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Executive function deficits, common in psychiatric disorders, hinder daily activities and may be linked to diminished neural plasticity, affecting treatment and training responsiveness. In this pioneering study, we evaluated the feasibility and preliminary efficacy of psilocybin-assisted frontal-midline theta neurofeedback (NF), a neuromodulation technique leveraging neuroplasticity, to improve executive functions (EFs). Thirty-seven eligible participants were randomized into an experimental group ( n = 18) and a passive control group ( n = 19). The experimental group underwent three microdose sessions and then three psilocybin-assisted NF sessions, without requiring psychological support, demonstrating the approach's feasibility. NF learning showed a statistical trend for increases in frontal-midline theta from session to session with a large effect size and non-significant but medium effect size dynamical changes within sessions. Placebo effects were consistent across groups, with no tasks-based EF improvements, but significant self-reported gains in daily EFs-working memory, shifting, monitoring and inhibition-showing medium and high effect sizes. The experimental group's significant gains in their key training goals underscored the approach's external relevance. A thorough study with regular sessions and an active control group is crucial to evaluate EFs improvement and their specificity in future. Psilocybin-enhanced NF could offer significant, lasting benefits across diagnoses, improving daily functioning. This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.

Physiological regulatory problems in infancy (i.e., problems with sleeping, feeding, and tactile reactivity) have been associated with impairing functional somatic symptoms (FSS) at ages 5-7. We aimed to extend this finding by examining not only the association of physiological regulatory problems but also other infancy factors (i.e., emotion dysregulation and contact problems) with FSS in pre- and late adolescence. Standardized behavioral assessments and self-report questionnaire data from assessment waves at 0-1, 11-12, and 16-17 years of the population-based Copenhagen Child Cohort (CCC2000) were linked with Danish register data on maternal postpartum psychiatric illness and family adversity as covariates. Multiple linear regression analyses were performed to examine the association between infancy factors and FSS in pre- and late adolescence. Only infancy physiological regulatory problems significantly predicted preadolescent FSS (b = 0.38, 95% CI [0.14, 0.62]), also when accounting for maternal postpartum psychiatric illness and family adversity. The association was attenuated for late adolescent FSS., Conclusion: Infancy physiological regulatory problems may represent early signs of a dysregulated stress system and were found to significantly predict FSS in pre- but not late adolescence. Implications for early FSS prevention could include testing interventions promoting infants' regulation of sleep, feeding, and tactile reactivity., What Is Known: • Functional somatic symptoms (FSS) are common in adolescence. • Explanatory models of FSS emphasize a multifactorial etiology involving interactions between early child-related vulnerabilities and contextual factors. • Infancy physiological regulatory problems (i.e., problems in the area of sleeping, feeding, and tactile reactivity) might represent early signs of a dysregulated stress system, and have been shown to predict impairing FSS in preschool childhood., What Is New: • This study investigated the association between infancy factors, namely physiological regulatory problems with feeding, sleeping, and/or tactile reactivity, emotion dysregulation, and contact problems, and FSS in pre- and late adolescence. • Only a combination of infancy physiological regulatory problems significantly predicted preadolescent FSS, with the association attenuating for FSS in late adolescence. • Implications for early FSS prevention could include parent-mediated interventions aiming to promote infants' physiological regulatory skills., Competing Interests: Declarations. Ethical approval: The CCC2000 and associated sub-studies were approved by the Danish Data Protection Agency (CSU-FCFS-2016–004, I-Suite 04544) and evaluated by the Committee on Health Research Ethics in the Capital Region of Denmark (protocol 16023242). Regulations on the use of personal data were handled in accordance with the Declaration of Helsinki. Cohort members and parents were contacted through an established governmental e-mail system and asked to fill in online questionnaires themselves (CC11/12 and CC16/17). Consent to participate: Informed consent for these assessment moments was automatically obtained from cohort members and parents by responding to online questionnaires. Consent for publication: As part of the informed consent form, cohort members were invited to be part of a research project on psychological development and well-being. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The project of scaling up noncommunicable disease (NCD) interventions in Southeast Asia aimed to strengthen the prevention and control of hypertension and diabetes, focusing on primary health care and community levels. In Vietnam, health volunteers who were members of the Intergenerational Self-Help Clubs (ISHCs) implemented community-based NCD screening and health promotion activities in communities. The ISHC health volunteers used an app based on District Health Information Software, version 2 (DHIS2) tracker (Society for Health Information Systems Programmes, India) to record details of participants during screening and other health activities., Objective: This study aimed to assess the strengths, barriers, and limitations of the NCD screening app used by the ISHC health volunteers on tablets and to provide recommendations for further scaling up., Methods: A mixed methods observational study with a convergent parallel design was performed. For the quantitative data analysis, 2 rounds of screening data collected from all 59 ISHCs were analyzed on completeness and quality. For the qualitative analysis, 2 rounds of evaluation of the screening app were completed. Focus group discussions with ISHC health volunteers and club management boards and in-depth interviews with members of the Association of the Elderly and Commune Health Station staff were performed., Results: In the quantitative analysis, data completeness of all 6704 screenings (n=3485 individuals) was very high. For anthropomorphic measurements, such as blood pressure, body weight, and abdominal circumference, less than 1% errors were found. The data on NCD risk factors were not adequately recorded in 1908 (29.5%) of the screenings. From the qualitative analysis, the NCD screening app was appreciated by ISHC health volunteers and supervisors, as an easier and more efficient way to report to higher levels, secure data, and strengthen relationships with relevant stakeholders, using tablets to connect to the internet and internet-based platforms to access information for self-learning and sharing to promote a healthy lifestyle as the strengths. The barriers and limitations reported by the respondents were a non-age-friendly app, incomplete translation of parts of the app into Vietnamese, some issues with the tablet's display, lack of sharing of responsibilities among the health volunteers, and suboptimal involvement of the health sector; limited digital literacy among ISHC health volunteers. Recommendations are continuous capacity building, improving app issues, improving tablet issues, and involving relevant stakeholders or younger members in technology adoption to support older people., Conclusions: The implementation of the NCD screening app by ISHC volunteers can be an effective way to improve community-led NCD screening and increase the uptake of NCD prevention and management services at the primary health care level. However, our study has shown that some barriers need to be addressed to maximize the efficient use of the app by ISHC health volunteers to record, report, and manage the screening data., (©Trang Thi Thu Nong, Giang Hoang Nguyen, Alexander Lepe, Thuy Bich Tran, Lan Thi Phuong Nguyen, Jaap A R Koot. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 02.12.2024.)

Odontogenic infections have a high prevalence and can lead to severe complications. Due to demographic changes, the number of geriatric patients has increased in recent years. The aim of this study was to analyse odontogenic abscesses in elderly patients and to differentiate them from non-elderly patients regarding clinical presentation, bacterial analysis and therapy. We retrospectively reviewed 1,173 inpatients with odontogenic abscesses from 2014 to 2020. Patients were divided into elderly patients (≥70 years, n  = 240) and non-elderly patients (<70 years, n  = 933). Demographics, clinical parameters, laboratory values and treatment parameters were analysed. Overall, elderly patients had a longer hospital stay (LOS) (median 4 [range 28] vs. 3 [range 22] days) and more complications (9.6% vs. 7.9%) than non-elderly patients, although these differences were not statistically significant. Peri-/submandibular ( p  = 0.015), parapharyngeal ( p  < 0.001) and oral base infections ( p  = 0.036) were associated with significantly longer LOS in the elderly. Chronic renal failure (CRF) was associated with LOS ( p  = 0.010) and complications ( p  = 0.006). In the elderly, c-reactive protein (CRP) correlated significantly with LOS ( p  < 0.001) and more complications ( p  = 0.036). This study identifies anatomical spaces and CRF as outcome predictors of odontogenic abscesses in the elderly. In addition, CRP level may serve as a predictor of complicated course in elderly patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships cthat could be construed as a potential conflict of interest., (© 2024 Kärcher, Thelen, Ruettermann, Li and Hamprecht.)

Multispecific antibodies are engineered antibody derivatives that can bind to two or more distinct epitopes or antigens. Unlike mixtures of monospecific antibodies, the binding properties of multispecific antibodies enable two specific molecules to be physically linked, a characteristic with important applications in cancer therapy. The field of multispecific antibodies is highly dynamic and expanding rapidly; to date, 15 multispecific antibodies have been approved for clinical use, of which 11 were approved for oncological indications, and more than 100 new antibodies are currently in clinical development. Nevertheless, substantial challenges limit the applications of multispecific antibodies in cancer therapy, particularly inefficient targeting of solid tumours and substantial adverse effects. Both PET and single photon emission CT imaging can reveal the biodistribution and complex pharmacology of radiolabelled multispecific antibodies. This Review summarizes the insights obtained from preclinical and clinical molecular imaging studies of multispecific antibodies, focusing on their structural properties, such as molecular weight, shape, target specificity, affinity and avidity. The opportunities associated with use of molecular imaging studies to support the clinical development of multispecific antibody therapies are also highlighted., Competing Interests: Competing interests D.J.A.d.G. declares that he received institutional financial support for clinical trials or contracted research from Amgen, Bayer, GE Healthcare, Hoffmann La Roche and Siemens. E.G.E.d.V. declares that she received institutional financial support for acting as a member of advisory boards or consultancy services from Crescendo Biologics, Daiichi Sankyo and NSABP, as well as institutional financial support for clinical trials or contracted research grants from Amgen, Bayer, Crescendo Biologics, Genentech, Regeneron, Roche and Servier. M.N.L.-d.H. declares that she received institutional financial support for acting as a member of advisory boards or consultancy services from Merck and institutional financial support for conducting clinical and preclinical studies from Amgen, Bayer and Servier. The other authors declare no competing interests., (© 2024. Springer Nature Limited.)

