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James P Williams,1 Paul Southern,2 Anya Lissina,3 Helen C Christian,4 Andrew K Sewell,3 Rodney Phillips,1,5,6 Quentin Pankhurst,2 John Frater1,5,6 1Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK; 2Davy-Faraday Research Laboratory, Royal Institution of Great Britain, London, UK; 3Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK; 4Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; 5James Martin 21st Century School, John Radcliffe Hospital, Oxford, UK; 6Oxford NIHR Biomedical Research Centre, Oxford, UK Abstract: The latent HIV-1 reservoir remains the major barrier to HIV-1 eradication. Although successful at limiting HIV replication, highly active antiretroviral therapy is unable to cure HIV infection, thus novel therapeutic strategies are needed to eliminate the virus. Magnetic field hyperthermia (MFH) generates thermoablative cytotoxic temperatures in target-cell populations, and has delivered promising outcomes in animal models, as well as in several cancer clinical trials. MFH has been proposed as a strategy to improve the killing of HIV-infected cells and for targeting the HIV latent reservoirs. We wished to determine whether MFH could be used to enhance cytotoxic T-lymphocyte (CTL) targeting of HIV-infected cells in a proof-of-concept study. Here, for the first time, we apply MFH to an infectious disease (HIV-1) using the superparamagnetic iron oxide nanoparticle FeraSpin R. We attempt to improve the cytotoxic potential of T-cell receptor-transfected HIV-specific CTLs using thermotherapy, and assess superparamagnetic iron oxide nanoparticle toxicity, uptake, and effect on cell function using more sensitive methods than previously described. FeraSpin R exhibited only limited toxicity, demonstrated efficient uptake and cell-surface attachment, and only modestly impacted T-cell function. In contrast to the cancer models, insufficient MFH was generated to enhance CTL killing of HIV-infected cells. MFH remains an exciting new technology in the field of cancer therapeutics, which, as technology improves, may have significant potential to enhance CTL function and act as an adjunctive therapy in the eradication of latently infected HIV-positive cells. Keywords: nanoparticles, HIV-1, thermotherapy, cytotoxic T-cell

The aim of our study was to analyze the potential survival benefit associated with HSCT according to clinico-biological scores which incorporate molecular data (MIPSS70 and MIPSS70+V2) to facilitate decision-making in this context. One transplant (n=241) and one non-transplant cohorts (n=239) were used to test the hypothesis that PMF patients with higher risk molecular score benefit from HSCT. A weighted propensity score was applied to balance confounding factors with the transplanted cohort as reference. Weighted Cox proportional hazard models and logistic regression analyses were performed. 105 non-transplanted patients could be matched to the 239 transplanted patients. Mean age in transplanted and non-transplanted matched patients was 55.5 and 57.9 years. Blood cell count and DIPSS score distribution were similar in both groups. HSCT was associated with a higher 6-year OS rate in intermediate-2 (60.1% versus 41.5%) and high-risk DIPSS patients (44.4% versus 6.55%), high-risk MIPSS70 (46.5 versus 23.9%), high-risk (73.2% versus 39.7%) or very high-risk MIPSS70V2 (51.8% versus 24%). Intermediate MIPSS70 patients have an advantage of survival with HSCT only when their MTSS were low or intermediate. Transplanted patients had an increased mortality risk the first year but a significant benefit with HSCT after the one-year landmark was observed in higher risk patients. This study confirms that similar to DIPSS, MIPSS70 and MIPSS70+V2 risk score in addition to MTSS can be used to determine which patients with primary myelofibrosis have survival benefit from HSCT over non-HSCT strategies., (Copyright © 2024 American Society of Hematology.)

