address the prognostic significance of these histologic features., Patients and Methods: This meta-analysis was performed according to PRISMA guidelines. PubMed, Web of Science and Embase databases were systematically searched for articles evaluating 13 known adverse histopathological prognostic factors of surgically treated HPV-associated OPSCC. Data analysis was done using R v4.0.5., Results: A total of 32 studies (n = 31,535) fulfilled the inclusion criteria. ENE and advanced pT stage were associated with poorer overall survival (OS) [hazard ratio (HR):1.80, 95% confidence interval (CI) [1.59-2.03], p < 0.0001, HR: 3.28, 95% CI [2.20-4.87], p = 0.0025]; disease-specific survival (DSS) (HR: 3.14, 95% CI [1.20-8.26], p = 0.0327, HR: 3.49, 95% CI [2.45-4.96], p = 0.0043) and disease-free survival (DFS) (HR: 2.03, 95% CI [1.05-3.94], p = 0.0397, HR: 3.66, 95% CI [2.81-4.77], p = 0.0001) respectively. The presence of lymphovascular invasion (HR: 1.46, 95% CI [1.22-1.75], p = 0.0018) and positive margins (HR: 1.50, 95% CI [1.185-1.899], p = 0.0069) significantly worsen OS., Conclusion: ENE, advanced pT stage, positive margins and lymphovascular invasion were adverse histologic prognostic marker among surgically treated HPV-positive OPSCC. The presence of these factors should be carefully evaluated in order to select the optimal patients for surgical treatment., Competing Interests: Disclosures: The authors have no conflicts of interest to declare. All authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work., (© 2024. Society of Surgical Oncology.)

Purpose: The recently developed EQ Health and Wellbeing Instrument (EQ-HWB) is a broad, generic measure of quality-of-life designed to be suitable for caregivers. The aim of this study was to investigate performance and validity of the 9-item version (EQ-HWB-S) for caregivers where families had experienced adverse-life-events., Methods: Using survey data from caregivers of children aged 0-8 years attending a community-health centre in 2021-2022, the general performance, feasibility, convergent and known-group validity, responsiveness-to-change, and test-retest reliability of the EQ-HWB-S was assessed. Twelve semi-structured interviews were conducted with survey respondents to assess acceptability and content validity., Results: The sample included  234 caregivers at baseline (81% female, mean age 36-years, 38% Australian-born) and 190 at 6-months follow-up. Most EQ-HWB-S item responses were evenly spread, except for 'Mobility'. The instrument showed good convergent validity with psychological distress (Kessler 6 (K6)) and personal-wellbeing (PWI-A) scales. EQ-HWB-S level sum-scores and preference-weighted scores were significantly different in all known-group analyses, in expected directions, and the instrument was responsive to change. For test-retest reliability, Intraclass Correlation Coefficients were excellent and individual item Kappa scores were moderate. The instrument was well received by interviewees who found the questions clear and relevant. The items were appropriate for parents experiencing adversity and carers of children with additional needs., Conclusion: The EQ-HWB-S appeared valid, responsive to change, feasible, and well accepted by caregivers. By demonstrating the validity of the EQ-HWB-S in this hard-to-reach population of caregivers in families experiencing adverse events, this study adds to existing international evidence supporting its use., Competing Interests: Declarations. Conflict of interest: Professor Nancy Devlin and Dr Tessa Peasgood are members of the EuroQol Group. There are no other known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. The Author(s).)

Competing Interests: Disclosure: The authors have no conflicts of interest to declare. All authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

Background: Prehabilitation has been increasingly utilized to optimize perioperative outcomes. In this study, we aim to evaluate the impact of uni- and multimodal prehabilitation on functional capacity and postoperative outcomes among surgical oncology patients undergoing major abdominal surgery., Patients and Methods: Three electronic databases (PubMed, Embase, Cochrane) were systematically searched up until December 2023. We included randomized controlled trials comparing prehabilitation to standard of care in surgical oncology patients undergoing major abdominal surgery. Our primary outcome was functional capacity as measured by the 6-min walk distance (6MWD). Secondary outcomes include postoperative complications, emergency readmissions, and length of stay (LOS). We stratified our findings to determine the impact of uni- versus multimodal prehabilitation on outcomes., Results: We included 27 studies with 2532 surgical oncology patients. Overall, patients undergoing prehabilitation demonstrated a significant improvement in preoperative functional capacity compared to those without prehabilitation (mean difference in 6MWD 28.32 meters [m], 95% CI 15.26, 41.39, p < 0.01). Prehabilitation was also associated with significantly lower odds of postoperative complications (odds ratio [OR] 0.60, 95% CI 0.46, 0.78, p < 0.01). There was no difference in emergency readmission (OR 0.90, 95% CI 0.59, 1.38, p = 0.61) or LOS (mean difference -0.42 days, 95% CI -1.01, 0.16, p = 0.15). Comparing uni- versus multimodal prehabilitation, multimodal prehabilitation was associated with greater improvements in functional capacity (6MWD 37.35 m versus 13.38 m) and lower odds of postoperative complications (OR 0.61, 95% CI 0.45, 0.82, p < 0.01 versus OR 0.63, 95% CI 0.36, 1.11, p = 0.10) CONCLUSION: Prehabilitation improves functional capacity and reduces postoperative complications among surgical oncology patients undergoing major abdominal surgery., Competing Interests: Disclosure: The Authors declare that there is no conflict of interest. The above study was approved by SingHealth Centralized Institutional Review Board and informed consent obtained prior to enrolment. Deidentified data are available upon requests. Ethical approval: The above study was approved by SingHealth Centralized Institutional Review Board and informed consent obtained prior to enrolment., (© 2024. Society of Surgical Oncology.)

