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Focuses on the ecology of organizational demography. Interorganizational interdependencies created by turnover processes in top management; Effect of differences in managerial tenure; Impact of overlap in managerial capabilities.

AIM: Excision repair cross complementation group 1 (ERCC1) is a promising biomarker in advanced non-small cell lung cancer (NSCLC). However, current evidence regarding the impact of ERCC1 on toxicity and quality of life (QOL) is limited. PATIENTS AND METHODS: Four hundred and forty three patients with advanced NSCLC were enroled in a phase III trial and randomized to triplet chemotherapy or standard doublet regimen. Immunohistochemical evaluation for ERCC1-status was mainly performed on bioptic material. Toxicity and patient-reported QOL were correlated to ERCC1-status. RESULTS: We observed a significantly improved outcome in patients with ERCC1-negative (ERCC1-neg) tumours and demonstrated interaction between ERCC1-status and adenocarcinomas. Numerically more toxicity was observed in the entire population of ERCC1-neg tumours and reached significance in patients with adenocarcinomas regarding leukopenia (P=0.015), nausea/vomiting (P=0.040) and neurotoxicity (P=0.037). Mean change in QOL in the entire population was -13.33 (ERCC1-neg; P=0.001) and -2.25 (ERCC1-positive (ERCC1-pos): P=0.607) and -14.86 (ERCC1-neg; P=0.006) and 0 (ERCC1-pos) in patients with adenocarcinomas. CONCLUSIONS: Patient-reported QOL deteriorated significantly among survival-favourable ERCC1-neg patients possibly due to increased toxicity especially in patients with adenocarcinomas. Our novel findings emphasise strict demands for careful patient selection, proper methodology and prospective validation of ERCC1 to prove a true survival benefit before clinical implementation. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To elucidate cellular features accountable for colorectal cancers’ (CRC) capability to invade normal tissue and to metastasize, we investigated the level of the collagenase matrix metalloproteinase 9 (MMP-9) and its physiological inhibitor tissue inhibitor of metalloproteinases 1 (TIMP-1) in cancer cells and supporting stroma cells of CRC. Methods: Immunoreactivity of MMP-9 and TIMP-1 by carcinoma cells, lymphocytes and fibroblasts in archival specimens of paraffin-embedded primary tumours were retrospectively associated with outcome in 340 consecutive patients completely resected for CRC stages II–IV and subsequently treated with adjuvant 5-fluorouracil. Results: Expression of MMP-9 by carcinoma cells was demonstrated in 9% of specimens without association to recurrence free survival (RFS) (HR=1.0; 95% CI: 0.6–1.8; P =0.9) or overall survival (OS) (HR=0.9; 95% CI: 0.5–1.6; P =0.6). TIMP-1 expression by carcinoma cells, which appeared in 64% of the specimens, was inversely related with RFS (HR=1.3; 95% CI: 0.9–1.8; P =0.08) and OS (HR=1.5; 95% CI: 1.1–2.1; P =0.02). Expression of TIMP-1 by fibroblasts at the invasive border was directly related to RFS (HR=0.7; 95% CI: 0.6–0.9; P =0.02) and OS (HR=0.7; 95% CI: 0.6–1.0; P =0.05). Expression of MMP-9 by lymphocytes correlated significantly with the degree of peritumoural inflammation (P =0.02) but not with RFS (HR=0.9; 95% CI: 0.7–1.1; P =0.2) or OS (HR=0.8; 95% CI: 0.7–1.0; P =0.07). Conclusion: TIMP-1 in cancer cells is associated with poor prognosis independent of its function as inhibitor of MMP-9. MMP-9 and TIMP-1 are important mediators of the host–cancer cell interaction in the tumour microenvironment with significant influence on the histopathology and on prognosis of CRC. [ABSTRACT FROM AUTHOR]