Network approaches to psychopathology have become increasingly common in mental health research, with many theoretical and methodological developments quickly gaining traction. This article illustrates contemporary practices in applying network analytical tools, bridging the gap between network concepts and their empirical applications. We explain how we can use graphs to construct networks representing complex associations among observable psychological variables. We then discuss key network models, including dynamic networks, time-varying networks, network models derived from panel data, network intervention analysis, latent networks, and moderated models. In addition, we discuss Bayesian networks and their role in causal inference with a focus on cross-sectional data. After presenting the different methods, we discuss how network models and psychopathology theories can meaningfully inform each other. We conclude with a discussion that summarizes the insights each technique can provide in mental health research., (© 2024 The Author(s). International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

Purpose: Clinical guidelines call for the inclusion of exercise interventions in every patient's dialysis session, but these recommendations are rarely adopted. Healthcare providers play a key role in this. Therefore, the aim of this study was to explore how healthcare providers perceive the benefits, risks and barriers of intradialytic exercise (IDE)., Methods: We conducted 21 individual, semi-structured interviews with 11 nurses, 5 nephrologists, 3 training assistants and 2 managers from two dialysis centres in Slovakia. Verbatim transcripts of digitally recorded interviews were thematically analysed using MAXQDA®., Results: Participants reported the benefits of IDE as improvements in patients' physical and psychosocial functioning, independence and self-efficacy, clinical profile and quality of therapy. As risks of IDE, they most frequently reported exercise-related damage to vascular access, insufficient individualization of training and musculoskeletal injuries. The presence of psychological problems among patients was reported as a major barrier for initiating and maintaining patients' exercise. Other reported barriers included limitations in financial and personnel resources of haemodialysis care., Conclusions: Safe and sustainable implementation of IDE, which might improve a patient's well-being, need to be prescribed in alignment with the patient's clinical profile, be delivered individually according to the patient's characteristics and requires adjustments in the available resources.

Exposure to pollutants like environmental cigarette smoke (CS) poses a major global health risk, affecting individuals from an early age. Therefore, this study explores how postnatal synbiotic supplementation affects allergic asthma symptoms in house-dust-mite (HDM)- challenged offspring maternally exposed to CS. In HDM-allergic offspring of CS-exposed dams, lung resistance was elevated, but synbiotic supplementation effectively reduced this resistance. Elevated eosinophil BALF counts following HDM challenge were intensified in pups maternally exposed to CS. Similarly, Th2 cell activation and serum IgE and IgG1 levels were more pronounced in HDM-allergic offspring of CS-exposed mothers. Synbiotics reduced eosinophil numbers and serum IgE and IgG1, and tended to decrease Th2 cell infiltration and activation. Synbiotics promoted beneficial gut bacteria like Bifidobacterium and Akkermansia. In conclusion, early-life synbiotic intervention mitigated allergic asthma associated with maternal air pollution exposure, highlighting the potential of synbiotics for clinical evaluation as a strategy to prevent allergy development in offspring., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Johan Garssen reports financial support was provided by Danone Nutricia Research. Jeroen van Bergenhenegouwen reports a relationship with Danone Nutricia Research that includes: employment. Johan Garssen reports a relationship with Danone Nutricia Research that includes: employment. Saskia Braber reports a relationship with Danone Nutricia Research that includes: employment. The remaining 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. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Bacterial respiratory infections are a major global health concern, often leading to lung injury and triggering lung repair mechanisms. Endogenous epithelial progenitor cells are crucial in this repair, yet the mechanisms remain poorly understood. This study investigates the response of lung epithelial progenitor cells to injury induced by lipopolysaccharide (LPS), a component of gram-negative bacteria, focusing on their regulation during lung repair. Lung epithelial cells (CD31 - CD45 - Epcam + ) from wild-type and tumor necrosis factor (TNF) receptor 1/2 knock-out mice were co-cultured with wild-type fibroblasts. Organoid numbers and size were measured after 14 days of exposure to 100 ng/mL LPS. Immunofluorescence was used to assess differentiation (after 14 days), RNA sequencing analyzed gene expression changes (after 72 hours), and MTS assay assessed proliferative effects of LPS on individual cell types (after 24 hours). LPS treatment increased the number and size of wild-type lung organoids and promoted alveolar differentiation, indicated by more SPC + organoids. RNA sequencing revealed upregulation of inflammatory and fibrosis-related markers, including Cxcl3, Cxcl5, Ccl20, Mmp13, and Il33, and enrichment of TNF-α signaling and epithelial-mesenchymal transition pathways. TNF receptor 1 deficiency inhibited LPS-induced progenitor cell activation and organoid growth. In conclusion, LPS enhances lung epithelial progenitor cell proliferation and differentiation via TNF receptor 1 signaling, highlighting potential therapeutic targets for bacterial lung injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The aim of this study was to examine whether repeated victimization relates to differential processing of social exclusion experiences. It was hypothesized that experiences of repeated victimization would modulate neural processing of social exclusion in the insula, anterior cingulate cortex, and lateral prefrontal cortex. Furthermore, we hypothesized that repeated victimization relates positively to intentions to punish excluders. Exploratively, associations between neural processing and intentions to punish others were examined. The sample consisted of children with known victimization in the past two years (n = 82 (behavioral) / n = 73 (fMRI), 49.4% girls, M age = 10.6). The participants played Cyberball, an online ball-tossing game, which was manipulated so that in the first block participants were equally included and in the second block they were excluded from play. Victimization was not related to neural activation during social exclusion, although there were indications that victimization may be related to increased insula activation during explicit exclusion. Behaviorally, repeated victimization was related to more intention to punish excluders. Neural activation during social exclusion did not predict intentions to punish excluders, but results tentatively suggested that increased insula activation during social exclusion may be related to increased intentions to punish. Together, these results provide a replication of earlier Cyberball studies and point toward differential processing of social exclusion by children who are victimized., Competing Interests: Compliance with Ethical Standards. Conflict of interest: Not applicable., (© 2024. The Author(s).)

Pathogenic SOX11 variants have been associated with intellectual developmental disorder with microcephaly, and with or without ocular malformations or hypogonadotropic hypogonadism (HH) (IDDMOH, OMIM # 615866). In this article, we report seven new patients with de novo SOX11 variants. Five of the variants are missense, one nonsense, and one whole-gene deletion, most of them are novel variants. The main clinical features included neurodevelopmental delay (7/7) and intellectual disability (5/7), autism/attention deficit hyperactivity disorder (5/7), microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7). HH was confirmed in two female patients with primary amenorrhea, nonvisualized/prepubertal size of the uterus, and nonvisualized ovaries. Two of the male patients presented with micropenis, two had cryptorchidism, and one had decreased testicular size, which are suggestive findings of HH. This article contributes to the clinical characterization of patients with SOX11 variants and supports the role of this gene in HH., Competing Interests: Competing interests: HZE and MS are employees of GeneDx, LLC. The other authors declare no competing interests. Ethical approval: Written consent for clinical data collection was given by legal guardians. Ethical approval was obtained by the respective institutional research ethics board for each individual., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Aims: PTC518 is an orally administered, centrally and peripherally distributed huntingtin (HTT) pre-mRNA splicing modifier being developed for the treatment of Huntington's disease (HD) for which there is a high unmet medical need as there are currently no approved disease-modifying treatments. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PTC518 in healthy volunteers., Methods: This phase 1, single-centre, randomized study in 77 healthy male and female volunteers evaluated the safety and tolerability and PK of PTC518 following single ascending doses and multiple ascending doses, PD as assessed by HTT mRNA and HTT protein levels after single and multiple doses, and food effects., Results: PTC518 demonstrated a favourable safety profile. The majority of treatment-emergent adverse events were mild and transient. PTC518 T max was reached at 6-7 h and the terminal T 1/2 was 54.0-75.3 h following a single oral dose. Exposure increased with dose though less than dose proportionally. The PTC518 concentrations in cerebrospinal fluid were approximately 2.6-fold higher than the unbound free-drug concentrations in plasma. A significant dose-dependent reduction of up to approximately 60% in HTT mRNA and a significant dose-dependent, time-dependent and sustained reduction in HTT protein levels of up to 35% were observed after PTC518 treatment., Conclusions: PTC518 was well tolerated, and proof of mechanism of this novel splicing modifier was demonstrated by the dose-dependent decrease in systemic HTT mRNA and HTT protein levels. Results from this first-in-human study support further studies in patients with HD and demonstrate the potential for PTC518 as a breakthrough treatment for HD., (© 2024 PTC Therapeutics, Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Lay Abstract: What is already known about the topic? Autistic children frequently often have accompanying physical health problems. However, this has been much less studied in autistic men and women during adulthood. What does this article add? This is one of the first studies to investigate the associations between autistic and somatic problems in adults from the general population. Using a continuous measure of autistic symptom scores and a categorical definition of autism (referred to below as probable autism) which considered symptom severity, childhood age of onset, and functional impairment, we found that autistic problems and irritable bowel syndrome, food allergy, pain, and fatigue were associated in adults. Sex differences were present for pain and fatigue, for which the associations with autistic symptom scores were somewhat stronger in females than males. Regarding age differences, the associations with fatigue and having food allergy were more pronounced in younger adults. Conversely, older individuals had a higher risk of developing irritable bowel syndrome or experiencing pain if they met the criteria for probable autism. Implications for practice, research, or policy There is a need for providing routine programs of screening, assessment, and treatment of autism-related somatic problems and developing evidence-based interventions for autistic individuals. These could be tailored to the needs of specific autistic populations. For example, autistic females could be given extra attention about the potential presence of pain and fatigue, younger adults about the potential presence of food allergy and fatigue, and older adults concerning the potential presence of irritable bowel syndrome and pain., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: While medication adherence (MA) is a key prerequisite for achieving optimal clinical and economic outcomes, nonadherence is highly prevalent. Assessing how healthcare professionals (HCPs) in Europe manage MA, focusing on measurement, reporting and interventions, is the subject of this study., Methods: A cross-sectional study was conducted among 40 European countries and quantitative analysis was conducted via an online survey. The multi-language online survey was created using Webropol 3.0 survey and reporting tool. Descriptive statistics and chi-squared tests were applied., Results: In total, 2875 HCPs (pharmacists: 39.9%; physicians: 36.7%; nurses: 16.4%) from 37 European countries participated. The most used methods for MA assessment were direct communication with patients (86.4%) and referring to personal patient records (56.7%) (P < 0.0001). Physicians (74.9%) and nurses (58.8%) were more aware of problems related to MA in contrast to pharmacists (48.6%) (P < 0.001). Almost all HCPs (92.6%) indicated that MA-enhancing interventions involved mainly direct communication with nonadherent patients (93.3%) and their caregivers (55.7%). Medication review and related optimization of therapy were mainly performed in Western European countries (46.8%). Technological solutions were ranked as one of the less applied approaches (10-15%) (P < 0.001)., Conclusions: HCPs in all European regions recognize MA management as an integral element of overall patient-centred care. More efforts are needed to ensure timely, adequate and relevant MA assessment, reporting and improvement and involvement of all HCPs, especially among pharmacists who were generally less aware of MA issues. Promotion and use of digital technological solutions should be the focus of current and future clinical practice to optimize MA management processes., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