Musculoskeletal injuries (MSKI) are one of the biggest challenges for military services globally, contributing to substantial financial burdens and lost training and working days. Effective evidence-based intervention strategies are essential to reduce MSKI incidence, and research has shown the positive effect of both nutritional interventions and physical training (PT) interventions on reducing MSKI incidence. Levels of vitamin D metabolites have been associated with MSKI and bone stress fracture risk, while calcium and vitamin D supplementation has been shown to reduce the incidence of stress fractures during military training. Protein and carbohydrate supplementation during arduous military training (high volume, high intensity) has also been shown to reduce MSKI risk and the number of limited/missed duty days. PT has played a key role in soldier development to meet the occupational demands of serving in the armed forces. Paradoxically, while PT is fundamental to enhancing soldier readiness, PT can also be a major contributor to MSKI; emerging evidence suggests that the nature of the PT being performed is a risk factor for MSKI. However, strategies like reducing training load and implementing PT programmes using evidence-based training principles can reduce MSKI incidence among military service members by 33-62%, and reduce the financial burdens for military services. This review provides a summary of effective MSKI reduction interventions and provides strategies to enhance the success and adoption of such interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Small cell lung cancer (SCLC) has an extremely poor prognosis. Despite high initial response rates to chemotherapy and modest survival improvements with the addition of immune checkpoint inhibitors (ICI), almost all patients experience relapse and fatal outcomes. Recent genomic insights uncovered extensive molecular heterogeneity in addition to the almost uniform loss of RB1 and TRP53. Additionally, defective DNA mismatch repair (MMR) has recently been described in some SCLC cases. Here, we generated a novel SCLC mouse model capturing MMR deficiency and assessed immunotherapy responses., Methods: We developed an MMR-deficient genetically engineered mouse model (GEMM) of SCLC by introducing a conditional Msh2 gene, crucial for maintaining MMR integrity, into the standard Rb1 fl/fl ;Trp53 fl/fl (RP) model. Genomic characteristics and preclinical therapy responses were evaluated by focusing on overall survival and whole exome sequencing (WES) analyses., Results: MMR-defective SCLC tumors (Rb1 fl/fl ;Trp53 fl/fl ;Msh2 fl/fl (RPM)) developed later than tumors in MMR-proficient mice. However, the time from tumor manifestation to death of the affected animals was substantially shortened (median survival 55 days in RP vs. 46.5 days in RPM), indicating increased aggressiveness of MMR-defective tumors. RPM tumors exhibited MMR deficiency, high tumor mutational burden (TMB), and an elevated load of candidate neoantigens, compared to RP lesions (p = 0.0106), suggesting increased immunogenicity. Importantly, the overall survival of RPM animals was significantly improved when exposed to ICI., Conclusion: We propose a novel RPM mouse model as a suitable system to mimic MMR-defective SCLC and tumors with high TMB. We provide in vivo evidence that Msh2 deficiency enhances ICI sensitivity. These findings could contribute to stratifying SCLC patients to immunotherapy, thereby improving treatment outcomes., Competing Interests: Declarations Conflict of interest H.C.R. received consulting and lecture fees from Abbvie, AstraZeneca, Vertex, and Merck. H.C.R. received research funding from AstraZeneca and Gilead Pharmaceuticals. H.C.R. is a co-founder of CDL Therapeutics GmbH. R.K.T. is a founder of Disco Pharmaceuticals GmbH, PearlRiver Bio (now part of Centessa), a shareholder of Centessa, founder and shareholder of Epiphanes Inc. and a consultant to PearlRiver Bio and Epiphanes Inc. R.K.T. has received research support from Roche. The remaining authors declare no competing financial interest. Animal ethics declaration Animal experiments in this study were approved by the local Ethics Committee of Animal Experiments authorities (LANUV, North Rhine-Westphalia, Germany) under license number 81-02.04.2019-A491. All mice were maintained according to FELASA recommendations and in compliance with the European Union and German guidelines., (© 2024. The Author(s).)

Introduction: The prevalence of mental health problems is increasing worldwide, particularly in the vulnerable group of older people. The limited availability of therapists, long wait periods and increasing shortage of healthcare resources limit adequate care. As a result, digital applications are becoming more commonplace as an alternative to human therapists. However, these tend to be used by younger people with higher education, digital health literacy and experience. In Germany, applications that are approved by the health authorities, so-called digital health applications (DiGAs), can be prescribed by physicians and psychotherapists. It remains unclear to the extent older people are experienced with, are willing and can use a DiGA. Therefore, this research aims to identify specific challenges of older people's accessibility, user experience and engagement with DiGA for depressive disorders. The DiGA4Aged project consists of: (1) a pilot study on usability, (2) a screening study on potential participants for a randomised controlled trial (RCT) evaluating the digital experience of the target population and (3) an RCT to test the effectiveness of a digital nurse as individualised user support in the intervention group. This paper focuses on the pilot study and the screening study., Methods and Analysis: The instrumental components in preparing for the RCT are a mixed-method pilot and observational quantitative screening study, which are described in this manuscript. The pilot study includes questionnaires (covering sociodemographic data, user experience, health literacy, electronic health literacy, media affinity, severity of depression and perceived usability of DiGA), a concurrent think aloud method and a semistructured interview to evaluate two applications with regard to their usability