Introduction: Healthcare providers' role in co-creating health interventions and implementation strategies has evolved significantly, and yet, there is little documentation of this from low-resource settings. This study aims to share the dilemmas of engaging healthcare providers in co-creating locally adapted clinical guidelines for maternity facilities in Dar es Salaam, Tanzania, and strategies used to address them., Methods: An ethnographic study explored the co-creation of locally adapted clinical guidelines for childbirth care within five maternity facilities in Dar es Salaam. Participant observations were conducted during 11 co-creation workshops. Six in-depth interviews explored participant experiences. Data were analyzed using Attride-Stirling's thematic network analysis framework., Results: The analysis revealed four themes representing dilemmas in the co-creation process and strategies to improve co-creation: (i) navigating diverse contexts: adapting a single set of guidelines to various, diverse facilities was challenging; this was addressed through engaging in dialogue and flexibility while adjusting care practices. (ii) Competing knowledge systems and sources: differing knowledge sources between researchers and healthcare providers challenged discussions on recommended practices. However, validating scientific recommendations with practical care experience in this context helped bridge this gap. (iii) Fostering meaningful participation: participation was time-consuming for some. However, early stakeholder engagement and facility-led participant selection facilitated the meaningful involvement of healthcare providers. (iv) Power imbalances: power dynamics influenced the co-creation process; involving stakeholders in planning and co-facilitating workshops helped mitigate these imbalances and encourage more equal participation., Conclusion: Navigating contextual variation, differences in knowledge systems, meaningful participation and power dynamics were key challenges in the co-creation process. However, reflexivity, open and honest dialogue with stakeholders and early engagement enhanced the co-creation process. Co-creating locally adapted clinical guidelines with frontline healthcare workers and scientific experts is essential for feasibility and safety. Further research is needed to explore context specificity, decision-making and the efficacy of co-creation in low-resource settings., Patient or Public Contribution: Healthcare providers and health managers from five maternity facilities who participated in the co-creation process were actively involved in this study by providing their consent to be interviewed about their experiences of participation., Clinical Trial Registration: This study is a substudy within the PartoMa project. PartoMa is a registered clinical trial with the trial registration number NCT04685668. PartoMa's date of initial trial registration is 28 December 2020., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Background: Most patients with advanced anaplastic lymphoma kinase ( ALK )-rearranged ( ALK +) non-small cell lung cancer (NSCLC) experience prolonged response to second-generation (2G) ALK-tyrosine kinase inhibitors (TKIs). Herein, we present a case of metastatic ALK + NSCLC rapidly progressing on first-line treatment due to de novo amplification of the mesenchymal-epithelial transition factor ( MET ) gene, which is a still elusive and underrecognized mechanism of primary resistance to ALK-TKIs., Case Description: A 43-year-old, female diagnosed with T4N3M1c NSCLC harboring the echinoderm microtubule-associated protein-like 4 ( EML4 ) -ALK fusion variant 1 ( EML4-ALK v.1) and TP53 co-mutation, displayed only mixed response after three months and highly symptomatic progression after 6 months of first-line brigatinib treatment. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis on re-biopsies from a new liver metastasis revealed overexpression of MET receptor (3+ in 80% of tumor cells) and heterogeneously increased MET gene copy number (CN) in tumor cells, including 20% with MET clusters (corresponds to ≥15 gene copies, thus exact CN uncountable by FISH) and the other 80% with median MET CN of 8.3, both changes indicating high-level MET- amplification. DNA and RNA next-generation sequencing (NGS) displayed preserved ALK fusion and TP53 co-mutation, but no additional genomic alterations, nor MET- amplification. Therefore, we retrospectively investigated the diagnostic biopsy from the primary tumor in the left lung with IHC and FISH revealing the presence of increased MET receptor expression (2+ in 100% of tumor cells) and MET- amplification (median MET CN of 6.1), which otherwise was not detected by NGS. Thus, given the well-documented efficacy of alectinib towards EML4-ALK v.1, combined second-line treatment with alectinib and the MET-TKI, crizotinib, was implemented resulting in very pronounced objective response, significantly improved quality of life, and no adverse events so far during the ongoing treatment (6 months)., Conclusions: The combination of alectinib and crizotinib may be a feasible and effective treatment for ALK + NSCLC with de novo MET- amplification. The latter may represent a mechanism of intrinsic ALK-TKI resistance and its recognition by FISH, in NGS-negative cases, may be considered before initiating first-line treatment. This recognition is clinically important as combined therapy with ALK-TKI and MET-inhibitor should be the preferred first-line treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-439/coif). E.M.U. reports research grants from AstraZeneca and Merck; speaker fees from Amgen, AstraZeneca, Janssen and Novartis; travel support related to participation in international scientific meeting from AstraZeneca and Roche; payment for participation in Advisory Board from AstraZeneca, Pfizer, Roche and Takeda. M.G. reports speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim and ThermoFisher Scientific, and received research grants from Merck and Roche. J.B.S. received consulting fees from AstraZeneca, Bristol-Myers Squibb, Merck, Janssen, Roche; received honoraria for lectures from Bristol-Myers Squibb, Janssen; received support for attending meetings and/or travel from AstraZeneca, Janssen, Merck; and received payment for participation in Advisory Board from AstraZeneca, Bristol-Myers Squibb, Genmab, Janssen, Merck, Roche. E.S.R. received research grants from Sanofi and Takeda; reports honoraria for lectures from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Roche, Takeda; and received payment for participation in Advisory Board from Roche and Takeda. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

The most common cause of dementia among elderly people is Alzheimer's disease (AD). The typical symptom of AD is the decline of cognitive abilities, which is caused by loss of synaptic function. Amyloid-β (Aβ) oligomers play a significant role in the development of this synaptic dysfunction. Neuroligin-(NL)1 is a postsynaptic cell-adhesion molecule located in excitatory synapses and involved in the maintenance and modulation of synaptic contacts. A recent study has found that Aβ interacts with the soluble N-terminal fragment of NL1. The present study aimed to elucidate the role of NL1 in Aβ-induced neuropathology. Employing surface plasmon resonance and competitive ELISA, we confirmed the high-affinity binding of NL1 to the Aβ peptide. We also identified a sequence motif representing the NL1-binding site for the Aβ peptide and showed that a synthetic peptide modeled after this motif, termed neurolide, binds to the Aβ peptide with high affinity, comparable to the NL1-Aβ interaction. To assess the effect of neurolide in vivo, wild-type and 5XFAD mice were subcutaneously treated with this peptide for 10 weeks. We observed an increase in Aβ plaque formation in the cortex of neurolide-treated 5XFAD mice. Furthermore, we showed that neurolide reduces the activity of neprilysin, the predominant Aβ-degrading enzyme in the brain. Accordingly, we suggest that neurolide is the NL1-binding site for Aβ peptide, and acts as an inhibitor of neprilysin activity. Based on these data, we confirm the involvement of NL1 in the development of AD and suggest a mechanism for NL1-induced Aβ plaque formation., (© 2024. The Author(s).)