Predictive genetic testing is increasingly available for individuals with a heightened risk of motor neuron disease (MND). However, little is known about how they decide whether or not to get tested, and how they experience this process. This paper reports findings from a constructivist grounded theory-informed interview study with 24 family members of people with identified or suspected inherited MND (iMND). Fourteen did not know their genetic status, and nine had decided to have predictive testing, of whom six tested positive for the pathogenic gene variant identified in their family and three tested negative. One additional person was identified as negative through a parent's negative result. This paper explores the diverse ways people approached testing, and the many factors and motivations involved, based on personal attitudes and goals, experiences of living with genetic risk, and wider family considerations and circumstances. Results were met with a range of emotions; whatever the outcome, the news disrupted each person's view of the future, and they adapted in their own way and time. Support after results was variable and a perceived lack of support impacted coping and the ability to move forwards. This paper situates findings against literature on other genetic conditions, highlighting experiences as grounded in the unique characteristics of iMND. Thus, it emphasizes the need for disease-specific guidelines and support structures around predictive genetic testing in this context. Understanding people's experiences and responding to these needs is particularly timely given the uptake of testing amongst this group is anticipated to rise with increasing access to genetic testing for people with MND, and gene-specific clinical trials., (© 2024 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Background & Aim: Understanding local vulnerability to heat and cold is crucial for public health planning, yet few studies have provided a nationwide analysis of temperature-related mortality across diverse communities. This study analyses the association between ambient air temperature and non-accidental mortality across mainland Norway, using a constrained hierarchical clustering algorithm to group municipalities with similar geographic, environmental, socioeconomic, and demographic patterns., Methods: This study analysed the association between ambient air temperature and non-accidental mortality across 356 Norwegian municipalities, using daily data from 1996 to 2018. We applied a case time series design with distributed lag non-linear models. A downscaling procedure assessed the effect of 21 vulnerability factors on temperature-related mortality risks, using Principal Components Analysis to explore heterogeneity across clusters., Findings: Cold temperatures contributed to an estimated 3879 deaths per year (95% CI 3718-4130), while heat was associated with 44 deaths annually (95%CI: 29-58). The highest heat-related mortality risk occurred in the South-East, and the highest cold-related risk in the Central-East. Greater heat-related mortality correlated with medium-to sparsely-populated areas, while higher education levels were linked to reduced vulnerability to both heat and cold., Interpretation: By providing the first comprehensive assessment of temperature-related excess mortality and associated risk factors in Norway, our findings underscore the need for targeted, equitable health policies that integrate environmental and socioeconomic factors. These insights are essential to guide climate adaptation strategies, prioritising vulnerable rural communities and socioeconomically disadvantaged groups to mitigate future climate-related health impacts., 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: International guidelines give greatly varying definitions of 25-hydroxyvitamin D (25OHD) insufficiency and deficiency. Vitamin D testing is increasing despite 2016 UK guidance for adults advising routine vitamin D supplementation October-March and year-round for high risk groups. A service evaluation of vitamin D testing and biochemical osteomalacia in the North-East of Scotland (57-58°N) could inform definitions and testing guidance., Methods: We identified adult 25OHD requests 8/7/2008-29/2/2020 and albumin-adjusted serum calcium (aCa), parathyroid hormone (PTH) and alkaline phosphatase (ALP) within 6 months of 25OHD testing. After excluding renal impairment and liver disease, we defined biochemical osteomalacia as ALP >130 IU/L and aCa <2.0 mmol/L and elevated PTH >9.2 or >6.8 pmol/L, depending on the assay. Possible biochemical osteomalacia was defined as 2 of these abnormalities in the absence of the third measurement. From these cases anonymised clinical data were then examined to confirm the diagnosis of osteomalacia., Results: 25,379 eligible patients had 25OHD measured: 25% were <25 nmol/L (6,258/25,379) and 18% <20 nmol/L (4,536/25,379). 0.5% (126/25,379) of eligible patients had biochemical or possible biochemical osteomalacia. After reviewing clinical records, only 0.1% (29/25,379) had clinically confirmed osteomalacia, equivalent to 2-3 cases/y for a population of 0.5 million, none of the untreated cases of clinically confirmed osteomalacia had 25OHD >25 nmol/L. For the entire tested population, when 25OHD was <25 nmol/L untreated osteomalacia confirmed by clinical records was rare (0.4%)., Conclusions: Osteomalacia is rare in North-East Scotland. Our data call into question designating 25OHD 25-50 nmol/L 'insufficiency'. The risk of osteomalacia even when 25OHD is <25 nmol/L is very low., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MJB is a recipient of a Health Research Council of New Zealand Clinical Practitioner Research Fellowship. The authors are independent of the HRC. The HRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. There are no competing interests for any other author.