for, acceptance by and needs of older people. The observational screening study collects data of older patients consecutively admitted to an acute care geriatric hospital ward using various questionnaires to identify which clinical and medical factors are associated with the access to, experience with and (non-)use of digital media. Data from the comprehensive geriatric assessment is collected as well as data on their digital media experience and digital health literacy., Ethics and Dissemination: The overall project DiGA4Aged received ethical approval on 17 November 2023 from the ethics committee of the Medical Faculty of Ruhr-University Bochum (registration number 23-7901). Results will be disseminated within the scientific community via publication in peer-reviewed journals as well as presentation at national conferences. The findings from the pilot study and the observational screening study will determine the selection of the DiGA and the recruitment strategy for the subsequent RCT., Trial Registration Numbers: The pilot study has been prospectively registered in the German Clinical Trials Register (DRKS00033640, registered on 18 March 2024, available from https://drks.de/search/de/trial/DRKS00033640). Likewise, the observational screening study has been prospectively registered in the German Clinical Trials Register (DRKS00032931, registered on 29 November 2023, available from https://drks.de/search/de/trial/DRKS00032931)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Point-of-care ultrasound (POCUS) has long been a diagnostic tool in family medicine, although most Norwegian general practitioners (GPs) who use POCUS, scans infrequently. The broad scope of family medicine, the relatively low prevalence of illnesses and infrequent use of POCUS imply that GPs may experience diagnostic uncertainty regularly., Aim: To explore how GPs perceived and managed diagnostic uncertainty when using POCUS., Design and Setting: A qualitative focus group study among Norwegian GPs using POCUS., Methods: Four focus group discussions were conducted. Total number of participants were 21. The interview guide was piloted, the focus group discussions were audio-recorded and transcribed, and Systematic Text Condensation, a thematic cross-case analysis, was used to analyse the data., Results: Diagnostic uncertainty using POCUS was considered as aligning to the general clinical uncertainties in family medicine, but there were also POCUS-specific uncertainties in clinical decision-making. We generated six themes: emotional, cognitive, and ethical uncertainty using POCUS, communicating uncertainty to patients, interaction with specialists when using POCUS, and coping strategies of participants. POCUS results were the only results the participants sometimes withheld when communicating with other specialists. POCUS itself stimulated a renewed interest in family medicine. Scanning enough patients was the recommended coping strategy., Conclusion: POCUS-using GPs experienced diagnostic uncertainty when using POCUS that aligned with other diagnostic uncertainties they experienced in everyday practice. However, they did not treat the results like other findings, as the GPs at times withheld their POCUS findings when interacting with secondary care specialists. This requires further investigation.

A variety of daily activities can intentionally or unintentionally cause the Valsalva manoeuvre, which induces a physiological response of elevated peripheral venous pressure. Studies have speculated that it may ultimately affect the choroidal anatomy. This is particularly important from a clinical point-of-view since patients occasionally hold their breath while undergoing macular optical coherence tomography (OCT). In this study, we systematically reviewed the literature to understand the impact of the Valsalva manoeuvre on the choroid and conducted meta-analyses on the changes induced in the subfoveal choroidal thickness (SFCT) and the choroidal vascularity index (CVI). We searched 12 literature databases for studies in healthy participants undergoing Valsalva manoeuvre with choroidal OCT scans before and during the manoeuvre. Seven studies with a total of 444 eyes of 279 individuals were eligible for the review. The Valsalva manoeuvre led to a statistically significant but numerically small increase in the SFCT of 6.5 μm (95% CI: 1.6-11.4 μm; p = 0.01) and a statistically significant increase in the CVI of 1.48 (95% CI: 1.23-1.73; p = 0.0002). Thus, the Valsalva manoeuvre has a measurable impact on the choroid, and we recommend careful observation of how the patient sits and behaves behind the OCT scanner while scanning in order to allow accurate measurements of the choroid for diagnosis and monitoring., (© 2024 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: The present study explores the dynamics of cell death in Hirschsprung's disease (HSCR) and control (CO) groups under inflammatory stress conditions., Methods: Using flow cytometry, we analyzed intestinal colonic organoid cultures derived from the ganglionic segment of the HSCR and CO groups. Our analysis focused on the quantification of RIPK1-independent and RIPK1-dependent apoptosis, as well as necroptosis in both viable and non-viable cells under acute and chronic inflammatory stress., Results: Our findings indicate that HSCR cells are particularly vulnerable to inflammation during acute proinflammatory stress, as evidenced by an increase in dead cells (Zombie +). Under chronic conditions, adaptive changes are observed in both HSCR and CO groups, indicating survival mechanisms. These adaptations are uniquely altered in HSCR, suggesting an impaired response to chronic inflammation. HSCR cells show significantly decreased RIPK1-dependent apoptosis in acute scenarios compared to chronic ones, unlike the CO group, implying varied responses to different inflammatory stresses. In non-viable cells, considerable changes in RIPK1-dependent apoptosis under chronic conditions in HSCR indicate a heightened inflammatory response compared to CO., Conclusion: This research provides insights into cell death regulation in HSCR under inflammatory stress by using patient-derived organoids, underscoring the complexity of its inflammatory response., (© 2024. The Author(s).)