In patients with the rare adult-type granulosa cell tumors (aGCT), surgery is the primary treatment for both primary and recurrent disease. In cases of inoperable disease, systematic therapy is administered, but variable response rates and drug resistance complicate predicting the most effective therapy. Drug screen testing on patient-derived cell lines may offer a solution. In a national prospective study on aGCT, fresh tissue was cultured into 2D cell lines, testing 27 clinically and experimental drugs. Dose-response curves and synergy were calculated using GraphPad Prism and Compusyn software. We established 34 patient-derived cell lines from tissue of 20 adult granulosa cell tumor patients. Of these, seven patients had a primary diagnosis of adult granulosa cell tumor and 13 patients had recurrent disease. In eight patients multiple tumor locations were cultured. On each cell line 10 monotherapies and 17 combinations of drugs were tested. Carboplatin/gemcitabine showed efficacy and synergy in almost all patient-derived cell lines. Synergy could not be detected in the regular carboplatin/paclitaxel and carboplatin/etoposide combinations. Experimental combinations alpelisib/fulvestrant and alpelisib/gemcitabine showed efficacy of more than 75%. Drug screens on patient-derived tumor cell lines reflects the reality of the variable response of systemic therapy in aGCT patients. In future research, this technique may be used to personalize the systemic treatment of aGCT patients in a clinical study. The good response to carboplatin/gemcitabine in our patient-derived cell lines can then be confirmed in a clinical setting.

The burden of non-communicable diseases (NCDs) in Indonesia is increasing, as evidenced by the latest Indonesian National Health Research, which shows an increase in diabetes prevalence, from 6.9% in 2013 to 10.9% in 2018, and hypertension, from 25.8% in 2013 to 34.1% in 2018. Hence, effective actions in community and primary health care (PHC) facility settings are necessary to tackle the burden of diabetes and hypertension, especially in low- and middle-income countries. The Indonesian government has issued numerous guidelines regarding NCDs. However, not all these guidelines can be applied to communities or PHCs. This study aimed to identify priority guidelines to support the community and PHC for NCD management using the Delphi survey method. These prioritized guidelines will serve as valuable resources for developing relevant, operational and comprehensive modules for community cadres and PHC staff involved in NCD management. The Delphi survey involved 25 experts and comprised three rounds using a questionnaire: 1) identification and assessment of guidelines, 2) assessment of the importance of guidelines, and 3) nomination of the three main priority guidelines. The results revealed three priority guidelines: NCD management guidelines, technical guidelines for Pos Pembinaan Terpadu (POSBINDU) NCDs, and integrated services for NCDs in PHC facilities. Additionally, priority guidelines were used to develop operational modules for community cadres and PHC staff in NCDs management. In conclusion, utilizing the Delphi method serves as a scientific approach to identify priority guidelines crucial for supporting the community and PHC in managing NCDs, particularly in countries with contexts similar to Indonesia., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pamungkasari 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.)

As chemotherapy is still a cornerstone of colorectal cancer (CRC) treatment, chemotherapy-induced peripheral neuropathy (CIPN) presents significant clinical challenges, affecting millions worldwide. A subset of colon cancer patients (approximately 30%) develop chronic CIPN, with detrimental, untreatable neuropathic pain symptoms. The risk factors of such intractable chronic CIPN are unknown. However, there is growing literature data investigating the intriguing interplay of neurons and cancer (cancer neuroscience). Recent data shows that this interplay might have a key role in the development and severity of CIPN. Given its vast (patho)physiological roles in both colon cancer and neuropathy, MMP9 seems to be a key factor that might drive the development of neuronal damage in colon cancer patients. This review investigates the role of matrix metalloproteinase 9 (MMP9) in linking CRC to neuropathy, aiming to uncover shared mechanisms that could offer new therapeutic targets. By synthesizing insights from a broad range of studies published over the last 20 years, we explore MMP9's involvement in CRC progression, its role in CIPN, and the interconnected pathways influencing both conditions. These studies reveal MMP9 as a pivotal mediator in ECM remodeling, inflammation, and signal transduction pathways, emphasizing its modulation by macrophages. These shared mechanisms of colon cancer and CIPN pathophysiology suggest MMP9's potential contribution to neuropathic conditions in CRC patients, positioning it as a critical factor in disease progression and a promising therapeutic target. Future research should focus on longitudinal studies to assess MMP9's impact on neuropathy outcomes in CRC patients, exploring MMP9 inhibitors, and developing targeted interventions to mitigate the detrimental symptoms of CIPN. MMP9 also seems to be a feasible driving factor in the development of chronic CIPN in colon cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Regalado and Balogh.)

A growing body of research shows that demographic attitudes and behaviors across the life course are socially stratified. Building on this and focusing on the transition to parenthood, we hypothesize that (i) parental socioeconomic status is associated with multiple dimensions of the transition to parenthood, including fertility norms (perceived lower age limit at first birth), ideals (ideal age at first birth), and behaviors (age at first birth), and that (ii) this association varies across national contexts, as national contexts determine the opportunities and constraints that guide young adults' life course attitudes and behaviors. Drawing on the European Social Survey 2006 and 2018 data, we analyze early fertility norms and ideals and later fertility behaviors of a pseudo-panel of individuals born between 1976 and 1988. We show that (i) parental socioeconomic status is positively associated with later fertility norms, later fertility ideals, and later childbearing, even when controlling for respondents' own socioeconomic status, and that (ii) national contexts partially moderate these associations. We conclude by discussing implications for theories of fertility and highlighting avenues for future research., Competing Interests: Declarations. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Introduction: Endothelin-1 (ET-1) regulates renal and vascular function, but the clinical utility of selective ET A receptor antagonists has been limited due to associated fluid retention. The mechanisms underlying fluid retention remain poorly understood but could be a consequence of changes in ET-1 binding to the unantagonized ET B receptor, either through increased ET-1 or non-selective ET B ., Methods: A mathematical model of ET-1 kinetics was developed to quantify effects of ET A antagonist exposure and selectivity on concentrations of ET-1 and its complexes with ET A and ET B receptors. The model describes ET-1 production, tissue and plasma distribution, ET A and ET B receptor binding, and receptor-mediated clearance, and was calibrated and validated with human ET-1 infusion studies., Results: The model confirmed the significant role of ET B in ET-1 clearance. By varying both drug ET A selectivity (K ib /K ia ) and concentration over a wide range, simulations predicted that while selective ET A antagonist (selectivity >1) always decreased [ET1-ET A ], the change in [ET1-ET B ] was more complex. It increased up to 45% as drug concentrations approached and exceeded K ia , but the increase was diminished as drug concentration increased further and fell below baseline at high concentrations. The drug concentration required to cause a decrease in [ET1-ET B ] was lower as ET A selectivity decreased., Discussion: This is the first mechanistic mathematical model of ET-1 kinetics that describes receptor-mediated clearance, and the consequence of ET B blockade on ET-1 concentrations. It provides a useful tool that can coupled with experimental studies to quantitively understand and investigate this complex and dynamic system., Competing Interests: KH has received research funding from AstraZeneca and Eli Lilly in the last 3 years. HY and PG are employees of AstraZeneca and own AstraZeneca stock or stock options. HH is a consultant for and received honoraria from AbbVie, Astellas, Astra Zeneca, Boehringer Ingelheim, Fresenius, Janssen and Merck; he has a policy that all honoraria are paid to his employer. This study received funding from AstraZeneca Pharmaceuticals. The funder had the following involvement in the study: interpretation of results and writing of the manuscript., (Copyright © 2024 Hallow, Greasley, Heerspink and Yu.)

Living donor kidney transplantation boasts superior patient and graft survival rates compared to deceased donor kidney transplantation. However, the impact of living donor body composition (BC) on post-transplant kidney function remains uncertain. In a cohort of 293 living kidney donor-recipients pairs, we utilized linear mixed model analyses, adjusted for time and including a multiplicative interaction term of time with the donor body composition measure, and found no significant associations between any donor BC measure and the annual change in recipient post-transplantation estimated glomerular filtration rate (eGFR) [donor body mass index (BMI): B =-0.01, 95%CI -0.13; 0.11, p =0.88; donor waist circumference: B =0.02, 95%CI -0.02; 0.06, p =0.38; donor skeletal muscle index: B =-0.02, 95%CI -0.07; 0.04, p =0.63; donor skeletal muscle radiation attenuation: B =-0.002, 95%CI -0.06; 0.06, p =0.96; donor visceral adipose tissue index: B =-0.001, 95%CI -0.02; 0.02, p =0.93; donor subcutaneous adipose tissue index: B =-0.001, 95%CI -0.02; 0.02, p =0.94; donor intramuscular adipose tissue index: B =-0.12, 95%CI -0.29; 0.06, p =0.19; donor total abdominal adipose tissue index: B =-0.001, 95%CI -0.01; 0.01, p =0.89]. Our study suggests that pre-donation BC does not affect post-transplantation recipient eGFR in donor populations with a BMI below 35 kg/m 2 ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Quint, Westenberg, Nieuwenhuijs-Moeke, van den Broek, Zorgdrager, Viddeleer, Bakker, Nolte, van Londen, Pol and TransplantLines Investigators.)