To address the challenges posed by influenza, its associated complications, and economic burden, the World Health Organization recommends a vaccination rate exceeding 75 % for populations at elevated risk of severe diseases. Presently, vaccination rates in Germany severely lag behind. To augment these rates, pilot projects have been initiated, allowing community pharmacists to administer vaccines. This study aimed to investigate the the acceptability of pharmacy-led influenza vaccinations among clients and pharmacists, clients' motivations to get vaccinated in community pharmacies, and the rate of adverse events during this process. Data were obtained through anonymous questionnaires from influenza vaccination pilot projects in various German regions between 2020 and 2023. The questionnaire consisted of two sections: one for the vaccinating pharmacist to record and document the vaccination process and one for the recipient, focusing on their experiences and views. In total 11,571 responses were evaluated. Notably, 44 % of participants mentioned they would not have sought vaccination outside a pharmacy setting. This percentage was higher (65 %) in those receiving their first influenza vaccination. Vaccinees reported high levels of satisfaction with the supplied information (88.5 %) and vaccination procedure (93.8 %). Furthermore, clients declared a high willingness to repeat the vaccination (93.9 %) and the possibility of receiving other vaccinations in pharmacies (79.7 %). Among all surveyees, only nine reported adverse reactions post pharmacy-administered vaccination, with none necessitating emergency intervention. Pharmacy-led influenza vaccinations were identified as safe, well-received by vaccinees and effective in increasing vaccination acceptability with the potential to enhance vaccination rates across diverse demographics in Germany., 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 Ltd.. All rights reserved.)

Levayer and colleagues assessed integrity issues in randomized controlled trials (RCTs) in four spine journals using baseline p -values from categorical variables, concluding that there was no evidence of 'systemic fraudulent behaviour'. We used their published dataset to assess the accuracy of reported p -values and whether observed and expected distributions of frequency counts and p -values were consistent. In 51 out of 929 (5.5%) baseline variables, the sum of frequencies did not agree with the reported number of participants. For one-third of reported p -values (172 out of 522), we could not calculate a matching p -value using a range of statistical tests. Sparse data were common: for 22% (74 out of 332) of variables in which the reported p -value matched the p -value calculated from a chi-square test, the expected cells were smaller than recommended for the use of chi-square tests. There were 20-25% more two-arm trials with differences in frequency counts of 1 or 2 between-groups than expected. There were small differences between observed and expected distributions of baseline p -values, but these depended on analysis methods. In summary, incorrectly reported p -values and incorrect statistical test usage were common, and there were differences between observed and expected distributions of baseline p -values and frequency counts, raising questions about the integrity of some RCTs in these journals., Competing Interests: We have no financial conflicts to declare. M.J.B. is the author of the reappraised statistical package., (© 2025 The Author(s).)

Subsequent fracture rates and associated mortality were compared before and after the introduction of fracture liaison service (FLS). In 100,198 women and men, FLS was associated with 13% and 10% lower risk of subsequent fragility fractures and 18% and 15% lower mortality. The study suggests that FLS may prevent fractures., Purpose: Efficient fracture prevention strategies are warranted to control the global fracture burden. We investigated the effect of a standardized fracture liaison service (FLS) intervention on subsequent fracture risk and mortality., Methods: The NoFRACT study was designed as a multicenter, pragmatic, register-supported, stepped-wedge cluster-randomized trial. The FLS intervention was introduced in three clusters with 4-month intervals starting May 2015 through December 2018 and included evaluation of osteoporosis and treatment in patients over 50 years with a low-energy fracture. Based on data from the Norwegian Patient Registry, patients with index fractures were assigned to the control period (2011-2015) or intervention period (2015-2018) depending on the time of fracture. Rates of subsequent fragility fractures (distal