Cryo-electron tomography (cryo-ET) has the potential to reveal cell structure down to atomic resolution. Nevertheless, cellular cryo-ET data is highly complex, requiring image segmentation for visualization and quantification of subcellular structures. Due to noise and anisotropic resolution in cryo-ET data, automatic segmentation based on classical computer vision approaches usually does not perform satisfactorily. Communication between neurons relies on neurotransmitter-filled synaptic vesicle (SV) exocytosis. Cryo-ET study of the spatial organization of SVs and their interconnections allows a better understanding of the mechanisms of exocytosis regulation. Accurate SV segmentation is a prerequisite to obtaining a faithful connectivity representation. Hundreds of SVs are present in a synapse, and their manual segmentation is a bottleneck. We addressed this by designing a workflow consisting of a convolutional network followed by post-processing steps. Alongside, we provide an interactive tool for accurately segmenting spherical vesicles. Our pipeline can in principle segment spherical vesicles in any cell type as well as extracellular and in vitro spherical vesicles., (© 2024 Khosrozadeh et al.)

Background: Rights-based Respectful Maternity Care (RMC) is crucial for quality of care and improved birth outcomes, yet RMC measurements are rarely included in facility improvement initiatives. We aimed to (i) co-create a routine RMC measurement tool (RMC-T) for congested maternity units in Dar es Salaam, Tanzania, and (ii) assess the RMC-T's acceptability among women and healthcare stakeholders., Method: We employed a participatory approach utilizing multiple mixed methods. This included a scoping review, stakeholder engagement involving postnatal women, healthcare providers, health leadership, and global researchers through interviews, focus groups, and two surveys involving 201 and 838 postnatal women. Cronbach's alpha and factor analysis were conducted for validation using Stata 15. Theories of social practice and Thematic Framework of Acceptability guided the assessment of stakeholder priorities and tool acceptability., Results: The multi-phased iterative co-creation process produced the 25-question RMC-T that measures satisfaction, communication, mistreatment (including physical, verbal, and sexual abuse; neglect; discrimination; lack of privacy; unconsented care; post-birth clean-up; informal payments; and denial of care), supportive care (such as food intake and mobility), birth companionship, post-procedure pain relief, bed-sharing, and newborn respect. The pragmatic validation process prioritized stakeholder feedback over strict statistics, lowering Cronbach's alpha from 0.70 in version 1 to 0.57 for the RMC-T. Women valued the opportunity to share their experiences., Conclusions: The RMC-T is contextualized, validated, and acceptable for measuring women's experiences of RMC. Routine use in facility-based quality improvement initiatives, along with targeted actions to address gaps, will advance rights-based RMC. Further validation and community-based studies are needed.

Background: High rates of labour augmentation with oxytocin have been found in some low- and lower-middle-income countries, causing potential perinatal harm. It is critical to understand the reasons for this overuse. Aim was to explore factors that shape practices around using oxytocin for labour augmentation in a high-volume labour ward in Dar es Salaam, Tanzania., Methods: Mixed-methods data collection was conducted from March 2021 to February 2022, including structured observations of 234 births, 220 h of unstructured labour ward observations and 13 individual in-depth interviews with birth attendants. Thematic network analysis and descriptive statistics were used to analyse data. We used a time-lens to understand practices of oxytocin for labour augmentation in time-pressured labour wards., Results: Birth attendants constantly had to prioritise certain care practices over others in response to time pressure. This led to overuse of oxytocin for augmentation to ensure faster labour progression and decongestion of the, often overburdened, ward. Simultaneously, birth attendants had little time to monitor foetal and maternal condition. Surprisingly, while oxytocin was used in 146 out of 234 (62.4%) structured labour observations, only 9/234 (4.2%) women had active labour lasting more than 12 h. Correspondingly, 21/48 (43.8%) women who were augmented with oxytocin in the first stage of labour had uncomplicated labour progression at the start of augmentation. While the partograph was often not used for decision-making, timing of starting oxytocin often correlated with natural cycles of ward-rounds and shift-turnovers instead of individual women's labour progression. This resulted in co-existence of 'too early' and 'too late' use of oxytocin. Liberal use of oxytocin for labour augmentation was facilitated by an underlying fear of prolonged labour and low alertness of oxytocin-related risks., Conclusions: Time scarcity in the labour ward often made birth attendants deviate from clinical guidelines for labour augmentation with oxytocin. Efforts to navigate time pressure resulted in too many women with uncomplicated labour progression receiving oxytocin with little monitoring of labour. Fear of prolonged labour and low alertness to oxytocin-mediated risks were crucial drivers. These findings call for research into safety and benefits of oxytocin in low-resource settings and interventions to address congestion in labour wards to prevent using oxytocin as a time-management tool., (© 2024. The Author(s).)