Autism spectrum disorder (ASD) often co-occurs with functional somatic syndromes (FSS), such as irritable bowel syndrome (IBS), multisite pain, and fatigue. However, the underlying genetic mechanisms and causality have not been well studied. Using large-scale genome-wide association study (GWAS) data, we investigated the shared genetic architecture and causality between ASD and FSS. Specifically, we first estimated genetic correlations and then conducted a multi-trait analysis of GWAS (MTAG) to detect potential novel genetic variants for single traits. Afterwards, polygenic risk scores (PRS) of ASD were derived from GWAS and MTAG to examine the associations with phenotypes in the large Dutch Lifelines cohort. Finally, we performed Mendelian randomization (MR) to evaluate the causality. We observed positive genetic correlations between ASD and FSS (IBS: r g  = 0.27, adjusted p = 2.04 × 10 -7 ; multisite pain: r g  = 0.13, adjusted p = 1.10 × 10 -3 ; fatigue: r g  = 0.33, adjusted p = 5.21 × 10 -9 ). Leveraging these genetic correlations, we identified 3 novel genome-wide significant independent loci for ASD by conducting MTAG, mapped to NEDD4L, MFHAS1, and RP11-10A14.4. PRS of ASD derived from both GWAS and MTAG were associated with ASD and FSS in Lifelines, and MTAG-derived PRS showed a bigger effect size, larger explained variance, and smaller p-values. We did not observe significant causality using MR. Our study found genetic associations between ASD and FSS, specifically with IBS, multisite pain, and fatigue. These findings suggest that a shared genetic architecture may partly explain the co-occurrence between ASD and FSS. Further research is needed to investigate the causality between ASD and FSS due to current limited statistical power of the GWASs., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Laccases are blue-multicopper containing enzymes that are known to play a role in the bioconversion of recalcitrant compounds. Their role in free radical polymerization of aromatic compounds for their valorization remains underexplored. In this study, we used a pBAD plasmid containing a previously characterized CotA laccase gene (abbreviated as Bli -Lacc) from Bacillus licheniformis strain ATCC 9945a to express this enzyme and explore its biotransformation/polymerization potential on β-naphthol., Methods: The protein was expressed from TOP10 cells of Escherichia coli after successful transformation of the plasmid. Immobilized metal affinity chromatography (IMAC) was used to generate pure protein. The biocatalytic polymerization reaction was optimized based on temperature, pH and starting enzyme concentration. 1 H and 13 C solution nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), and solid-state NMR (ssNMR) were used to characterize the formed polymer. A one-gram conversion reaction was done to explore applicability of the reaction in a pilot-scale., Results: The polymerization reaction generated a brown precipitate, and its chemical structure was confirmed using 1 H and 13 C NMR and FTIR. SsNMR revealed the presence of two different orientational hydroxyl functional groups in the polymer in addition to the presence of a very small amount of ether linkages (< 2%). This analysis elucidated that polymerization occurred mainly on the carbons of the aromatic rings, rather than on the carbons attached to the hydroxyl groups, resulting in a condensed ring or polynuclear aromatic structure. The reaction was optimized, and the highest yield was attained under conditions of 37°C, pH 10 and a starting enzyme concentration of 440 nM in 50 mM phosphate buffer. A one-gram conversion yielded 216 mg of polymer as dry mass. The crystal structure of the enzyme was solved at 2.7 Å resolution using X-ray crystallography and presented with a hexagonal space group. The final structure was deposited in the Protein Databank (PDB) with an ID-9BD5., Discussion: This article provides a green/enzymatic pathway for the remediation of phenolics and their valorization into potential useful polymeric materials. The comprehensive analysis of the formed polymer provides insight into its structure and functional moieties present. Based on the yield of the one-gram conversion, this synthetic method proves useful for a pilot-scale production level and opens opportunities to invest in using this polymer for industrial/environmental applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Refaat, ElRakaiby, El Hariri El Nokab, Es Sayed, Elshewy, Sebakhy, Moneib, Wang, Smith and Habib.)

Gliding birds lack a vertical tail, yet they fly stably rudderless in turbulence without needing discrete flaps to steer. In contrast, nearly all airplanes need vertical tails to damp Dutch roll oscillations and to control yaw. The few exceptions that lack a vertical tail either leverage differential drag-based yaw actuators or their fixed planforms are carefully tuned for passively stable Dutch roll and proverse yaw. Biologists hypothesize that birds stabilize and control gliding flight without rudders by using their wing and tail reflexes, but no rudderless airplane has a morphing wing or tail that can change shape like a bird. Our rudderless biohybrid robot, PigeonBot II, can damp its Dutch roll instability (caused by lacking a vertical tail) and control flight by morphing its biomimetic wing and tail reflexively like a bird. The bird-inspired adaptive reflexive controller was tuned in a wind tunnel to mitigate turbulent perturbations, which enabled PigeonBot II to fly autonomously in the atmosphere with pigeon-like poses. This work is a mechanistic confirmation of how birds accomplish rudderless flight via reflex functions, and it can inspire rudderless aircraft with reduced radar signature and increased efficacy.

Background: Several Patient Reported Outcome Measurements (PROMs) can be used to quantify participation in rehabilitation patients, yet there is limited comparative research on their content and psychometric properties to make an informed decision between them., Objective: To compare the content and several psychometric properties of the Restriction and Satisfaction subscales of the Utrecht Scale for Evaluation of Rehabilitation - Participation (USER-P) with the Patient-Reported Outcomes Measurement Information System Ability to Participate in Social Roles and Activities (PROMIS-APS) and Satisfaction with Social Roles and Activities (PROMIS-SPS) v2.0 8-item short forms., Methods: A cross-sectional survey among patients who received rehabilitation treatment ( N  = 563). Coverage of participation domains, distributions, inter-item correlations, internal consistency, construct validity, and discriminative validity were compared between the PROMs., Results: The USER-P subscales cover more participation domains than the PROMIS short forms. All PROMs demonstrated adequate internal consistency ( α  > 0.82) and each had >75% of the hypotheses regarding construct validity confirmed., Conclusions: The internal consistency, construct and discriminative validity were similar between the USER-P subscales and the PROMIS short forms. It appeared that the USER-P offers more broad information about participation on item level and the total scores of PROMIS short forms offer more precise general information regarding participation.

Introduction: Several studies described that COVID-19 vaccinations can cause menstrual disorders. Our study aimed to describe whether this also resulted in more general practitioner (GP) consultations for menstrual disorders after COVID-19 vaccination, based on a large cohort study., Methods: A retrospective self-controlled cohort study was performed including vaccinated women in 2021 aged 12-49 years from two large, representative GP databases in the Netherlands. Incidence rates and incidence rate ratio's (IRR) were calculated using Poisson regression, adjusting for SARS-CoV-2 infection as time-varying confounder. The exposed period was set at maximum six months after each COVID-19 vaccination and the non-exposed period was defined as all-time outside the exposed period., Results: The cohort included 631,802 women, of which 18,986 (3 %) consulted the GP for a menstrual disorder during 2021. Increased GP consultations were observed among 12-14 year olds for amenorrhea/hypomenorrhea/oligomenorrhea (IRR: 1.85, 95 % CI: 1.30-2.65) and irregular/frequent menstruation (IRR: 1.33, 95 % CI: 1.06-1.69) after COVID-19 vaccination in general, and after Pfizer/BioNTech vaccination (IRR: 1.87, 95 % CI: 1.31-2.67 for amenorrhea/hypomenorrhea/oligomenorrhea and IRR: 1.35, 95 % CI: 1.06-1.70 for irregular/frequent menstruation). Persons from this age group were in general also vaccinated with Pfizer/BioNTech. No increase in the frequency of GP consultations were observed for older age groups, other vaccine brands, and potential risk groups., Conclusion: For the majority of women, no increased GP consultations for menstrual disorders was found. Solely for the youngest age group (12-14 year olds) increased GP consultations for specific types of menstrual disorders was found after Pfizer/BioNTech vaccination., 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.)

Normothermic machine perfusion (NMP) is a clinical strategy to reduce renal ischemia-reperfusion injury (IRI). Optimal NMP should restore metabolism and minimize IRI induced inflammatory responses. Microdialysis was used to evaluate renal metabolism. This study aimed to assess the effect of complement inhibition on NMP induced inflammatory responses. Twenty-two pig kidneys underwent 18 h of static cold storage (SCS) followed by 4 h of NMP using a closed-circuit system. Kidneys were randomized to receive a C5-inhibitor or placebo during SCS and NMP. Perfusion resulted in rapidly stabilized renal flow, low renal resistance, and urine production. During SCS, tissue microdialysate levels of glucose and pyruvate decreased significantly, whereas glycerol increased (p < 0.001). In the first hour of NMP, glucose and pyruvate increased while glycerol decreased (p < 0.001). After 4 h, all metabolites had returned to baseline. Inflammatory markers C3a, soluble C5b-9, TNF, IL-6, IL-1β, IL-8, and IL-10 increased significantly during NMP in perfusate and kidney tissue. C5-inhibition significantly decreased perfusate and urine soluble C5b-9 ( p < 0.001; p = 0.002, respectively), and tissue IL-1β ( p = 0.049), but did not alter other inflammatory markers. Microdialysis can accurately monitor the effect of NMP on renal metabolism. Closed-circuit NMP induces inflammation, which appeared partly complement-mediated. Targeting additional immune inhibitors should be the next step., Competing Interests: TM is a consultant for UCB Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 de Boer, Sokolova, Jager, Schjalm, Weiss, Liavåg, Maassen, van Goor, Thorgersen, Pettersen, Christiansen, Ludviksen, Jespersen, Mollnes, Leuvenink and Pischke.)

Huntington's disease (HD) is caused by a polyglutamine expansion of the huntingtin protein, resulting in the formation of polyglutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here, we show that nuclear polyglutamine aggregates induce nuclear envelope (NE) blebbing and ruptures that are often repaired incompletely. These ruptures coincide with disruptions of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. Furthermore, we found that NE repair factors often accumulated near nuclear aggregates, consistent with stalled repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntington's disease and other polyglutamine diseases., (© 2024 Korsten et al.)