forearm, proximal humerus, or hip) and all-cause mortality were calculated., Results: A total of 100,198 patients (mean age 69.6 years) suffered an index fracture of any type. During a maximum follow-up of 4.7 years, 11% (6948) of the women and 6% (2014) of the men experienced a subsequent fragility fracture, and 20% (14,324) of the women and 22% (8,326) of the men died. FLS was associated with 13% lower subsequent fragility fracture risk in women (hazard ratio (HR) 0.87, 95% confidence intervals (CI) 0.83-0.92) and 10% in men (HR 0.90, 95% CI 0.81-0.99) and 18% lower mortality in women (HR 0.82, 95% CI 0.79-0.86) and 15% in men (HR 0.85, 95% CI 0.81-0.89)., Conclusion: A standardized FLS intervention was associated with a lower risk of subsequent fragility fractures and mortality and may contribute to reduce the global fracture burden., Competing Interests: Declarations. Ethical approval: All procedures performed in the study were in accordance with the 1964 Helsinki Declaration and its later amendments. The study was approved by the Regional Committee of Medical and Health Research Ethics (REK 2015/334). The merging of data using the personal identification number and exemption from obtaining consent for the collection of data was approved by the Regional Committee of Medical and Health Research Ethics (REK 2015/334). A Data Protection Impact Assessment (DPIA) in agreement with the General Data Protection Regulation was performed by The University of Oslo. The study was approved by the Patient Data Protection Officer (PVO) at each of the hospitals and the PVO provided exemption from obtaining consent from the participants and authorized a secure research server for storage of the audit data. Conflict of interest: CA, CD, TB, TW, GH, JMS, IL, AKH, FIN, LN, TKO, and ÅB no support from any organization for the submitted work; FF reports lecturing fees from UCB and Amgen; TTB reports speaker fees from UCB, Amgen, Roche Diagnostics, and Pharma Prim and participation in an advisory board for UCB. Further, FF is president of the Fragility Fracture Network which is sponsored by Amgen, UCB, and Danone; JEG reports lecture fees from Ortomedic Norway, Smith and Nephew, Heraeus Medical, and LINK Norway; WF reports lecture fees from Ortomedic Norway and Zimmer Biomet Norway; EMA reports participation in the advisory board for UCB and Amgen; RMJ reports consulting fees from Norwegian Directorate of Health, Norwegian Diabetes Association, and Northern Norway Regional Health Authority and lecture fees from Novo Nordisk, Eli-Lilly, Astra-Zeneca, and Sanofi; US reports speaker and consulting fees from Amgen, UCB, and Novartis; EFE reports consultant fees from Novartis, UCB, Amgen, Takeda, and Pharma Medico and research support from Takeda and Amgen. Further, EFE has worked as a medical consultant for the Norwegian Osteoporosis Society; LBS reports speaker fees from Eli Lilly, Amgen, and UCB. Further, LBS is the president of Fragility Fracture Network Norway., (© 2025. The Author(s).)

Objectives: Restriction of life space mobility is associated with adverse health outcomes including depression, morbidity, mortality and poorer quality of life. In this study, we aimed to determine the impact of COVID-19 and associated employment loss on the life space of older adults in Singapore., Methods: An in-person survey was administered to a cohort of older Singaporeans above 50 years old (N = 1,118). Data collected included self-report measures of life space, sensory function, well-being, cognitive function, depression, frailty, and objective measures of muscle mass and body mass index. Tests of association and linear regression were performed to test the hypotheses, while accounting for the effects of health and sociodemographic covariates., Results: The life space of older adults have significantly diminished after the pandemic. This loss remained significant despite controlling for covariates and was more pronounced amongst those who had lost employment during the pandemic. In addition, losing employment during the pandemic was associated with having smaller life spaces., Discussion: Life space assessments are a potential important noninvasive marker for not only health and longevity, but the ability to sustain employment. Public health crises like the COVID-19 pandemic and employment loss negatively impacts the life spaces of older adults. It is needful to emphasize the maintenance of life space when faced with disruptive life events and provide multidisciplinary collaborative solutions to restore the quality of life amongst vulnerable older adults., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Gerontological Society of America.)