Plant leaves play a pivotal role in automated species identification using deep learning (DL). However, achieving reproducible capture of leaf variation remains challenging due to the inherent "black box" problem of DL models. To evaluate the effectiveness of DL in capturing leaf shape, we used geometric morphometrics (GM), an emerging component of eXplainable Artificial Intelligence (XAI) toolkits. We photographed Ranunculus auricomus leaves directly in situ and after herbarization. From these corresponding leaf images, we automatically extracted DL features using a neural network and digitized leaf shapes using GM. The association between the extracted DL features and GM shapes was then evaluated using dimension reduction and covariation models. DL features facilitated the clustering of leaf images by source populations in both in situ and herbarized leaf image datasets, and certain DL features were significantly associated with biological leaf shape variation as inferred by GM. DL features also enabled leaf classification into morpho-phylogenomic groups within the intricate R. auricomus species complex. We demonstrated that simple in situ leaf imaging and DL reproducibly captured leaf shape variation at the population level, while combining this approach with GM provided key insights into the shape information extracted from images by computer vision, a necessary prerequisite for reliable automated plant phenotyping., (© 2024 The Author(s). The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Introduction: While ample data demonstrate the effectiveness of inpatient psychosomatic treatment, clinical observation and empirical evidence demonstrate that not all patients benefit equally from established therapeutic methods. Especially patients with a comorbid personality disorder often show reduced therapeutic success compared to other patient groups. Due to the heterogeneous and categorical personality assessment, previous studies indicated no uniform direction of this influence. This complicates the derivation of therapeutic recommendations for mental disorders with comorbid personality pathology., Methods: Analyzing n = 2094 patients from German university hospitals enrolled in the prospective "MEPP" study, we tested the dynamic interaction between dimensionally assessed personality functioning and psychopathology of anxiety and depression., Results: Longitudinal structural equation modelling replicated the finding that the severity of symptoms at admission predicts symptom improvement within the same symptom domain. In addition, we here report a significant coupling parameter between the baseline level of personality function and the change in general psychopathology - and vice versa., Discussion and Conclusion: These results imply that personality pathology at admission hinders the therapeutic improvement in anxiety and depression, and that improvement of personality pathology is hindered by general psychopathology. Furthermore, the covariance between both domains supports the assumption that personality functioning and general psychopathology cannot be clearly distinguished and adversely influence each other. A dimensional assessment of the personality pathology is therefore recommendable for psychotherapy research and targeted therapeutic treatment., Competing Interests: Declaration of competing interest Christoph Herrmann-Lingen reports financial support was provided by Hogrefe Publishing. Christoph Herrmann-Lingen reports financial support was provided by Novartis AG. All authors, except for Stephan Doering, are working at one of the German university departments of psychosomatic medicine and psychotherapy. 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 Inc. All rights reserved.)

Identifying macular neovascularization (MNV) in eyes with central serous chorioretinopathy (CSC) has important implications for its management. Optical coherence tomography angiography (OCTA) is increasingly used for this purpose. Here, we systematically reviewed the literature and conducted meta-analysis to determine the diagnostic accuracy of OCTA for detecting MNV in eyes with CSC. We systematically searched the literature in 12 databases for relevant studies from database inception until 18 November 2023. Eligible studies had eyes with CSC with MNV and CSC without MNV. Index test was OCTA. Reference test was retinal dye angiography. Study selection and data extraction were performed in duplicate, and study was evaluated using the Quality Assessment of Diagnostic Accuracy Studies 2. Our main outcome of interest was the sensitivity and specificity of OCTA for detecting MNV in CSC. Pooled diagnostic test accuracy estimates were computed using MetaDTA. Of 177 records screened, seven fulfilled the eligibility criteria for our study. These studies summarized data from a total of 1061 eyes. Summary estimate sensitivity and specificity to diagnose MNV in eyes with CSC using OCTA was 92.9% (95% CI: 81.7%-97.5%) and 99.4% (95% CI: 84.1%-100.0%), respectively. The main source of bias across studies was the reference standard, as four studies used multimodal imaging including OCTA for the reference standard. OCTA alone is excellent for detecting MNV in CSC compared to retinal dye angiography or multimodal imaging. Using OCTA first before considering retinal dye angiography could potentially save an important number of retinal dye angiographies., (© 2024 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The structural dynamics of the interactions between defensins or lysozymes and various saccharide chains that are covalently linked to lipids or proteins were analyzed in relation to the sub-molecular architecture of the carbohydrate binding sites