Background: Educational attainment and income are often, but not always, associated with disease incidence. Existing research typically examines single diseases, resulting in disparate analyses with little comparability. In this study, we aimed to assess educational and income inequalities across diseases in Denmark., Methods: This register-based study included all Danish residents aged at least 30 years between Jan 1, 2013, and Dec 31, 2022, who were born after 1920, and with known educational attainment and income. We used a disease-wide approach to assess associations between education and income and the incidence of 751 diagnostic codes determined upon hospital admission. We estimated age-standardised incidence rates and incidence rate ratios (IRRs) using Poisson regression, adjusted for birth cohort and stratified by sex. Participants were followed up until time of diagnosis, death, emigration, or until Dec 31, 2022., Findings: 4 541 309 individuals aged 30 years and older were registered as living in Denmark between Jan 1, 2013, and Dec 31, 2022. 121 083 were excluded due to limited or missing information about educational attainment. 4 420 226 individuals were included in the analysis of educational inequalities (2 232 200 [50%] were female and 2 188 026 [50%] were male). 23 708 were excluded due to absence of income information, and 4 396 518 were included in the analysis of income inequalities (2 223 217 (51%) were female and 2 173 301 (49%) were male). Socioeconomic differences in incidence rates were observed across all disease groups; incidence rates of most diseases decreased with higher educational attainment and income. The magnitude of the socioeconomic inequalities varied substantially. Among non-communicable diseases, the strongest positive association with regard to education was observed in chronic obstructive pulmonary disease for female individuals (low education vs high education, IRR 2·7 [95% CI 2·4-3·0]) and schizophrenia for male inividuals (low education vs high education, IRR 4·4 [2·2-8·8]), and the strongest negative association was in melanoma and other skin cancers for females (low education vs high education, IRR 0·7 [0·7-0·8]) and melanoma and skin cancers for males (low education vs high education, 0·7 [0·6-0·8]). With regard to income, for females, the strongest positive association was observed in schizophrenia (quartile 1 [Q1] vs quartile 4 [Q4], IRR 10·1 [6·1-17·2]), whereas the strongest negative association was in melanoma and other skin cancers (Q1 vs Q4, IRR 0·5 [0·5-0·6]). For males, the strongest positive assocation was schizophrenia (Q1 vs Q4, IRR 18·4 [95% CI 8·5-39·9]) and the strongest negative association was also melanoma and other skin cancers (Q1 vs Q4, IRR 0·5 [0·5-0·6]). The most prevalent disease category, other digestive diseases, was also strongly positively associated with education (low education vs high education, IRR 1·6 [95% CI 1·6-1·6] for females; IRR 1·5 [1·4-1·5] for males) and income (Q1 vs Q4, IRR 1·5 [1·5-1·5] for females; IRR 1·3 [1·3-1·4] for males)., Interpretation: Our study provides a detailed representation of the association between two socioeconomic indicators and disease incidence. A broad spectrum of diseases, and not only the most prevalent, show socioeconomic disparities. This finding highlights the need for not only policies that address specific diseases, but also universal policies addressing the root causes of socioeconomic disparities and their health consequences., Funding: The Novo Nordisk Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aim: To identify the most relevant factors with respect to the management of fracture-related infection (FRI) and to develop a comprehensive FRI classification that guides decision-making and allows scientific comparison., Method: An international group of FRI experts determined the preconditions, purpose, primary factors for inclusion, format and detailed description of the elements of an FRI classification through a consensus driven process., Results: Three major elements were identified and grouped together in the FRI Classification: Fracture (F), Related patient factors (R) and Impairment of soft tissues (I). Each element was divided into five levels of complexity. Fractures can be healed (F1) or unhealed (F2-5). Patients may be fully healthy (R1) or have 4 levels of compromise, with and without end-organ damage (R2-5). Soft tissue condition ranges from well vascularized and easily closed (I1) to major skin defects requiring free flaps (I4). In all three elements, the fifth level (F5, R5 or I5) describes a patient who has an unreconstructible bone, soft tissue envelope or is not fit for surgery., Conclusion: The FRI classification, which is based on the three major elements Fracture (F), Related patient factors (R) and Impairment of soft tissues (I) is intended to guide decision-making and improve the quality of scientific reporting for FRIs in the future. The proposed classification is based on expert opinion and therefore an essential next step is clinical validation, in order to realize the ultimate goal of improving outcomes in the management of FRI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Soccer coaches are critical to academies as they are central to identifying players with the potential to succeed (i.e., talent). Research suggests coaches perceive skill as determining players' potential. Regardless, researchers only broadly explored their views and quantified players' skill using objective measures, which is problematic as coaches still rely on their subjective intuition. A plausible reason is that skill assessments do not meet coaches' needs., Objective: So,this study explored academy soccer coaches' perspectives on skilfulness., Methods: Participants required a minimum B-level AFC/FA Pro Coaching Licence and five years' experience for inclusion. Australian soccer coaches ( n  = 4) and academy directors ( n  = 7) ( M age  = 35.90 ± 8.36 years; M experience  = 14 ± 7.02 years) participated in semi-structured interviews ( M time  = 50.73 ± 7.33)., Results: We analysed coaches' responses using reflexive thematic analysis, generating four themes describing skilful players as i) technically proficient, ii) adaptable, iii) effective decision-makers, and iv) influential to their team's success. We produced three themes on the situational and contextual nature of their views, perceiving skill through a v) developmental lens, relying on their vi) experiential knowledge, and their views were vii) context-specific., Conclusion: Additional research is needed to create a refined conceptual model for assessing soccer skilfulness.

Aims: The purpose of this study was to develop a convolutional neural network (CNN) for fracture detection, classification, and identification of greater tuberosity displacement ≥ 1 cm, neck-shaft angle (NSA) ≤ 100°, shaft translation, and articular fracture involvement, on plain radiographs., Methods: The CNN was trained and tested on radiographs sourced from 11 hospitals in Australia and externally validated on radiographs from the Netherlands. Each radiograph was paired with corresponding CT scans to serve as the reference standard based on dual independent evaluation by trained researchers and attending orthopaedic surgeons. Presence of a fracture, classification (non- to minimally displaced; two-part, multipart, and glenohumeral dislocation), and four characteristics were determined on 2D and 3D CT scans and subsequently allocated to each series of radiographs. Fracture characteristics included greater tuberosity displacement ≥ 1 cm, NSA ≤ 100°, shaft translation (0% to < 75%, 75% to 95%, > 95%), and the extent of articular involvement (0% to < 15%, 15% to 35%, or > 35%)., Results: For detection and classification, the algorithm was trained on 1,709 radiographs (n = 803), tested on 567 radiographs (n = 244), and subsequently externally validated on 535 radiographs (n = 227). For characterization, healthy shoulders and glenohumeral dislocation were excluded. The overall accuracy for fracture detection was 94% (area under the receiver operating characteristic curve (AUC) = 0.98) and for classification 78% (AUC 0.68 to 0.93). Accuracy to detect greater tuberosity fracture displacement ≥ 1 cm was 35.0% (AUC 0.57). The CNN did not recognize NSAs ≤ 100° (AUC 0.42), nor fractures with ≥ 75% shaft translation (AUC 0.51 to 0.53), or with ≥ 15% articular involvement (AUC 0.48 to 0.49). For all objectives, the model's performance on the external dataset showed similar accuracy levels., Conclusion: CNNs proficiently rule out proximal humerus fractures on plain radiographs. Despite rigorous training methodology based on CT imaging with multi-rater consensus to serve as the reference standard, artificial intelligence-driven classification is insufficient for clinical implementation. The CNN exhibited poor diagnostic ability to detect greater tuberosity displacement ≥ 1 cm and failed to identify NSAs ≤ 100°, shaft translations, or articular fractures., Competing Interests: R. W. A. Spek received payments of an amount between USD 10,000 and USD 100,000 from the Flinders Foundation (Adelaide, Australia) for the purpose of this study. During the study period, R. W. A. Spek received payments of an amount between USD 10,000 and USD 100,000 from Prins Bernhard Cultuurfonds (Amsterdam, the Netherlands), Stichting Zabawas (The Hague, The Netherlands), and with an amount of less than USD 10,000 from Michael van Vloten Foundation (Rotterdam, The Netherlands) and Anna Fonds NOREF (Mijdrecht, the Netherlands), all of which were unrelated to this specific study. B. Jadav provided paid consultations for Johnson & Johnson, unrelated to the current study. G. I. Bain received a Flinders Foundation grant for this study, paid to Flinders University, as well as royalties or licenses from Fusetec, stock or stock options in Fusetec, and speaker payments or honoraria from Depuy Synthes and Medartis, none of which are related to this study. G. I. Bain also holds fiduciary roles in the Australian Hand Surgery Society, the Shoulder and Elbow Society of Australia, the Asia Pacific Wrist Association, the International Federation for the Societies for Surgery of the Hand, and the Journal of Wrist Surgery. J. L. Jaarsma is an unpaid executive of the Australian Orthopaedic Association. B. Jadav received a one-off consultation payment and payment for teaching courses from Johnson & Johnson, unrelated to this study. M. P. J. van den Bekerom receives fellowship support from Smith & Nephew, which contributed to this study., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Background: Medication adherence is essential for the achievement of therapeutic goals. Yet, the World Health Organization estimates that 50% of patients are nonadherent to medication and this has been associated with 125 billion euros and 200,000 deaths in Europe annually., Objective: This study aimed to unravel barriers and unmet training needs regarding medication adherence management across Europe., Design: A cross-sectional study was conducted through an online survey. The final survey contained 19 close-ended questions., Participants: The survey content was informed by 140 global medication adherence experts from clinical, academic, governmental, and patient associations. The final survey targeted healthcare professionals (HCPs) across 39 European countries., Main Measures: Our measures were barriers and unmet training needs for the management of medication adherence across Europe., Key Results: In total, 2875 HCPs (pharmacists, 40%; physicians, 37%; nurses, 17%) from 37 countries participated. The largest barriers to adequate medication adherence management were lack of patient awareness (66%), lack of HCP time (44%), lack of electronic solutions (e.g., access to integrated databases and uniformity of data available) (42%), and lack of collaboration and communication between HCPs (41%). Almost all HCPs pointed out the need for educational training on medication adherence management., Conclusions: These findings highlight the importance of addressing medication adherence barriers at different levels, from patient awareness to health system technology and to fostering collaboration between HCPs. To optimize patient and economic outcomes from prescribed medication, prerequisites include adequate HCP training as well as further development of digital solutions and shared health data infrastructures across Europe., Competing Interests: Declarations Conflict of Interest The authors declare no competing interests., (© 2024. The Author(s).)