Objective: To assess the acceptability and impacts of a co-designed health education model aiming to improve outcomes for children with emotional and behavioural difficulties., Design: Qualitative focus group study., Setting: Six primary schools from metropolitan and rural settings in the state of Victoria, Australia., Participants: 36 educators who engaged with the intervention between July and December 2021., Intervention: Co-designed community of practice, led by a paediatrician, with fortnightly tailored case-based discussions aiming to build educator capacity to identify and support children with emotional and behavioural difficulties., Main Outcome Measures: At the completion of the intervention, all educators were invited to participate in focus groups with their school group. The lead author facilitated the groups. Semistructured questions guided the sessions focusing on the motivation of participants, their experience of the intervention, its impact on their work and suggestions for possible improvements and impact upon their own well-being. Sessions were audio recorded, and field notes were taken by the facilitator. Interpretative phenomenological analysis was carried out to evaluate the data collected., Results: 36 of 46 educators completed six focus groups (one per school). Participants were highly motivated due to the mental health needs of their students. Participants experienced the intervention as stimulating and providing practical strategies. Participants discussed the positive impact it had on their capacity to support children with emotional and behavioural difficulties as well as their own well-being., Conclusions: The intervention is highly acceptable to educators, and evaluating this intervention with a larger sample will inform expansion., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: The challenges of recruiting and retaining rural GPs are well described. UK data suggests high levels of burnout, characterised by detachment, exhaustion and cynicism, plays a role in GP turnover. The contrast is engagement with work. There is limited evidence examining the relationship between work engagement and recruitment and retention in rural areas., Aim: To qualitatively investigate GPs decisions to move or stay in rural areas through exploring areas that can promote work engagement., Design and Setting: A secondary analysis of qualitative data of Scottish GPs., Method: A secondary analysis of 44 semi-structured interviews with GPs from across Scotland. Data was analysed thematically and the Areas of Worklife Scale (AWS) was used to structure data., Results: Factors associated with burnout were identified and experienced as barriers to moving or staying rurally. Fear of dealing with pre-hospital emergency cases, clinical isolation and rural training were concerns. Personal factors such as lack of partner employment played a key role in migration decisions. Factors associated with engagement were identified and experienced as facilitators for moving or staying rurally. Professional networks reduced professional isolation and rural GPs valued increased autonomy and time. Many felt rural GP was more aligned with their professional values and highly valued the rural lifestyle for themselves and their families., Conclusion: Our data suggests that factors associated with engagement and burnout can contribute to rural GPs' migration decisions. We highlight four areas that could promote desirable work environments through mitigation of burnout and promoting engagement at work., (Copyright © 2024, The Authors.)

The role of biomarkers in risk-based early detection of lung cancer may enable screening to become cost effective and widely accessible. EarlyCDT-Lung is an example of such a blood-based autoantibody biomarker which may improve accessibility to Low dose Computed Tomography (LDCT) screening for those at highest risk. We randomized 12 208 individuals aged 50-75 at high risk of developing lung cancer to either the test or to standard clinical care. Outcomes were ascertained from Register of Deaths and Cancer Registry. Cox proportional hazards models were used to estimate the hazard ratio of the rate of deaths from all causes and lung cancer. Additional analyses were performed for cases of lung cancer diagnosed within two years of the initial test. After 5 years 326 lung cancers were detected (2.7% of those enrolled). The total number of deaths reported from all causes in the intervention group was 344 compared to 388 in the control group. There were 73 lung cancer deaths in the intervention arm and 90 in the controls (Adjusted HR 0.789 (0.636, 0.978). An analysis of cases of lung cancer detected within 2 years of randomization in the intervention group showed that there were 34 deaths from all causes and 29 from lung cancer. In the control group there were 56 deaths with 49 from lung cancer. In those diagnosed with lung cancer within 2 years of randomization the hazard ratio for all cause mortality was 0.615 (0.401,0.942) and for lung cancer 0.598 (0.378, 0.946). Further large-scale studies of the role of biomarkers to target lung cancer screening, in addition to LDCT, are likely to provide additional value., Competing Interests: F.M. Sullivan reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. F.S. Mair reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. W. Anderson has nothing to disclose. C. Chew has nothing to disclose. A. Dorward has nothing to disclose. J. Haughney has nothing to disclose. F. Hogarth reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and from Oncimmune, during the conduct of the study. D. Kendrick has nothing to disclose. R. Littleford reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. A. McConnachie reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. C. McCowan has nothing to disclose. N. McMeekin reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. M. Patel has nothing to disclose. P. Rauchhaus reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. L. Ritchie has nothing to disclose. J. Robertson reports other funding from Oncimmune, during the conduct of the study; and other funding from Oncimmune, outside the study. J. Robertson was a founder of Oncimmune, a company spun out from the University of Nottingham based on his academic research. Between 2003 and 2013 he was Chief Scientific Officer of Oncimmune and a Director of the company. During this time, he was responsible for the original drafting of the ECLS protocol. Since 2013 he has had no involvement in the science or management of the company. He has been and remains a shareholder in the company. J. Sarvesvaran has nothing to disclose. H. Sewell reports other funding from Oncimmune, outside the submitted work; and was an external member of the Oncimmune Scientific Advisory Board from 2006 to 2013. T. Taylor reports grants, nonfinancial support and other funding from Oncimmune, grants and personal fees from the Chief Scientist Office for Scotland, and grants and nonfinancial support from the Scottish Government, outside the submitted work. S. Treweek reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. K. Vedhara has nothing to disclose. S. Schembri reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study., (Copyright: © 2025 Sullivan 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.)