of lectins. Using tissue materials from rare and endangered domestic animals as well as from dogs it was possible to compare these results with data obtained from a human glioblastoma tissue. The binding mechanisms were analyzed on a cellular and a sub-molecular size level using biophysical techniques (e.g. NMR, AFM, MS) which are supported by molecular modeling tools. This leads to characteristic structural patterns being helpful to understand glyco-biochemical pathways in which galectins, defensins or lysozymes are involved. Carbohydrate chains have a distinct impact on cell differentiation, cell migration and immunological processes. The absence or the presence of sialic acids and the conformational dynamics in glycans are often correlated with zoonoses such as influenza- and coronavirus-infections. Receptor-sensitive glycomimetics could be a solution. The new findings concerning the function of galectin-3 in the nucleus in relation to differentiation processes can be understood when the binding specificity of neuroleptic molecules as well as the interactions between proteins and nucleic acids are describable on a sub-molecular size level., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: FHIR (Fast Healthcare Interoperability Resources) has been proposed to enable health data interoperability. So far, its applicability has been demonstrated for selected research projects with limited data., Objective: This study aimed to design and implement a conceptual medical intelligence framework to leverage real-world care data for clinical decision-making., Methods: A Python package for the use of multimodal FHIR data (FHIRPACK [FHIR Python Analysis Conversion Kit]) was developed and pioneered in 5 real-world clinical use cases, that is, myocardial infarction, stroke, diabetes, sepsis, and prostate cancer. Patients were identified based on the ICD-10 (International Classification of Diseases, Tenth Revision) codes, and outcomes were derived from laboratory tests, prescriptions, procedures, and diagnostic reports. Results were provided as browser-based dashboards., Results: For 2022, a total of 1,302,988 patient encounters were analyzed. (1) Myocardial infarction: in 72.7% (261/359) of cases, medication regimens fulfilled guideline recommendations. (2) Stroke: out of 1277 patients, 165 received thrombolysis and 108 thrombectomy. (3) Diabetes: in 443,866 serum glucose and 16,180 glycated hemoglobin A 1c measurements from 35,494 unique patients, the prevalence of dysglycemic findings was 39% (13,887/35,494). Among those with dysglycemia, diagnosis was coded in 44.2% (6138/13,887) of the patients. (4) Sepsis: In 1803 patients, Staphylococcus epidermidis was the primarily isolated pathogen (773/2672, 28.9%) and piperacillin and tazobactam was the primarily prescribed antibiotic (593/1593, 37.2%). (5) PC: out of 54, three patients who received radical prostatectomy were identified as cases with prostate-specific antigen persistence or biochemical recurrence., Conclusions: Leveraging FHIR data through large-scale analytics can enhance health care quality and improve patient outcomes across 5 clinical specialties. We identified (1) patients with sepsis requiring less broad antibiotic therapy, (2) patients with myocardial infarction who could benefit from statin and antiplatelet therapy, (3) patients who had a stroke with longer than recommended times to intervention, (4) patients with hyperglycemia who could benefit from specialist referral, and (5) patients with PC with early increases in cancer markers., (©Alexander Brehmer, Christopher Martin Sauer, Jayson Salazar Rodríguez, Kelsey Herrmann, Moon Kim, Julius Keyl, Fin Hendrik Bahnsen, Benedikt Frank, Martin Köhrmann, Tienush Rassaf, Amir-Abbas Mahabadi, Boris Hadaschik, Christopher Darr, Ken Herrmann, Susanne Tan, Jan Buer, Thorsten Brenner, Hans Christian Reinhardt, Felix Nensa, Michael Gertz, Jan Egger, Jens Kleesiek. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 31.10.2024.)

Introduction: Familial adenomatous polyposis (FAP) is caused by pathogenic variants in the APC gene. FAP is usually categorized according to phenotype: classical FAP (CFAP) and attenuated FAP (AFAP); the latter is considered to have a milder disease course. We aimed to assess the risk of overall and specific cancers in CFAP and AFAP patients compared to matched, non-exposed individuals., Methods: All known Danish FAP patients were classified as either CFAP or AFAP and assigned four matched, non-exposed individuals. The risk of overall and specific cancers, and mortality were analyzed., Results: The analysis included 311 CFAP patients, 134 AFAP patients, and 1,600 non-exposed individuals. The overall cancer risk was significantly higher for both CFAP and AFAP patients than for non-exposed individuals, with hazard ratios (HR) of 4.77 (95% confidence interval (CI), 3.61-6.32; P<0.001) for CFAP and 3.22 (95% CI, 2.16-4.80; P<0.001) for AFAP. No significant difference was observed when comparing CFAP and AFAP (HR=1.48; 95% CI, 0.98-2.25; P=0.0646). The HR of colonic cancer was 2.16 (95% CI, 0.99-7.72; P=0.0522) and 2.72 (95% CI, 1.19-6.22; P=0.0177 for CFAP and AFAP), respectively compared to non-exposed and did not differ between CFAP and AFAP patients (HR=0.80; 95% CI, 0.32-2.00; P=0.6278). Mortality was significantly higher in CFAP (HR=2.96; 95% CI, 2.04-4.28; P<0.001), but not in AFAP (HR=1.40; 95% CI, 0.73-2.69; P=0.311)., Conclusion: Nationwide data reveal differing risk profiles for specific cancers and mortality in AFAP and CFAP compared to non-exposed individuals. The cancer burden of AFAP necessitates consistent monitoring of these patients., (Copyright © 2024 by The American College of Gastroenterology.)