Organs obtained from brain dead donors can have suboptimal outcomes. Activation of the innate immune system and translocation of intestinal bacteria could be causative. Thirty two pigs were assigned to control, brain death (BD), BD + luminal intestinal polyethylene glycol (PEG), and BD + luminal intestinal University of Wisconsin solution (UW) groups. Animals were observed for 360 min after BD before organ retrieval. 2,000 mL luminal intestinal preservation solution was instilled into the duodenum at the start of organ procurement. Repeated measurements of plasma C3a, Terminal Complement Complex (TCC), IL-8, TNF, and lipopolysaccharide binding protein were analysed by immunoassays. C3a was significantly higher in the BD groups compared to controls at 480 min after brain death. TCC was significantly higher in BD and BD + UW, but not BD + PEG, compared to controls at 480 min. TNF was significantly higher in the BD group compared to all other groups at 480 min. LPS binding protein increased following BD in all groups except BD + PEG, which at 480 min was significantly lower compared with all other groups. Brain death induced innate immune system activation was decreased by luminal preservation using PEG during organ procurement, possibly due to reduced bacterial translocation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Weiss, de Jong, Seegert, Moeslund, Maassen, Schjalm, de Boer, Leuvenink, Mollnes, Eijken, Keller, Dijkstra, Jespersen and Pischke.)

Background: Subjective reports can reveal relevant information regarding the nature of the impairment of brain tumor patients, unveiling potential gaps in current assessment practices. The co-occurrence of language and memory impairments has been previously reported, albeit scarcely. The aim of this study is therefore to understand the co-occurrence of subjective language and memory complaints in the preoperative state of brain tumor patients and its impact on Quality of Life (QoL)., Methods: 31 brain tumor patients (12 LGG, 19 HGG) underwent a semi-structured interview to assess subjective complaints of language deficits, co-occurrences between language and memory dysfunction, and changes in QoL. Group and subgroup analyses were conducted to provide general and tumor grade specific data., Results: 48.4% of patients mentioned co-occurrence of language and memory impairments in reading, writing, and conversation. The HGG group reported co-occurrences in all three of these (reading: 31.6%; writing: 21.1%; conversation: 26.3%), while the LGG only described co-occurrences in reading (25%) and conversation (8.3%), although these were not statistically significant. All patients with co-occurring language and memory deficits reported these to be linked to reduced QoL (48.4%). In patients with an HGG, this number was slightly higher (52.6%) than in patients with an LGG (41.7%)., Conclusion: Language impairments co-occur with memory dysfunction as perceived in patients' daily life. Patients see these impairments as affecting their quality of life. Further attention to dedicated language and memory tasks seems necessary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rybka, Jonkers, Burzlaff, Rosenstock, Vajkoczy, Picht, Faust and Rofes.)

Objectives: The World Health Organization supports both the screen-and-treat (ST) approach and the screen, triage and treat (STT) approach to cervical cancer screening using high-risk human papillomavirus (hrHPV) testing. For Uganda, the sequence of hrHPV-ST and hrHPV-STT could be similar, with visual inspection with acetic acid (VIA) after positive hrHPV tests in both. To consider potential tradeoffs (overtreatment in ST versus missed cancer cases in STT), we compared hrHPV-STT with VIA triage (STT-VIA), and STT with HPV 16/18 genotyping risk stratification, to hrHPV-ST for Uganda, in terms of overtreatment, cervical cancer incidence, and life years, for the general female population of Uganda., Methods: A microsimulation model of cervical cancer was adapted. Incremental benefit-harm ratios of STT were calculated as ratios of prevented overtreatment to reduced life years, and to increased cancer cases. Additional scenarios with 20% difference in intra- and inter-screening follow-up between ST and STT were modeled., Results: Both STT strategies resulted in life year losses on average compared to ST. STT-VIA prevented more overtreatment but led to increased cervical cancer incidence and life year losses. STT-G-VIA resulted in better harm-benefit ratios and additional costs. With better follow-up, STT prevented overtreatment and improved outcomes., Discussion: For Uganda, the STT approach appears preferrable, if the screening sequences of hrHPV-based ST and STT are similar in practice. While VIA triage alone would reduce overtreatment the most, it could also result in more cancer cases. Risk stratification via genotyping could improve STT. Potential follow-up differences and resource availability should be considered by decision-makers when planning Uganda's hrHPV-based screening strategy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sultanov 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.)

Pharmacogenetics is a promising approach in future personalized medicine. This field holds excellent prospects for healthcare quality acceleration. It promotes the transition to the precision medicine era, whereby a health treatment is driven by a deeper understanding of individual characteristics by interpreting the underlying genomic variation. Pharmacogenetics has been developing rapidly since the human genome project. Many pharmacogenetics studies have shown the association between genetic variants and therapy outcomes. Several pharmacogenetics working groups have recommended guidelines for the clinical application of pharmacogenetics. However, the development of pharmacogenetics in low- and middle-income countries (LMICs) is still retarded behind. The problems mainly include clinical evidence, technology, policy and regulation, and human resources. Currently, available genome and drug effect data in LMICs are scarce. Pharmacogenetics development should be escalated with evidence proof through research collaboration across countries. The challenges of pharmacogenetics implementation are discussed comprehensively in this article, along with the prospect of pharmacogenetics-guided personalized medicine in developed countries. Stepwise is expected to help the researchers and stakeholders define the problem that hindered the pharmacogenetics application., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Ausi et al.)

P21 activated kinase 6 (PAK6) is a serine-threonine kinase with physiological expression enriched in the brain and overexpressed in a number of human tumors. While the role of PAK6 in cancer cells has been extensively investigated, the physiological function of the kinase in the context of brain cells is poorly understood. Our previous work uncovered a link between PAK6 and the Parkinson's disease (PD)-associated kinase LRRK2, with PAK6 controlling LRRK2 activity and subcellular localization via phosphorylation of 14-3-3 proteins. Here, to gain more insights into PAK6 physiological function, we performed protein-protein interaction arrays and identified a subgroup of PAK6 binders related to ciliogenesis. We confirmed that endogenous PAK6 localizes at both the centrosome and the cilium, and positively regulates ciliogenesis not only in tumor cells but also in neurons and astrocytes. Notably, PAK6 rescues ciliogenesis and centrosomal cohesion defects associated with the G2019S but not the R1441C LRRK2 PD mutation. Since PAK6 binds LRRK2 via its GTPase/Roc-COR domain and the R1441C mutation is located in the Roc domain, we used microscale thermophoresis and AlphaFold2-based computational analysis to demonstrate that PD mutations in LRRK2 affecting the Roc-COR structure substantially decrease PAK6 affinity, providing a rationale for the differential protective effect of PAK6 toward the distinct forms of mutant LRRK2. Altogether, our study discloses a novel role of PAK6 in ciliogenesis and points to PAK6 as the first LRRK2 modifier with PD mutation-specificity., (© 2024. The Author(s).)

Background: Cardiovascular diseases (CVDs) and neoplasms are leading causes of mortality worldwide., Objective: This study aims to provide a comprehensive analysis of the mortality burden and disability-adjusted life years (DALYs) attributable to CVDs and neoplasms in Western Europe, investigate associated risk factors, and identify regional disparities. Additionally, the study evaluates the effectiveness of the Action Plan for the Prevention and Control of Non-Communicable Diseases (NCDs) in promoting healthier lives in the region., Methods: The study collected data on mortality and DALYs due to CVDs and cancers from 24 Western European countries using the Global Burden of Disease Study 2021. The analysis explored age, sex, and country-specific patterns, as well as risk factors contributing to these deaths. Additionally, the study examined time trends by calculating the annual percent change in mortality rates from 1990 to 2021 by region and cause., Results: In 2021, CVDs and neoplasms accounted for 27.8% and 27.1% of total deaths in Western Europe, with age-standardized death rates of 106.8 and 125.8 per 100,000, respectively. The top two CVDs in this region were ischemic heart disease and stroke, with age-standardized death rates of 47.27 (95% uncertainty interval [UI] 50.42-41.45) and 27.06 (95% UI 29.17-23.00), respectively. Similarly, the top two neoplasms were lung cancer and colorectal cancer, with age-standardized death rates of 26.4 (95% UI 27.69-24.47) and 15.1 (95% UI 16.25-13.53), respectively. Between 1990 and 2021, CVD mortality rates decreased by 61.9%, while cancer rates decreased by 28.27%. Finland had the highest CVD burden (39.5%), and Monaco had the highest rate of cancer-related deaths (34.8%). Gender differences were observed, with males experiencing a higher burden of both CVDs and cancer. Older individuals were also more at risk. Smoking had a stronger impact on CVD mortality and DALYs in males, while a higher Human Development Index was associated with increased cancer deaths and DALYs in females., Conclusions: The study findings highlight the substantial burden of NCDs, particularly CVDs and cancer, in Western Europe. This underscores the critical need for targeted interventions and effective implementation of the Action Plan for the Prevention and Control of NCDs to achieve the goal of ensuring healthy lives for all., (© Sumaira Mubarik, Shafaq Naeem, Hui Shen, Rabia Mubarak, Lisha Luo, Syeda Rija Hussain, Eelko Hak, Chuanhua Yu, Xiaoxue Liu. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).)

Over 40 years ago, the 1982 Splicing Life report outlined the two distinctions that have orientated much of the normative and legal landscape of genetic intervention or genome editing since - that of somatic versus germline (or heritable interventions) and medical versus non-medical (or enhancement) applications. During this time, these distinctions have been used to ethically prioritize some areas of research and potential application, such as somatic treatments, while considering others for prohibition, such as germline enhancements. Nevertheless, somatic interventions may also be done for controversial enhancement purposes while some germline interventions may be done with greater prima facie justification (e.g., the enhancement of athletic ability versus the avoidance of Tay-Sachs disease). Even with new somatic treatments that are generally lauded, exemplified with the case of Casgevy, many issues still arise - such as cost and access, particularly salient on a global level. The concerns over a dystopian future of genetic haves and have nots, as a result of enhancement and/or germline interventions, that perhaps may happen, should not distract us from a greater attention to what is happening in the here and now. In this paper, we will highlight the limits of the two distinctions in terms of moving from questions of "should a technology be used" to "how should a technology be used." We argue that an additional focus on vulnerability and marginalization can be useful to support the attempt to better prioritize which interventions should be permitted or prohibited. We show how this can better dovetail with calls for effective (global) governance and reasonable consensus by focusing on the most urgent issues and developing policy accordingly, while leaving aside more abstract issues for further discussion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Angelioudaki, Badea, Bodo, Fernández-Soto, Karyampa, Kokkinakis, Kolisis, Kominea, Ozáez Armijos, Vogel and Feeney.)