Purpose: The introduction of immunotherapy in pleural mesothelioma (PM) has highlighted the need for effective outcome predictors. This study explores the role of [18F]FDG PET/CT in predicting outcomes in PM treated with immunotherapy., Methods: Patients from the NIPU trial, receiving ipilimumab and nivolumab +/- telomerase vaccine in second-line, were included. [18F]FDG PET/CT was obtained at baseline (n = 100) and at week-5 (n = 76). Metabolic tumour volume (MTV) and peak standardised uptake value (SUV peak ) were evaluated in relation to survival outcomes. Wilcoxon rank-sum test was used to assess differences in MTV, total lesion glycolysis (TLG), maximum standardised uptake value (SUV max ) and SUV peak between patients exhibiting an objective response, defined as either partial response or complete response according to the modified Response Criteria in Solid Tumours (mRECIST) and immune RECIST (iRECIST), and non-responders, defined as either stable disease or progressive disease as their best overall response., Results: Univariate Cox regression revealed significant associations of MTV with OS (HR 1.36, CI: 1.14, 1.62, p < 0.001) and PFS (HR 1.18, CI: 1.03, 1.34, p = 0.02), while multivariate analysis showed a significant association with OS only (HR 1.35, CI: 1.09, 1.68, p = 0.007). While SUV peak was not significantly associated with OS or PFS in univariate analyses, it was significantly associated with OS in multivariate analysis (HR 0.43, CI: 0.23, 0.80, p = 0.008). Objective responders had significant reductions in TLG, SUV max and SUV peak at week-5., Conclusion: MTV provides prognostic value in PM treated with immunotherapy. High SUV peak was not associated with inferior outcomes, which could be attributed to the distinct mechanisms of immunotherapy. Early reductions in PET metrics correlated with treatment response., Study Registration: The NIPU trial (NCT04300244) is registered at clinicaltrials.gov. https://classic., Clinicaltrials: gov/ct2/show/NCT04300244?cond=Pleural+Mesothelioma&cntry=NO&draw=2&rank=4., (© 2024. The Author(s).)

Aims: Sleep problems constitute a significant public health problem due to their high prevalence and impact on mental health and health behaviours, with major consequences for individuals and society. Therefore, the aim of this study was to investigate the association between sleep problems (duration and quality), mental health and health behaviours., Methods: Cross-sectional data was derived from the 2021 health survey 'How are you?' from the Central Denmark Region. The study population was a stratified random sample of 33,925 respondents aged 16 years or older. We used logistic regression models to analyse the associations between sleep problems and indicators of mental health and health behaviour. The models were adjusted for sex, age, educational attainment, labour market attachment, cohabitation, and indicators of mental health and health behaviour., Results: A prevalence of around 10% for both short- and long sleep duration and poor sleep quality was found. All were associated with poor mental health-related quality of life, depression, stress, perceived stressors and obesity. In addition, short sleep duration was associated with daily smoking, and long sleep duration was associated with physical inactivity and daily smoking., Conclusions: Our findings revealed a stronger association between sleep problems and mental health indicators in comparison to health behaviours. We found that sleep duration and sleep quality in broad terms were associated with similar variables within mental health and health behaviour. These findings underline the importance of adopting a comprehensive approach to addressing sleep problems in the context of health promotion, disease prevention, treatment and rehabilitation., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Malignant pleural mesothelioma (MPM) is a rare thoracic malignancy with poor prognosis and limited treatment options. Immunotherapy shows potential for improved outcomes; however, real-world evidence on its use will take time to accumulate. This study examined patient characteristics, treatment patterns, overall survival (OS), and predictors of mortality among patients diagnosed with MPM in Denmark prior to the introduction of newer treatments., Methods: This historical cohort study based on routinely collected Danish National Registry data included adults newly diagnosed with MPM between 01 January 2011 and 31 May 2018. Summary statistics were used to describe patient characteristics and initial treatment. OS was estimated using Kaplan-Meier methods; Cox regression was used to compare patient mortality against the (age/sex-matched) general population and to investigate mortality predictors., Results: Overall, 880 patients were included; 44% had advanced MPM, 37% had non-advanced MPM, and 19% had unknown MPM stage. Median age at diagnosis was 71.9 years, and 82% of the patients were male. Within 180 days of diagnosis, no treatment was recorded for 215 patients (54%) with advanced MPM and 150 (46%) with non-advanced MPM. Median time-to-initial treatment (interquartile range) was 47 days (31-111) overall, 40 days (28-77) in patients with advanced MPM, and 53 days (35-121) with non-advanced MPM. Median OS was 13.7 months overall (non-advanced MPM: 18.0 months vs. advanced MPM: 10.0 months). Predictors of higher mortality were older age at diagnosis, histology, and advanced MPM stage., Interpretation: These findings provide a baseline upon which to evaluate MPM epidemiology as newer treatments are adopted in routine practice.

Guinea-Bissau has among the world's highest maternal and perinatal mortality rates. To improve access to quality maternal and child health (MCH) services and thereby reduce mortality, a national health system strengthening initiative has been implemented. However, despite improved coverage of MCH services, perinatal mortality remained high. Using a systems-thinking lens, we conducted a situation analysis to explore factors shaping timeliness and quality of facility-based care during labour, childbirth, and the immediate postpartum period in rural Guinea-Bissau. We implemented in-depth interviews with eight peripartum care providers and participant observations at two health facilities (192 h) in 2021-22, and analysed interview transcripts and field notes using thematic network analysis. While providers considered health facilities as the only reasonable place of birth and promoted facility birth uptake, timeliness and quality of care were severely compromised by geographical, material and human-resource constraints. Providers especially experienced a lack of human resources and materials (e.g., essential medicines, consumables, appropriate equipment), and explained material constraints by discontinued donor supplies. In response, providers applied several adaptation strategies including prescribing materials for private purchase, omitting tests, and delegating tasks to birth companions. Consequences included financial barriers to care, compromised patient and occupational safety, delays, and diffusion of health worker responsibilities. Further, providers explained that in response to persisting access barriers, women conditioned care seeking on their perceived risk of developing birthing complications. Our findings highlight the need for continuous monitoring of factors constraining timeliness and quality of essential MCH services during the implementation of health system strengthening initiatives., (© 2024. The Author(s).)