Purpose: Documentation of the wrist stabilizing effect and mechanical properties of common splinting materials is warranted to support evidence-based condition-specific recommendations for wrist immobilization. The objectives of this study were to assess the wrist stabilizing properties of volar and dorsal short-arm splints made of four different materials and evaluate the mechanical properties of the splinting materials., Methods: Dorsal and volar short arm splints made of plaster of Paris (PoP) (eight layers), Woodcast (2 mm, rigid vented), X-lite (classic, two layers) or a 3D-printed material (polypropylene) were sequentially mounted on 10 cadaveric arm specimens and fixed in a radiolucent fixture. This enabled the evaluation of maximum wrist flexion and extension relative under an orthogonal load of 42 N via radiographic images. In addition, a three-point bending test was performed on ten sheet duplicates of each of the four splinting materials., Results: When applied as a volar splint, PoP had the highest capability to resist wrist flexion and extension. However, when applied as a dorsal splint, Woodcast exhibited a lower wrist flexion and a similar wrist extension. The 3D-printed splints-both volar and dorsal-showed the highest mean wrist flexion and extension. The mechanical properties of the Woodcast, X-lite and 3D-printed splinting materials were very similar. PoP exhibited distinct properties with a stiffness of 146 (95% confidence interval [CI]: 120-173) N/mm and a deflection at F max of 0.6 (95% CI: 0.5-0.7) mm compared to ≤7.7 (95% CI: 7.4-7.9) N/mm and ≥20 (95% CI: 18-22) mm for the other materials., Conclusion: PoP displayed better wrist stabilizing properties and material stiffness than Woodcast, X-lite and 3D-printed polypropylene. When considering wrist stabilizing properties, PoP may still prove to be the preferred choice for wrist immobilization., Level of Evidence: Not applicable., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Cell death is a critical biological process necessary for development, tissue maintenance, and defense against diseases. To date, more than 20 forms of cell death have been identified, each defined by unique molecular pathways. Understanding these different forms of cell death is essential for investigating the pathogenesis of diseases such as cancer, neurodegenerative disorders, and autoimmune conditions and developing appropriate therapies. Paraptosis is a distinct form of regulated cell death characterized by cytoplasmic vacuolation and dilatation of cellular organelles like the mitochondria and endoplasmic reticulum (ER). It is regulated by several signaling pathways, for instance, those associated with ER stress, calcium overload, oxidative stress, and specific cascades such as insulin-like growth factor I receptor (IGF-IR) and its downstream signaling pathways comprising mitogen-activated protein kinases (MAPKs) and Jun N-terminal kinase (JNK). Paraptosis has been observed in diverse biological contexts, including development and cellular stress responses in neuronal, retinal, endothelial, and muscle cells. The induction of paraptosis is increasingly important in anticancer therapy, as it targets non-apoptotic stress responses in tumor cells, which can be utilized to induce cell death. This approach enhances treatment efficacy and addresses drug resistance, particularly in cases where cancer cells are resistant to apoptosis. Combining paraptosis-inducing agents with traditional therapies holds promise for enhancing treatment efficacy and overcoming drug resistance, suggesting a valuable strategy in anticancer therapy., Competing Interests: The authors declare no conflicts of interest.

The localized surface-plasmon resonances of coinage-metal clusters and nanoparticles enable many applications, the conception and necessary optimization of which require precise theoretical description and understanding. However, for the size range from few-atom clusters through nanoparticles of a few nanometers, where quantum effects and atomistic structure play a significant role, none of the methods employed previously has been able to provide high-quality spectra for all sizes. The main problem is the description of the filled shells of d electrons which influence the optical response decisively. We show that the DFT+U method, employed with real-time time-dependent density-functional theory calculations (RT-TDDFT), provides spectra in good agreement with experiment for silver clusters ranging from 4 to 923 atoms, the latter representing a nanoparticle of 3 nm. Both the electron-hole-type discrete spectra of the smallest clusters and the broad plasmon resonances of the larger sizes are obtained. All calculations use the value of the effective U parameter that provides good results in bulk silver. The agreement with experiment for all sizes shows that the U parameter is surprisingly transferable. Our results open the pathway for calculations of many practically relevant systems including clusters coupled to bio-molecules or to other nano-objects., (© 2024. The Author(s).)