Importance: Despite the recovery advantages of minimally invasive surgical techniques, delayed return of gut function after colectomy is a common barrier to timely discharge from hospital., Objective: To evaluate the effect of 2% perioperative intravenous lidocaine infusion on return of gut function after elective minimally invasive colon resection., Design, Setting, and Participants: The ALLEGRO trial was a randomized, placebo-controlled, double-blind trial conducted in 27 UK hospitals. A total of 590 adults scheduled for elective minimally invasive colon resection for benign or malignant disease were randomized 1:1 to 2% intravenous lidocaine or saline placebo. Enrollment occurred from August 13, 2018, to April 11, 2023, with a pause in recruitment from March 20, 2020, through July 6, 2020; final follow-up was on August 10, 2023., Interventions: The intervention patients received 2% intravenous lidocaine administered as 1.5-mg/kg bolus at induction of anesthesia followed by 1.5 mg/kg/h for 6 or 12 hours. Control patients received 0.9% saline placebo for 6 or 12 hours., Main Outcomes and Measures: The primary outcome was the proportion of patients with return of gut function at 72 hours after surgery, defined by the GI-3 composite end point of tolerating diet (ingestion of food and drink without significant nausea or vomiting for 3 consecutive meals) and passage of flatus or stool. There were 11 secondary outcomes, including time to GI-3 recovery, time to GI-2 recovery (tolerance of oral diet and passage of stool), prolonged postoperative ileus, postoperative nausea and vomiting score, Overall Benefit of Analgesia Score, postoperative opioid consumption, Quality of Recovery-15, quality of life (EuroQol 5-Dimension 5-Level), enhanced recovery protocol adherence, time to meeting medically defined criteria for discharge, and time to patient self-assessed readiness for discharge., Results: The trial enrolled 590 patients (295 intervention, 295 control); after 33 postrandomization exclusions, 557 patients were included (279 intervention, 278 control; 249 female patients [44.7%]; mean [SD] age, 66 [10.9] years); 532 (96%) received the randomized treatment. Return of gut function as defined by the GI-3 composite outcome was achieved at 72 hours by 160 patients (57.3%) in the intravenous lidocaine group vs 164 patients (59.0%) in the placebo group (adjusted absolute difference, -1.9% [95% CI, -8.0% to 4.2%]; relative risk, 0.97 [95% CI, 0.88 to 1.07]). There was no significant difference between the intervention and control groups in any of the 11 secondary end points., Conclusions and Relevance: Among patients undergoing elective minimally invasive colon resection, perioperative administration of 2% intravenous lidocaine did not improve return of gut function at 72 hours., Trial Registration: isrctn.org Identifier: ISRCTN52352431.

Objective: Identification of patients with head-and-neck malignancies who are especially vulnerable to malnutrition is critical for optimizing outcomes. The objectives are; to correlate Bioelectrical-impendence-analysis (BIA) parameters with Subjective-Global-Assessment (SGA) scores, and determine the association of BIA parameters with common perioperative complications in patients undergoing head-and-neck surgery., Study Design: Patients underwent formal SGA scoring and BIA preoperatively in a multidisciplinary allied health clinic., Settings: This is a cohort study of 61 patients with head-and-neck malignancies who were admitted for elective surgery from 2018 to 2019 in a tertiary hospital in Singapore., Methods: BIA was performed using the Bodystat Quadscan 4000. Kruskal-Wallis rank sum tests and were performed for associations between SGA and BIA parameters. Wilcoxon rank sum tests and multivariable logistic regression models (Firth's bias reduction method) were performed to evaluate associations between BIA parameters and perioperative complications. Receiver-operating-characteristic (ROC) curves were plotted for determination of optimal cut-off values of phase angle and Wellness marker in detecting malnutrition and perioperative pneumonia using Youden's-Index (YI)., Results: 45 males and 16 females with median age of 62 were included in the study. Significant differences were observed in Wellness Marker ( P  = .006) and phase angle ( P  = .008) among patients in the 3 SGA categories. The Wellness Marker ( P  = .02) was associated with perioperative pneumonia in the univariate analysis. No significant differences were observed for other perioperative complications studied., Conclusion: BIA shows promise as a preoperative tool, in conjunction with SGA, to detect malnutrition in patients undergoing surgery for head-and-neck malignancies and highlight patients at risk of developing perioperative pneumonia., Competing Interests: None., (© 2025 The Author(s). OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background: Acceptance and Commitment Therapy (ACT) has been found to be beneficial for individuals dealing with chronic pain. The theoretical mechanisms of change proposed by ACT are based on the Hexaflex model. To comprehensively reflect this model, the Multidimensional Psychological Flexibility Inventory (MPFI) and Psy-Flex have been developed. The study aimed to adapt the MPFI-24 and the Psy-Flex for Spanish-speaking populations with chronic pain and to examine their dimensionality, internal consistency, convergent validity and incremental validity., Methods: This cross-sectional study involved 309 Spanish-speaking adults with chronic pain who completed an online survey. The majority of the participants were women (88.3%). The ages ranged from 18 to 79 years., Results: Factor analysis showed that the Spanish version of the MPFI-24 has 12 factors, consisting of six flexibility and six inflexibility factors, similar to the original version, but lacking second-order general factors. The Psy-Flex demonstrated a single-factor structure, maintaining the general factor of psychological flexibility seen in the original version. The MPFI-24 showed good internal consistency and adequate convergent validity, with the exception of the Acceptance and Experiential Avoidance subscales. The Psy-Flex showed good internal consistency and convergent validity. Notably, both the MPFI-24 and Psy-Flex scores significantly explained additional variance in psychological distress beyond other ACT-related measures of Hexaflex processes; however, only the Psy-Flex explained pain interference., Conclusions: The Spanish adaptations