Genomic instability is a driver and accelerator of tumorigenesis and influences disease outcomes across cancer types. Although genomic instability has been associated with immune evasion and worsened disease prognosis, emerging evidence shows that genomic instability instigates pro-inflammatory signaling and enhances the immunogenicity of tumor cells, making them more susceptible to immune recognition. While this paradoxical role of genomic instability in cancer is complex and likely context-dependent, understanding it is essential for improving the success rates of cancer immunotherapy. In this review, we provide an overview of the underlying mechanisms that link genomic instability to pro-inflammatory signaling and increased immune surveillance in the context of cancer, as well as discuss how genomically unstable tumors evade the immune system. A better understanding of the molecular crosstalk between genomic instability, inflammatory signaling, and immune surveillance could guide the exploitation of immunotherapeutic vulnerabilities in cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Requesens, Foijer, Nijman and de Bruyn.)

Background: Preventing high heart rates in patients with atrial fibrillation (AF) is a key objective of AF management. Data regarding heart rates in patients with paroxysmal AF (PAF) is lacking. This analysis aimed to provide insight into heart rates during PAF episodes measured with continuous implantable loop monitoring., Methods: In present analysis of the Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilization in the Progression of AF study, we included 349 patients with at least one year of continuous rhythm monitoring and an episode of AF. Mean heart rates and duration of AF episodes were used to calculate total AF duration and AF duration above different heart rate cut-offs., Results: The median age was 64.0 (58.4 to 70.5) years, 152 (44%) were women and CHA 2 DS 2 -VASc score ≥2 or higher in 255 (73%) patients. During 28.3 (21.3 to 35.0) months of follow-up, the median number of AF episodes was 62 (12 to 293) with a median total AF duration of 4.6 (0.8 to 26.8) days. At baseline, 172 (49%) patients used beta-blockers, 64 (18%) used diltiazem or verapamil and 5 (1%) used digoxin. A total of 133 patients (38%) experienced a heart rate >110 bpm for more than 50% of the time during AF. Fifty-six (16%) patients had a heart rate >130 bpm for more than 50% of the time while in AF. During follow-up, 39 patients (11%) received an increase of rate-controlling medication., Conclusion: Continuous rhythm monitoring revealed that more than a third of PAF patients had heart rates above 110 bpm for more than half of their time in AF., Trial Registration Number: Clinicaltrials.gov identifier NCT02726698., Competing Interests: Competing interests: RGT reports grants from Medtronic and Abbott, and personal fees from Boehringer Ingelheim, Bayer and Pfizer/Bristol Myers Squibb all outside submitted work. RGT is coinventor of the MyDiagnostick, not receiving royalties for the past 5 years. MDM is a Medtronic employee and WP Coordinator in the H2020 ITN My-Atria (No: 766082). The remaining authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The 2021 European Society of Cardiology prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding initiation of prevention. We aimed to update and systematically recalibrate the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model to four European risk regions for the estimation of lifetime CVD risk for apparently healthy individuals., Methods and Results: The updated LIFE-CVD (i.e. LIFE-CVD2) models were derived using individual participant data from 44 cohorts in 13 countries (687 135 individuals without established CVD, 30 939 CVD events in median 10.7 years of follow-up). LIFE-CVD2 uses sex-specific functions to estimate the lifetime risk of fatal and non-fatal CVD events with adjustment for the competing risk of non-CVD death and is systematically recalibrated to four distinct European risk regions. The updated models showed good discrimination in external validation among 1 657 707 individuals (61 311 CVD events) from eight additional European cohorts in seven countries, with a pooled C-index of 0.795 (95% confidence interval 0.767-0.822). Predicted and observed CVD event risks were well calibrated in population-wide electronic health records data in the UK (Clinical Practice Research Datalink) and the Netherlands (Extramural LUMC Academic Network). When using LIFE-CVD2 to estimate potential gain in CVD-free life expectancy from preventive therapy, projections varied by risk region reflecting important regional differences in absolute lifetime risk. For example, a 50-year-old smoking woman with a systolic blood pressure (SBP) of 140 mmHg was estimated to gain 0.9 years in the low-risk region vs. 1.6 years in the very high-risk region from lifelong 10 mmHg SBP reduction. The benefit of smoking cessation for this individual ranged from 3.6 years in the low-risk region to 4.8 years in the very high-risk region., Conclusion: By taking into account geographical differences in CVD incidence using contemporary representative data sources, the recalibrated LIFE-CVD2 model provides a more accurate tool for the prediction of lifetime risk and CVD-free life expectancy for individuals without previous CVD, facilitating shared decision-making for cardiovascular prevention as recommended by 2021 European guidelines., Competing Interests: Conflict of interest: Due to the very long author list, these will be provided per author using ICMJE forms at the revision stage, if applicable., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Advances in medical imaging have made it possible to classify ankle fractures using Artificial Intelligence (AI). Recent studies have demonstrated good internal validity for machine learning algorithms using the AO/OTA 2018 classification. This study aimed to externally validate one such model for ankle fracture classification and ways to improve external validity., Methods: In this retrospective observation study, we trained a deep-learning neural network (7,500 ankle studies) to classify traumatic malleolar fractures according to the AO/OTA classification. Our internal validation dataset (IVD) contained 409 studies collected from Danderyd Hospital in Stockholm, Sweden, between 2002 and 2016. The external validation dataset (EVD) contained 399 studies collected from Flinders Medical Centre, Adelaide, Australia, between 2016 and 2020. Our primary outcome measures were the area under the receiver operating characteristic (AUC) and the area under the precision-recall curve (AUPR) for fracture classification of AO/OTA malleolar (44) fractures. Secondary outcomes were performance on other fractures visible on ankle radiographs and inter-observer reliability of reviewers., Results: Compared to the weighted mean AUC (wAUC) 0.86 (95%CI 0.82-0.89) for fracture detection in the EVD, the network attained wAUC 0.95 (95%CI 0.94-0.97) for the IVD. The area under the precision-recall curve (AUPR) was 0.93 vs. 0.96. The wAUC for individual outcomes (type 44A-C, group 44A1-C3, and subgroup 44A1.1-C3.3) was 0.82 for the EVD and 0.93 for the IVD. The weighted mean AUPR (wAUPR) was 0.59 vs 0.63. Throughout, the performance was superior to that of a random classifier for the EVD., Conclusion: Although the two datasets had considerable differences, the model transferred well to the EVD and the alternative clinical scenario it represents. The direct clinical implications of this study are that algorithms developed elsewhere need local validation and that discrepancies can be rectified using targeted training. In a wider sense, we believe this opens up possibilities for building advanced treatment recommendations based on exact fracture types that are more objective than current clinical decisions, often influenced by who is present during rounds., (© 2024. The Author(s).)

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 pleiotropic cancer locus in squamous cell lung carcinoma. Overall, we report twelve novel risk loci for overall lung cancer, lung adenocarcinoma, and squamous cell lung carcinoma, nine of which are externally replicated. Finally, we perform PheWAS on polygenic risk scores for lung cancer, with and without conditioning on smoking. The unconditioned lung cancer polygenic risk score is associated with smoking status in controls, illustrating a reduced predictive utility in non-smokers. Additionally, our polygenic risk score demonstrates smoking-independent pleiotropy of lung cancer risk across neoplasms and metabolic traits., (© 2024. The Author(s).)

Collaboration among various professions often faces barriers owing to divergent perspectives, priorities, and expertise shaped by distinct socialization processes. These differences can hinder effectiveness, efficiency, and workforce well-being. The Extended Professional Identity Theory (EPIT) addresses this issue by fostering an interprofessional identity without weakening professional identities. Drawing from psychological theories, EPIT explains the coexistence of interprofessional and professional identities, and predicts associated behaviors. It also emphasizes the importance of combining interprofessional identity formation with developing interprofessional competencies and adapting to environmental factors to achieve synergy in (temporary or permanent) mixed profession groups. Introduced in 2018, EPIT research initially relied on the measurement of congruent interprofessional behaviors as indirect indicators of interprofessional identity that could not yet be measured. An experiment demonstrated that enhancing social identification in mixed profession groups with interprofessional assignments reduced the social hierarchy within 6 h across three meetings. The 2020 development of the Extended Professional Identity Scale (EPIS) confirmed interprofessional identity as a three-dimensional social construct. So far, several scientific studies have supported many propositions of EPIT. These propositions are related to dimensionality and various psychometric properties, cross-cultural similarities, evidence and clues for interprofessional identity formation, and its predictive validity in interprofessional education and collaborative practice. Türkiye is among several countries (e.g., the Netherlands, Belgium, Germany, Lithuania, Finland, and Indonesia) where EPIT-based interprofessional identity is being investigated. To illustrate contextual differences and their potential cross-cultural implications, it is valuable to explore how interprofessional identity adds value in the Turkish context. This approach facilitates understanding the regional implications of interprofessional identity, including interprofessional education initiatives, increased university engagement, the development of measurement instruments, challenges and future directions, and national and international collaborations. This paper aims to explain and clarify EPIT propositions compared to other theories, describe current evidence, and outline future research directions, with a focus on developments within the Turkish context as a showcase., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Reinders, Başer Kolcu and Kolcu.)