Prognostic tests and treatment approaches for optimized clinical care of prostatic neoplasms are an unmet need. Prostate cancer (PCa) and derived extracellular vesicles (EVs) proteome changes occur during initiation and progression of the disease. PCa tissue proteome has been previously characterized, but screening of tissue samples constitutes an invasive procedure. Consequently, we focused this study on liquid biopsies, such as urine samples. More specifically, urinary small extracellular vesicle and particles proteome profiles of 100 subjects were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC-MS/MS). We identified 171 proteins that were differentially expressed between intraductal prostate cancer/cribriform (IDC/Crib) and non-IDC/non-Crib after correction for multiple testing. However, the strong correlation between IDC/Crib and Gleason Grade complicates the disentanglement of the underlying factors driving this association. Nevertheless, even after accounting for multiple testing and adjusting for ISUP (International Society of Urological Pathology) grading, two proteins continued to exhibit significant differential expression between IDC/Crib and non-IDC/non-Crib. Functional enrichment analysis based on cancer hallmark proteins disclosed a clear pattern of androgen response down-regulation in urinary EVs from IDC/Crib compared to non-IDC/non-Crib. Interestingly, proteome differences between IDC and cribriform were more subtle, suggesting high proteome heterogeneity. Overall, the urinary EV proteome reflected partly the prostate pathology., (© 2024. The Author(s).)

Liver diseases represent a worldwide health problem accountable for two million deaths per year. Oxidative stress is critical for the development of these diseases. N-acetyl cysteine (NAC) is effective in preventing liver damage, both in experimental and clinical studies, and evidence has shown that the pharmacodynamic mechanisms of NAC are related to its antioxidant nature and ability to modulate key signaling pathways. Here, we provide a comprehensive description of the beneficial effects of NAC in the treatment of liver diseases, addressing the first evidence of its role as a scavenger and precursor of reduced glutathione, along with studies showing its immunomodulatory action, as well as the ability of NAC to modulate epigenetic hallmarks. We searched the PubMed database using the following keywords: oxidative stress, liver disease, epigenetics, antioxidants, NAC, and antioxidant therapies. There was no time limit to gather all available information on the subject. NAC has shown efficacy in treating liver damage, exerting mechanisms of action different from those of free radical scavengers. Like different antioxidant therapies, its effectiveness and safety are related to the administered dose; therefore, designing new pharmacological formulations for this drug is imperative to achieve an adequate response. Finally, there is still much to explore regarding its effect on epigenetic marker characteristics of liver damage, turning it into a drug with broad therapeutic potential. According to the literature reviewed, NAC could be an appropriate option in clinical studies related to hepatic injury and, in the future, a repurposing alternative for treating liver diseases., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

NASH is characterized by hepatic lipid accumulation and inflammation; and JMJD2B-a histone demethylase-upregulation has been linked to its progression. Pirfenidone (PFD) is an antifibrotic agent with anti-inflammatory and antioxidant effects recognized to decrease NASH symptoms. Herein, our aim was to investigate PFD-induced epigenetics mechanisms involving JMJD2B and histone modifications in experimental NASH. Male C57BL/6J mice were fed with normo-diet, or high fat/carbohydrate diet (HF) for 16 weeks. A HF-subgroup was treated with PFD 300 mg/kg/d from week 8th to the end of protocol. Insulin tolerance test and liver and fat histological and biochemical analyses were carried out. Hepatic transcriptome was examined. Liver proteins were studied by western blot (WB) and Chromatin immunoprecipitation. In vitro, lipotoxicity was induced in HepG2 cells and proteins were evaluated using WB. Molecular docking was used to explore binding of PFD to JMJD2B. Mice treated with PFD reduced weight gain, epididymal fat and inflammatory nodules, and steatosis in liver tissue, as well as, improved biochemical test. PFD modified the expression of Jmjd2b, Pparg, Fasn and Srebp1, and restored JMJD2B protein and H3K9me3 repressive mark, both in animal and cell models. PFD increased hepatic enrichment of H3K9me2 and H3K9me3 at the promoter region of Fasn and Srebp1, and Pparg. In HepG2 cells, PFD reduced lipid vacuole accumulation. In silico, PFD interacted with JMJD2B catalytic site. PFD is an epigenetic regulator modifying JMJD2B activity, resulting in reduced NASH traits., (© 2024. The Author(s).)