of the MPFI-24 and Psy-Flex are valid and reliable instruments for assessing the Hexaflex model processes in Spanish-speaking adults with chronic pain., Significance Statement: Practitioners and researchers in chronic pain will find the Spanish versions of the MPFI-24 and the Psy-Flex here, along with recommendations for their use and scoring based on a robust psychometric rationale. It should be noted that these measures surpass the Chronic Pain Acceptance Questionnaire (CPAQ) and the Psychological Inflexibility in Pain Scale (PIPS), which are considered gold standards in chronic pain assessment., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background: Immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) are a treatment-limiting barrier. There are few large-scale studies that estimate irAE prevalence. This paper presents a systematic review that reports the prevalence of irAE by cancer type and ICI., Methods: A systematic review was undertaken in MEDLINE OVID, EMBASE and Web of Science databases from 2017-2021. A total of 293 studies were identified for analysis and, of these, event rate was calculated for 272 studies, which involved 58,291 patients with irAE among 305,879 total patients on ICI. Event rate was calculated by irAE and ICI type., Results: Mean event rate for general irAE occurrence across any grade was 40.0% (37.3-42.7%) and high grade was 19.7% (15.8-23.7%). Mean event rates for six specific types of irAE are reported. Mean event rate for ICI monotherapy was 30.5% (28.1-32.9%), 45.7% (29.6-61.7%) for ICI combination therapy, and 30.0% (25.3-34.6%) for both ICI monotherapy and combination therapy., Conclusion: This systematic review characterises irAE prevalence across current research that examines irAE risk factors across cancers and ICI. The findings confirms that irAE occurrence is very common in the real-world setting, both high grade and irAE across any grade., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Traditional methods for medical device post-market surveillance often fail to accurately account for operator learning effects, leading to biased assessments of device safety. These methods struggle with non-linearity, complex learning curves, and time-varying covariates, such as physician experience. To address these limitations, we sought to develop a machine learning (ML) framework to detect and adjust for operator learning effects., Materials and Methods: A gradient-boosted decision tree ML method was used to analyze synthetic datasets that replicate the complexity of clinical scenarios involving high-risk medical devices. We designed this process to detect learning effects using a risk-adjusted cumulative sum method, quantify the excess adverse event rate attributable to operator inexperience, and adjust for these alongside patient factors in evaluating device safety signals. To maintain integrity, we employed blinding between data generation and analysis teams. Synthetic data used underlying distributions and patient feature correlations based on clinical data from the Department of Veterans Affairs between 2005 and 2012. We generated 2494 synthetic datasets with widely varying characteristics including number of patient features, operators and institutions, and the operator learning form. Each dataset contained a hypothetical study device, Device B, and a reference device, Device A. We evaluated accuracy in identifying learning effects and identifying and estimating the strength of the device safety signal. Our approach also evaluated different clinically relevant thresholds for safety signal detection., Results: Our framework accurately identified the presence or absence of learning effects in 93.6% of datasets and correctly determined device safety signals in 93.4% of cases. The estimated device odds ratios' 95% confidence intervals were accurately aligned with the specified ratios in 94.7% of datasets. In contrast, a comparative model excluding operator learning effects significantly underperformed in detecting device signals and in accuracy. Notably, our framework achieved 100% specificity for clinically relevant safety signal thresholds, although sensitivity varied with the threshold applied., Discussion: A machine learning framework, tailored for the complexities of post-market device evaluation, may provide superior performance compared to standard parametric techniques when operator learning is present., Conclusion: Demonstrating the capacity of ML to overcome complex evaluative challenges, our framework addresses the limitations of traditional statistical methods in current post-market surveillance processes. By offering a reliable means to detect and adjust for learning effects, it may significantly improve medical device safety evaluation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Considering that the remission rate for major depressive disorder (MDD) in elderly patients is below 50%, there is a compelling requirement for an enhanced comprehension of the underlying mechanisms. Chronic low-grade inflammation has been posited as one potential contributor to treatment-resistant MDD in the elderly. Accordingly, the objective of our study was to explore the longitudinal trends of systemic immune markers in elderly inpatients referred to electroconvulsive therapy due to an episode of treatment resistant unipolar MDD., Methods: The study encompassed 64 elderly inpatients with unipolar MDD that had failed to respond to therapy in primary health care, and 18 non-depressed controls. Blood samples were collected at pre-treatment, mid-treatment, post-treatment and 12 weeks follow-up. We assessed 27 immune markers via multiplex assays. Depressive symptoms were evaluated using the Hamilton Rating Scale of Depression at these timepoints. For controls, the immune markers and depressive symptoms, were measured at baseline and eight weeks follow-up using identical methods., Results: At follow-up, patients showed higher concentrations of 23 immune markers compared to controls, although the concentration of 19 immune markers decreased significantly from pre-treatment to follow-up. No differences in immune marker concentrations between treatment responders and non-responders were observed pre- and post-treatment in the patient group., Conclusion: Our findings suggest that a pro-inflammatory trait persists in elderly after an episode of treatment resistant unipolar MDD. Thus, our study supports that chronic low-grade inflammation may characterise elderly with treatment-resistant unipolar MDD.