Aim: To investigate the association between women's health literacy and attendance in the Danish national breast cancer screening programme., Methods: In a population-based cross-sectional study, information on two health literacy subscales, measured using the Health Literacy Questionnaire (HLQ), and sociodemographic factors was obtained from the 'How are you? 2017' survey in the Central Denmark Region. Information on screening attendance was obtained from register data from 2016-2017. Data were linked based on individual civil registration numbers. To account for missing data, multiple imputation by chained equations was implemented to fill in missing values on all variables. Unadjusted and adjusted logistic regression analyses were performed separately for two HLQ subscales to estimate odds ratio (OR) of screening attendance. Both multiple imputation analyses and complete case analyses were performed., Results: A total of 6012 women were included in multiple imputed statistical analyses. Generally, women had high health literacy levels. In multiple imputed analyses, the unadjusted OR of the primary HLQ subscale, understanding, was 1.32 (95% confidence interval (CI): 1.10-1.59), indicating higher odds for screening attendance with higher health literacy level. However, after adjustment no significant association between the HLQ subscale of understanding and screening attendance was found (OR 1.09 (95% CI: 0.90-1.33)). Similar results were found for the secondary HLQ subscale of engaging (insignificant association in adjusted analysis). No effect modification from sociodemographic characteristics was found. Similar results were found in complete case analyses., Conclusions: No significant association was found between health literacy and attendance in the Danish breast cancer screening programme., Competing Interests: Declaration of conflicting interestsThe authors have no conflicts of interest to declare.

Here, we present a protocol for quantifying pyramidal neuron hyperexcitability in a mouse model of STXBP1 neurodevelopmental encephalopathy (Stxbp1 hap ). We describe steps for preparing brain slices, positioning electrodes, and performing an excitability test to investigate microcircuit failures. This protocol is based on recording layer 2/3 cortical pyramidal neurons in response to stimulation of two independent sets of excitatory axons that recruit feedforward inhibition microcircuits. For complete details on the use and execution of this protocol, please refer to Dos Santos et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The NIPU-trial investigates the effect of adding the telomerase vaccine UV1 to treatment with ipilimumab and nivolumab for patients with pleural mesothelioma (PM)., Methods: In this phase 2 open-label trial, patients with PM progressing after first-line chemotherapy were randomised to receive ipilimumab and nivolumab alone (arm B) or combined with UV1 (arm A). The primary endpoint was progression-free survival (PFS) as determined by BICR. It was estimated that 69 PFS events were needed to detect a hazard ratio (HR) of 0.60 with 80% power and a one-sided alpha level of 0.10., Results: 118 patients were randomised. The median PFS determined by blinded independent central review (BICR) was 4.2 months (95%CI 2.9-9.8) in arm A and 4.7 months (95%CI 3.9-7.0) in arm B (HR 1.01, 80%CI 0.75-1.36 P = 0.979), after a median follow-up of 12.5 months (95%CI 9.7-15.6). The investigator-determined median PFS was 4.3 months (95%CI 3.0-6.8) in arm A and 2.9 months (95%CI 2.4-5.5) in arm B (HR 0.60, 80%CI 0.45-0.81 P = 0.025). Confirmed objective response rate (ORR) by BICR was 31% in arm A and 16% in arm B (odds ratio 2.44 80%CI 1.35-4.49 P = 0.056). After a median follow-up time of 17.3 months (95%CI 15.8-22.9), the OS was 15.4 months (95%CI 11.1-22.6) in arm A and 11.1 months (95%CI 8.8-18.1) in arm B, (HR 0.73, 80%CI 0.53-1.0, P = 0.197)., Conclusion: The primary endpoint was not met. Predefined analyses of response rates are in favour of adding the vaccine., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vilde Drageset Haakensen - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Roche, Takeda, Pfizer, BMS, MSD, Janssen. Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, Astra Zeneca, BMS. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Board member of lung cancer patient organization from 2022. Support from the South-Eastern Norway Regional Health Authorities, grant number 2021083. Maria Bjaanæs - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Pfizer, BMS. Weronika Maria Szejniuk – none declared. Solfrid Thunold - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS. Susana Cedres - Participation on a Data Safety Monitoring Board or Advisory Board: F. Hoffmann La Roche AG, MSD Oncology, Pfizer, Amphera, Boehringer Ingelheim, BMS Wee L Chin – none declared. Tonje Sofie Dalen – none declared. Saima Farooqi - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Merck. Oscar Grundberg – none declared. Åslaug Helland - All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): South-Eastern Norway Regional Health Authorities, grant number 202007 and 2016056, Ultimovacs, BMS. Grants or contracts from any entity: Roche, InCyte, Astra Zeneca, Merck, Novartis, Eli Lilly, GSK, Illumina, Nanopore. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Janssen, Medicovver, Bayer, Eli Lilly, MSD, BMS, Merck, Sanofi, Abbvie, Pfizer, Takeda, Novartis, Roche. Participation on a Data Safety Monitoring Board or Advisory Board: AMGEN (DSMC), AdBoard: Roche, AstraZeneca, Pfizer, Janssen, BMS, EliLilly, Abbvie, Bayer, Sanofi, Merck, Takeda. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Board member of lung cancer patient organization until 2022 Marius Lund Iversen – none declared. Anna K Nowak - Grants or contracts from any entity: Astra Zeneca. Participation on a Data Safety Monitoring Board or Advisory Board: AstraZeneca, BMS, Douglas Pharmaceuticals Åsa Kristina Öjlert – none declared. Jens Benn Sørensen - Participation on a Data Safety Monitoring Board or Advisory Board: BMS, Merck, Astra Zeneca., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To explore healthcare workers' and women's experiences of providing and seeking childbirth care in a busy urban maternity facility in Tanzania., Design: A qualitative study with observations, in-depth interviews, and informal conversations, using thematic network analysis., Setting: This study was conducted in a busy urban maternity unit in Dar es Salaam, Tanzania which is a low-resource setting with a need to improve childbirth care., Participants: Six frontline healthcare providers and four hospital managers from the facility, along with six postpartum women who gave birth at the facility., Findings: Delays were observed throughout the childbirth care cascade, encompassing various stages. During antenatal care, timely provision of care was hindered by a high patientto-provider ratio, resulting in inadequate monitoring of risk factors. At the onset of labor, women delayed seeking care, sometimes, attempting a trial of labor after a previous Caesarean section. Within the facility, delays in care decision-making and patient management were evident due to insufficient resources. The accumulation of these delays over time influenced the quality of care provided and challenged the management of obstetric emergencies at the study facility., Key Conclusions: The study findings show that delays are prevalent throughout the entire childbirth care cascade. The accumulation of these delays over time has influenced the quality of care provided at the facility and increased the vulnerability of women experiencing obstetric emergencies. To effectively address the imperative of reducing maternal mortality in low-resource settings, it is essential to develop appropriate interventions that span the entire spectrum of childbirth care. Additionally, further research is needed to delve into the complexities of care decision-making and the quality of care delivered within urban maternal facilities., Implications for Practice: Our findings stress the need for comprehensive childbirth interventions and contextspecific guidelines to address challenges across the care cascade, particularly in lowresource settings. Urgent attention is required to prioritize care during patient triage and address systemic challenges within the healthcare system to improve birth outcomes and ensure effective facility-based care provision., Trial Registration Number: NCT04685668 Date of initial trial registration: December 28th, 2020., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