Multiculturalism and tolerance, as two sets of normative beliefs about how to deal with intergroup diversity, have been recognized as effective at reducing outgroup negativity among majority group members. However, whether majority group members' normative beliefs regarding them might motivate their solidarity-based collective actions and how their political ideology might qualify this influence remained unclear. To answer these questions, we conducted two pre-registered experimental studies (N = 626), both zooming in on the multiculturalism issues in the context of the relationships between native Dutch citizens and citizens with a Moroccan background within Dutch university campuses (Study 1) and broader Dutch society (Study 2). In both studies, we found an ingroup norm of tolerance (vs. control) undermined majority group members' engagement in collective actions in support of ethnic minorities. Additionally, ideological leftists were more sensitive to norms than rightists: Study 1 showed a facilitative effect of the multiculturalism norm (vs. control) on solidarity-based collective action intentions particularly among leftists, whilst Study 2 revealed a dampening effect of the tolerance norm (vs. control) on these intentions particularly among leftists., (© 2024 The Author(s). British Journal of Social Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Background: Capmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib., Methods: In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1-7. Here, we report the final clinical outcomes from all METex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1-7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed., Findings: Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had METex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46·4 months (IQR 41·8-65·4) for the treatment-naïve patients and 66·9 months (56·7-73·9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55·0-79·7) of 60 treatment-naive patients and 44 (44%; 95% CI 34·1-54·3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3-4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported., Interpretation: These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC., Funding: Novartis Pharmaceuticals., Competing Interests: Declaration of interests JW reports research grant support (to their institution) from Bristol Myers Squibb, Janssen Pharmaceutica, Novartis, and Pfizer; and consulting fees or honoraria for lectures and for attending meetings from Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre Fabre, Roche, Seattle Genetics, Takeda, and Turning Point. MH declares personal honoraria for lectures and presentations from Boehringer Ingelheim, AstraZeneca, Takeda, Amgen, MSD, and Roche. J-YH reports research grants from Pfizer, Takeda, and ONO; consulting fees or honoraria for lectures and presentations from AstraZeneca, Jassen, Amgen, Oncobix, Daiichi Sankyo, Merck, Norvatis, Abion, Takeda, Pfizer, and Yuhan; participation in data safety monitoring board for AstraZeneca, Jassen; and a leadership role for National Cancer Drug Assessment Committee. NR declares research grants from Artidis, MSD, Amgen, and Roche; honoraria for lectures and presentations from Amgen, AstraZeneca, Bristol Myers Squibb, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, Takeda, and Regeneron; support for attending the meetings from Takeda, Regeneron, and Roche; and participation in a data safety monitoring and advisory board for AbbVie, Amgen, AstraZeneca, Bayer, Boehringer, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, Takeda, and Regeneron. P-JS reports the research grants received (to their institution) from AstraZeneca, Bristol Myers Squibb, Genentech, and Gilead; and consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, Pfizer, and Takeda. EFS reports consulting fees support to their institution from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche, Sanofi, Takeda, and Merck; honoraria for lectures and presentations for self from Boehringer Ingelheim and Daiichi Sankyo; and participation in a data safety monitoring and advisory board for Daiichi Sankyo and Taiho for institution. JV declares consulting fees received from Bristol Myers Squibb, Janssen, and PDCline; honoraria for lectures and presentations from AstraZeneca, Daiichi Sankyo, and Merck; and participation in a data safety monitoring and advisory board for AstraZeneca, Boehringer, and Transgene. MN reports honoraria received for lectures and presentations from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, Lilly, AstraZeneca, MSD, AbbVie, Takeda Pfizer, Boehringer, Ingelheim, Novartis, Nippon, Kayaku, Merck, and Janssen; and support for attending meetings from Novartis. WA declares research grants received from Bristol Myers Squibb, AstraZeneca, Bioatla, Imugene, Astride, BridgeBio, AbbVie, and Novocure; and participation in data safety monitoring and advisory board for Lilly. EBG reports research grants received (to their institution) from ABL-Bio, Arrivent, AstraZeneca, Bristol Myers Squibb, Daiichi, Sanko, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Prelude, Regeneron, and Synthekine; consulting fees from AbbVie, Arcus, AstraZeneca, Arrivent, Atreca, BridgeBio, Bristol Myers Squibb, EMD Serono, Eli Lilly, Gilead, GlaxoSmithKline, Hookipa, LianBio, Merckl Merus, Novartis, Nuvalent, Personalis, Regeneron, Sanofi, Seagan, Sensei, Sumitomo, Strata, Summit, Synthekine, Xilio, and Zymeworks; support for attending meetings from A2 and Novartis; patents issued (to their institution); and other financial support for independent medical education from Daiichi Sankyo and Ipsen. DSWT reports research grants support to their institution from ACM Biolabs, Amgen, AstraZeneca, Bayer, and Pfizer, outside of the submitted work; consulting fees from Amgen, AstraZeneca, Bayer, Boehringer, Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, and Takeda; honoraria for lectures and presentations from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda, BeiGene, Regeneron, and Zymeworks; and support for attending meetings from Bayer, Merck, Pfizer, Regeneron, and Zymeworks. TS declares honoraria for lectures from Amgen, AnHeart Therapeutics, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, GlaxoSmithKline, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Takeda Pharmaceutical, and Towa Pharmaceutical. GMF declares the stocks and shareholder for Roche. AR, MC, SLM, CB, YY, LJ, LF, and AY are employees of Novartis. AB reports stocks and stock options from Novartis and Daiichi Sankyo. RSH declares research grants received to their institution for clinical trials from AbbVie, Agios, Corvus, Daichii Sankyo, Erasca, Lilly, Mirati, Mythic, Novartis, and Turning Point; and consulting fees for self from AbbVie, Astrazeneca, Biohaven, Claim Therapeutics, Daichii Sankyo, EMD Serono, Lilly, Merck, Novartis, Regeneron, and Sanofi. SVO, HJMG, and MJ declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Amyloid-β (Aβ) plaques is a significant hallmark of Alzheimer's disease (AD), detectable via amyloid-PET imaging. The Fluorine-18-Fluorodeoxyglucose ([ 18 F]FDG) PET scan tracks cerebral glucose metabolism, correlated with synaptic dysfunction and disease progression and is complementary for AD diagnosis. Dual-scan acquisitions of amyloid PET allows the possibility to use early-phase amyloid-PET as a biomarker for neurodegeneration, proven to have a good correlation to [ 18 F]FDG PET. The aim of this study was to evaluate the added value of synthesizing the later from the former through deep learning (DL), aiming at reducing the number of PET scans, radiation dose, and discomfort to patients., Methods: A total of 166 subjects including cognitively unimpaired individuals (N = 72), subjects with mild cognitive impairment (N = 73) and dementia (N = 21) were included in this study. All underwent T1-weighted MRI, dual-phase amyloid PET scans using either Fluorine-18 Florbetapir ([ 18 F]FBP) or Fluorine-18 Flutemetamol ([ 18 F]FMM), and an [ 18 F]FDG PET scan. Two transformer-based DL models called SwinUNETR were trained separately to synthesize the [ 18 F]FDG from early phase [ 18 F]FBP and [ 18 F]FMM (eFBP/eFMM). A clinical similarity score (1: no similarity to 3: similar) was assessed to compare the imaging information obtained by synthesized [ 18 F]FDG as well as eFBP/eFMM to actual [ 18 F]FDG. Quantitative evaluations include region wise correlation and single-subject voxel-wise analyses in comparison with a reference [ 18 F]FDG PET healthy control database. Dice coefficients were calculated to quantify the whole-brain spatial overlap between hypometabolic ([ 18 F]FDG PET) and hypoperfused (eFBP/eFMM) binary maps at the single-subject level as well as between [ 18 F]FDG PET and synthetic [ 18 F]FDG PET hypometabolic binary maps., Results: The clinical evaluation showed that, in comparison to eFBP/eFMM (average of clinical similarity score (CSS) = 1.53), the synthetic [ 18 F]FDG images are quite similar to the actual [ 18 F]FDG images (average of CSS = 2.7) in terms of preserving clinically relevant uptake patterns. The single-subject voxel-wise analyses showed that at the group level, the Dice scores improved by around 13% and 5% when using the DL approach for eFBP and eFMM, respectively. The correlation analysis results indicated a relatively strong correlation between eFBP/eFMM and [ 18 F]FDG (eFBP: slope = 0.77, R 2  = 0.61, P-value < 0.0001); eFMM: slope = 0.77, R 2  = 0.61, P-value < 0.0001). This correlation improved for synthetic [ 18 F]FDG (synthetic [ 18 F]FDG generated from eFBP (slope = 1.00, R 2  = 0.68, P-value < 0.0001), eFMM (slope = 0.93, R 2  = 0.72, P-value < 0.0001))., Conclusion: We proposed a DL model for generating the [ 18 F]FDG from eFBP/eFMM PET images. This method may be used as an alternative for multiple radiotracer scanning in research and clinical settings allowing to adopt the currently validated [ 18 F]FDG PET normal reference databases for data analysis., (© 2024. The Author(s).)

Pseudomonas aeruginosa infections are difficult to treat due to rapid development of antibiotic drug resistance. The synergistic combination of already-in-use drugs is an alternative to developing new antibiotics to combat antibiotic-resistant bacteria. Here we demonstrate that bismuth-based drugs (bismuth subsalicylate, colloidal bismuth subcitrate) in combination with different classes of antibiotics (tetracyclines, macrolides, quinolones, rifamycins and so on) can eliminate multidrug-resistant P. aeruginosa and do not induce development of antibiotic resistance. Bismuth disrupts iron homeostasis by binding to P. aeruginosa siderophores. Inside cells, bismuth inhibits the electron transport chain, dissipates the proton motive force and impairs efflux pump activity by disrupting iron-sulfur cluster-containing enzymes, including respiration complexes. As a result, bismuth facilitates antibiotic accumulation inside bacteria, enhancing their efficacy. The combination therapy shows potent antibacterial efficacy and low toxicity in an ex vivo bacteraemia model and increases the survival rate of mice in in vivo mouse lung-infection models. Our findings highlight the potential of bismuth-based drugs to be repurposed to combat P. aeruginosa infections in combination with clinically used antibiotics., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The operative treatment of thoracolumbar fractures is a rapidly evolving improvement in the care of patients with this injury after trauma. This article describes the different techniques and principles. Considerations and methods of treatment are scientifically addressed and illustrated according to the classification and severity of the fracture pattern. The use of computer navigation and optimisation of minimally invasive techniques is inevitable. The timing of surgery as well the removal of the material after fracture healing are also discussed. The operative treatment of spinal fractures is emerging and there is still much more knowledge to gain., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)