Background: There is evidence of rapidly growing resistance to antibiotics across Africa. We aimed to establish whether blood culture and sensitivity (BCS) testing is a feasible component of the response to antimicrobial resistance (AMR) in large Kenyan hospitals., Methods: We used a qualitative study design and conducted key informant interviews (KIIs) using iteratively developed, semi-structured interviews with purposively sampled health-care workers (HCWs) within a network of facilities in Kenya called the Clinical Information Network. Only hospital laboratories that either reported fewer than 50 BCS tests in the previous 6 months or had not recorded use of BCS tests for the past 6 months were included in this study. This selection was further limited by considerations of timing, logistics, and data saturation. Our purposive selection of interviewees was guided by the level of expertise, profession, the number of key informants per hospital, and existing relations with the hospital staff. Each interview took an average of 45 min. Our thematic analysis used inductive coding to identify key themes, and we used causal loop diagrams (CLDs) to explain interactions between themes. The CLDs illustrate how health system issues relate to each other and influence the use of BCS testing in these study settings., Findings: We conducted 72 KIIs across eight tertiary-level Kenyan hospitals between Oct 27 and Dec 2, 2021. Of the 72 HCWs interviewed, 33 (46%) were women and 39 (54%) were men. The participants consisted of 24 clinicians, 26 laboratory staff, and 22 pharmacists with a median age of 36 years (IQR 31-40). We found that the main issues that led to insufficient use of BCS testing in these hospitals related to demand and supply. A host of issues influence clinician demand for BCS testing, including: the use and uptake of BCS, normalisation of clinical diagnosis, unaffordability of the BCS test, turnaround time of the BCS test, preferential use of alternative biochemistry and haematology tests by clinicians, diagnosis by malaria confirmation, and negative results discouraging clinicians from ordering this test. Similarly, health system logistics or supply issues, including laboratory capacity, support and goodwill from hospital management, and scarcity of refresher training opportunities, hinder the availability and sustenance of BCS testing. The CLDs show that these multiple factors can create mutually reinforcing feedback loops that undermine efforts to provide BCS testing in hospitals., Interpretation: The findings suggest that sustainable and routine provision of BCS testing would require many issues to be targeted simultaneously and continuously at the health system level, which is unlikely to be feasible in the short term for Kenyan hospitals. Therefore, in these settings, alternatives to routine BCS testing-such as the adoption of a targeted or vertical approach and the use of survey-informed antimicrobial stewardship to inform local treatment guidelines-should be considered for the control of AMR., Funding: Wellcome Trust., Competing Interests: Declaration of interests SA, JM, and ME received a grant from the Wellcome Trust (London, UK). The funding from the grant supported this work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To perform an economic evaluation to determine whether or not teledermatology (TD) units in primary care (PC) centers offer an alternative in terms of cost-utility and cost per quality-adjusted life years (QALYs) to conventional dermatology consultations (face-to-face dermatology [F-F/D]) at the hospital from the perspective of the Public Health System (PHS) and the patients., Methods: This is a randomized, controlled, nonblinded, and multicenter study. During 6 months, data from 450 patients (TD: 225 vs. F-F/D: 225) were collected. From both perspectives, costs, quality of life, and costs per QALYs were analyzed. The QALY scores were estimated from the EuroQol-5D-5L (EQ5D-5L) questionnaire responses., Results: From the perspective of the PHS, the cost per patient was 53.04% lower in the TD group (p < 0.001). Hospital visits decreased by 72.43% in the TD group (p < 0.001). From the patients' perspective, TD reduced costs per patient by 77.59% (p < 0.001). The cost per QALY was 63.34% higher in the F-F/D group (p < 0.001). The TD group's total costs were 56.34% lower (p < 0.001). Furthermore, patients in the TD group gained 0.05 QALYs more than those in the F-F/D group (p = 0.004)., Conclusions: This study shows that TD units in PC represent a significant cost-effective alternative to conventional hospital follow-up. To enhance TD in PC, it is important to introduce remote consultation platforms incorporating artificial intelligence for prediagnosis. This will enable general practitioners and nurses to make more accurate initial assessments. It is also crucial to provide thorough training to healthcare personnel using these technologies to ensure more efficient and personalized care. Public health nurses will benefit from gaining new skills in managing digital tools, which will help in the early identification of dermatological diseases and reduce unnecessary referrals to specialists. This will optimize resources and improve response times for patients., (© 2024 Wiley Periodicals LLC.)