SNAP25 is one of three neuronal SNAREs driving synaptic vesicle exocytosis. We studied three mutations in SNAP25 that cause epileptic encephalopathy: V48F, and D166Y in the synaptotagmin-1 (Syt1)-binding interface, and I67N, which destabilizes the SNARE complex. All three mutations reduced Syt1-dependent vesicle docking to SNARE-carrying liposomes and Ca 2+ -stimulated membrane fusion in vitro and when expressed in mouse hippocampal neurons. The V48F and D166Y mutants (with potency D166Y > V48F) led to reduced readily releasable pool (RRP) size, due to increased spontaneous (miniature Excitatory Postsynaptic Current, mEPSC) release and decreased priming rates. These mutations lowered the energy barrier for fusion and increased the release probability, which are gain-of-function features not found in Syt1 knockout (KO) neurons; normalized mEPSC release rates were higher (potency D166Y > V48F) than in the Syt1 KO. These mutations (potency D166Y > V48F) increased spontaneous association to partner SNAREs, resulting in unregulated membrane fusion. In contrast, the I67N mutant decreased mEPSC frequency and evoked EPSC amplitudes due to an increase in the height of the energy barrier for fusion, whereas the RRP size was unaffected. This could be partly compensated by positive charges lowering the energy barrier. Overall, pathogenic mutations in SNAP25 cause complex changes in the energy landscape for priming and fusion., Competing Interests: AK, JM, MØ, AM, JM, FL, WN, TS, JS No competing interests declared, (© 2023, Kádková, Murach, Østergaard et al.)

Purpose: Suicide and self-harm by pesticide self-poisoning is common in low- and middle-income countries (LMICs). Alcohol is an important risk factor for self-harm; however, little is known about its role in pesticide self-poisoning. This scoping review explores the role that alcohol plays in pesticide self-harm and suicide., Methods: The review followed the Joanna Briggs Institute scoping review guidance. Searches were undertaken in 14 databases, Google Scholar, and relevant websites. Articles were included if they focussed on pesticide self-harm and/or suicide and involvement of alcohol., Results: Following screening of 1281 articles, 52 were included. Almost half were case reports (n = 24) and 16 focussed on Sri Lanka. Just over half described the acute impact of alcohol (n = 286), followed by acute and chronic alcohol use (n = 9), chronic use, (n = 4,) and only two articles addressed harm to others. One systematic review/meta-analysis showed increased risk of intubation and death in patients with co-ingested alcohol and pesticides. Most individuals who consumed alcohol before self-harming with pesticides were men, but alcohol use among this group also led to pesticide self-harm among family members. Individual interventions were recognised as reducing or moderating alcohol use, but no study discussed population-level alcohol interventions as a strategy for pesticide suicide and self-harm prevention., Conclusion: Research on alcohol's role in pesticide self-harm and suicide is limited. Future studies are needed to: further assess the toxicological effects of combined alcohol and pesticide ingestion, explore harm to others from alcohol including pesticide self-harm, and to integrate efforts to prevent harmful alcohol use and self-harm., (© 2023. The Author(s).)

Objectives: Gestational diabetes mellitus (GDM) has implications for the future health of both mother and offspring, and there is a risk that mothers are held responsible and blamed for their own and their offspring's long-term health. The media plays a significant role in shaping public perceptions of health. Therefore, our study aimed to investigate how GDM and women with GDM are portrayed in Danish written media., Design: We identified written newspaper articles reporting on GDM from 2018 to 2019 and analysed them using thematic network analysis and elements from critical discourse analysis., Results: In total, 130 articles were included in the analysis. Four themes emerged: (1) ways of introducing GDM, (2) descriptions of causes and prevention of GDM, (3) descriptions of consequences of GDM and (4) value-laden descriptions of GDM. GDM was often mentioned in relation to other conditions or factors and with lack of differentiation. Maternal responsibility was emphasised via oversimplified descriptions of causal relations, descriptions of individual agency and no emphasis on structural causes and preventive measures. GDM was positioned as resulting in 'bad pregnancies' using value-laden wordings., Conclusion: We identified various aspects of how GDM is portrayed in written media. The findings signal the importance of clear, nuanced and respectful communication on GDM, including conveying the complexity of the condition and the role of structural factors., Competing Interests: Competing interests: ED and KKN are employed at Steno Diabetes Center Copenhagen, a public hospital and research institution under the Capital Region of Denmark, which is partly funded by a grant from the Novo Nordisk Foundation. No funding was received for this specific study, and the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. FRE and JBS declare no conflicts of interest., (© 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.)

Mesothelioma of the tunica vaginalis testis (MTVT) is a rare tumour and a cause of hydrocele. This case report concerns a 26-year-old male with hydrocele treated with left hydrocelectomy. Histopathology revealed MTVT, and left radical orchiectomy was performed followed by chemotherapy. Fluorescence in situ hybridization, DNA and RNA next-generation sequencing showed no mesothelioma-associated tumour suppressor gene mutations, but deletion of CDKN2A and a rare TFG-ADGRG7 fusion both reported in pleural mesotheliomas, were detected. Clinicians should consider malignancy in case of discrepancy between symptoms and objective findings in scrotal conditions., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Aim: Platforms on social media are increasingly used for public health research. While social media provides an exceptional opportunity to explore communication about public health topics, this practice is not without ethical dilemmas. Our aim was to identify and unfold some of these dilemmas and to suggest possible solutions and ways forward for future research., Methods: Using our own research within a closed forum for people experiencing suicidal thoughts as a case, we explored certain dilemmas and possible answers relating to whether what is to be researched falls under a public or private social media domain; we investigated avenues for obtaining access to participants in an evolving online environment; how to secure informed consent from participants; and ways of ensuring anonymity., Results: We provide recommendations and reflections that we hope will offer inspiration for researchers embarking on similar social media public health research within and beyond suicide research., Conclusions: The ethical framework commonly referred to in health research, based on confidentiality, anonymity, informed consent and doing no harm must be adjusted to be relevant for a social media context where technologies and regulations are constantly being altered., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Risky alcohol use is a major public health problem globally and in Sri Lanka. While a reduction in alcohol consumption can result in physical, mental, and social benefits, behaviour change is difficult to achieve. Effective, context-adapted interventions are required to minimise alcohol-related harm at a community level. THEATRE is a complex, community-based intervention evaluating whether a promising Sri Lankan pilot study that utilised arts-based research to moderate alcohol use can be scaled up. While the scaled-up pilot study protocol is presented elsewhere, the aim of this protocol paper is to describe the intervention programme theory and evaluation design, and modifications made to the study resulting from COVID-19 and the financial crisis. Drawing on the Behaviour Change Wheel (BCW) and Theoretical Domains Framework, behaviour change theories are presented with potential pathways to guide implementation and evaluation. Alcohol consumption patterns and context of drinking is detailed. The multifaceted intervention targets individuals and communities using arts-based interventions. Four of nine BCW functions are employed in the design of the intervention: education, persuasion, modelling and enablement, and training. Modifications made to the study due to COVID-19 and the financial crisis are described. Ethical approval was obtained from the Ethics Review Committee, Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka (ERC/2018/21-July 2018 and Feb 2022) and the University of Sydney (2019/006). Findings will be disseminated locally to community members and key stakeholders and via international peer-reviewed publications.

De novo mutations in STXBP1 are among the most prevalent causes of neurodevelopmental disorders and lead to haploinsufficiency, cortical hyperexcitability, epilepsy, and other symptoms in people with mutations. Given that Munc18-1, the protein encoded by STXBP1, is essential for excitatory and inhibitory synaptic transmission, it is currently not understood why mutations cause hyperexcitability. We find that overall inhibition in canonical feedforward microcircuits is defective in a P15-22 mouse model for Stxbp1 haploinsufficiency. Unexpectedly, we find that inhibitory synapses formed by parvalbumin-positive interneurons were largely unaffected. Instead, excitatory synapses fail to recruit inhibitory interneurons. Modeling confirms that defects in the recruitment of inhibitory neurons cause hyperexcitation. CX516, an ampakine that enhances excitatory synapses, restores interneuron recruitment and prevents hyperexcitability. These findings establish deficits in excitatory synapses in microcircuits as a key underlying mechanism for cortical hyperexcitability in a mouse model of Stxbp1 disorder and identify compounds enhancing excitation as a direction for therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

With the increasing popularity of cryo-electron tomography (cryo-ET) in recent years, the quest to establish a method for growing primary neurons directly on electron microscopy grids (EM grids) has been ongoing. Here we describe a straightforward way to establish a mature neuronal network on EM grids, which includes formation of synaptic contacts. These synapses were thin enough to allow for direct visualization of small filaments such as SNARE proteins tethering the synaptic vesicle (SV) to the active zone plasma membrane on a Titan Krios without prior focused ion-beam milling.

Objectives: Prolonged or excessive stress can have a negative impact on health and well-being, and stress therefore constitutes a major public health issue. A central question is what are the main sources of stress in contemporary societies? This study examines the effects of work-related and non-work-related stressors and perceived social support on perceived stress within a causal framework., Methods: Panel data were drawn from two waves (2013 and 2017) of the population-based health survey "How are you?" conducted in the Central Denmark Region. The analytical sample comprised 9,194 subjects who had responded to both surveys. Work-related and non-work-related stressors included major life events, chronic stressors, daily hassles and lack of social support. Perceived stress was measured with the 10-item Perceived Stress Scale (PSS). Data were analysed using fixed effects regression in a fully balanced design., Results: The largest effects on PSS were seen in own disease, work situation and lack of social support. Other stressors affecting the perceived stress level were financial circumstances, relationship with partner, relationship with family and friends, and disease among close relatives. Most variables had a symmetrical effect on PSS., Conclusions: The results point to the need for comprehensive policies to promote mental health that span life domains and include both the individual and the group as well as organizational and societal levels. The study indicates that there are multiple potential entry points for stress prevention and stress management. However, it also shows that disease, work situation and social support weigh heavily in the overall picture. This points to the healthcare system and workplace as key institutional venues for action., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Larsen 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.)

Amplification of the mesenchymal epithelial transition ( MET ) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR -mutated ( EGFR m+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2-8% of EGFR m+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR -mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3-19 months.

Introduction: Alcohol and pesticides are toxic substances that each cause acute and chronic harm to humans. Alcohol plays an important and complex role in pesticide self-poisoning, involving toxicological, public health, and social aspects important for research, prevention, and interventions., Alcohol Use Disorder and Social Harms: While the evidence on alcohol co-ingestion in the context of pesticide self-poisoning is limited, it appears that alcohol use increases complications. Even fewer studies address alcohol use disorder and dependence among pesticide self-poisoning patients. The harmful use of alcohol also impacts social life, families, and communities in several ways, including pesticide self-poisoning among individuals around the alcohol user. This, however, is vastly understudied., Outside Influences: Agrochemicals and alcohol are produced by industries with financial interests, and the outcome of individual acts of pesticide self-poisoning depends on the lethality of the pesticide purchased and ingested. The promotion of acutely toxic pesticides by companies must be acknowledged within this issue., Conclusion: The relationship between alcohol and pesticide self-poisoning is increasingly clear, but more studies are needed to guide management. We cannot ignore that pesticide self-poisoning and harmful use of alcohol occur within the context of wider, often structural, stressors and are influenced by commercial entities.

Background: Suicide is a global public health problem. Compared to other middle-income countries, much literature has been generated on the topic of self-harm and suicide in Sri Lanka. Harmful use of alcohol is a well-known risk factor to self-harm and suicide, however the connection needed further exploration., Aim: The aim was to investigate alcohol's role in self-harm and suicide in Sri Lanka to inform policy and prevention programs and future research priorities., Methods: We performed a scoping review exploring how the association between alcohol use, self-harm and suicide in Sri Lanka is presented in scientific literature from August 1, 2008 to December 31, 2022. Thematic analysis was used to explore emerging themes., Results: Altogether 116 peer-reviewed articles were included. Three themes emerged: (i) gendered, inter-relational explanations of alcohol's role in self-harm, (ii) hospital management of patients who co-ingested alcohol and pesticides, and (iii) proposed research and interventions targeting alcohol, self-harm and suicide. The articles' recommendations for policy, prevention and research priorities included: Family- and community-based alcohol, self-harm and suicide reduction interventions; viewing self-harm as a window of opportunity for health personnel to intervene in families affected by harmful alcohol consumption; and introduction of and increased access to treatment of alcohol use disorder at the individual level., Conclusion: Suggestions for alcohol, self-harm, and suicide prevention interventions were primarily targeted at the community, though this might also reflect the limited treatment, mental health, and alcohol support available in the country. Future research should explore and test context-appropriate interventions integrating alcohol and self-harm prevention and treatment., Competing Interests: There are no conflicts of interest., (© 2023 The Authors.)

Synaptic vesicle (SV) fusion with the plasma membrane (PM) proceeds through intermediate steps that remain poorly resolved. The effect of persistent high or low exocytosis activity on intermediate steps remains unknown. Using spray-mixing plunge-freezing cryo-electron tomography we observe events following synaptic stimulation at nanometer resolution in near-native samples. Our data suggest that during the stage that immediately follows stimulation, termed early fusion, PM and SV membrane curvature changes to establish a point contact. The next stage-late fusion-shows fusion pore opening and SV collapse. During early fusion, proximal tethered SVs form additional tethers with the PM and increase the inter-SV connector number. In the late-fusion stage, PM-proximal SVs lose their interconnections, allowing them to move toward the PM. Two SNAP-25 mutations, one arresting and one disinhibiting spontaneous release, cause connector loss. The disinhibiting mutation causes loss of membrane-proximal multiple-tethered SVs. Overall, tether formation and connector dissolution are triggered by stimulation and respond to spontaneous fusion rate manipulation. These morphological observations likely correspond to SV transition from one functional pool to another., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)