Background: Inappropriate prescribing may have detrimental consequences for the patient and increase healthcare utilisation and costs. Academic detailing (AD) is an interactive outreach method to deliver non-commercial evidence-based medical information to healthcare professionals, aiming to improve patient care. Performing AD virtually has recently become more relevant, especially with the COVID-19 pandemic., Objectives: The aim of this study was to explore general practitioners' (GP's) experiences and perceptions of virtually delivered AD., Methods: We invited practicing GPs that had received virtual AD in Norway during autumn 2020. Semistructured individual interviews were audio and video recorded during February-May 2021. Interviews were transcribed and analysed applying thematic analysis according to Braun and Clarke., Results: From interviews with nine GPs, we identified five themes concerning (1) informants' satisfaction with virtual AD and their opinions about the detailers and their characteristics, (2) factors that are important for participation in AD, with the campaign topic being the most important, (3) a paradox between the informants' desire for more time for discussion and the time constraint they are facing, (4) the many benefits of virtual AD compared with in-person AD and (5) the informants' perceived learning outcomes are unaffected by mode of AD delivery., Conclusion: Virtual AD worked very well in terms of scheduling the visit, using technology to facilitate the visit and achieving the same learning outcomes. Virtual AD should be offered to GPs as an alternative to the traditional in-person AD, especially in remote geographical areas or in circumstances when physical outreach is challenging., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although adequate physical activity has been shown to be beneficial in early breast cancer, evidence in metastatic breast cancer is sparse and contradictory, which could be related to distinct effects of physical activity on the different molecular cancer subtypes. Therefore, we here evaluated the effect of physical activity on progression-free and overall survival (PFS, OS) in metastatic breast cancer, specifically looking at molecular subtypes., Methods: International Physical Activity Questionnaire (IPAQ) questionnaires, filled out by patients enrolled in the prospective PRAEGNANT registry (NCT02338167; n = 1,270) were used to calculate metabolic equivalent task (MET) minutes, which were subsequently categorized into low (n = 138), moderate (n = 995) or high IPAQ categories (n = 137). Cox regression analyses were used to evaluate the impact of IPAQ categories and its interaction with molecular subtypes on PFS and OS., Results: Patient and tumor characteristics were equally distributed across IPAQ categories. HER2pos, HRpos and TNBC were present in 23.1%, 65.7% and 11.2% of patients, respectively. IPAQ scores did not have an impact on PFS and OS in addition to established prognostic factors, either overall or in particular molecular subtypes (PFS: p = 0.33 and OS: p = 0.08, likelihood ratio test). Exploratory analyses showed higher overall survival rates for high IPAQ categories compared to low/moderate IPAQ categories in luminal B-like breast cancer., Conclusions: Self-reported physical activity using the IPAQ questionnaire did not significantly affect PFS or OS in patients suffering from metastatic breast cancer. Nevertheless, some hypothesis-generating differences between molecular subtypes could be observed, which may be interesting to evaluate further., (© 2024. The Author(s).)

Background: Poor adherence to photoprotection in Xeroderma Pigmentosum (XP) increases morbidity and shortens lifespan due to skin cancers., Objective: To test a highly personalised intervention (XPAND) to reduce the dose of ultraviolet radiation (UVR) reaching the face in adults with XP, designed using known psychosocial determinants of poor photoprotection., Methods: A two-arm parallel group randomised controlled trial, including patients with sub-optimal photoprotection to receive XPAND or a delayed intervention control arm that received XPAND the following year. XPAND comprises seven one-to-one sessions targeting photoprotection barriers (e.g., misconceptions about UVR) supported by personalised text messages, activity sheets, and educational materials incorporating behaviour change techniques. The primary outcome, mean daily UVR dose-to-face across 21 days in June-July 2018, was calculated by combining UVR exposure at the wrist with a face photoprotection activity diary. Secondary outcomes were UVR dose-to-face across 21 days in August 2018, time spent outside, photoprotective measures used outside, mood, automaticity, confidence-to-photoprotect. Financial costs and quality-adjusted life years (QALYs) were calculated., Results: 16 patients were randomised, 13 provided sufficient data for primary outcome analysis. The XPAND group (n=8) had lower mean daily UVR dose-to-face [0.03 SED (SD 0.02] compared to control (n=7) [0.36 SED (SD 0.16)] (adjusted difference=-0.25, p<0.001, Hedge's g=2.2). No significant between-group differences were observed in time spent outside, photoprotection outside, mood, or confidence. The delayed intervention control showed improvements in UVR dose-to-face (adjusted difference=-0.05, Hedge's g=-0.1) , time outside (adjusted difference=-69.9, Hedge's g=-0.28), and photoprotection (adjusted difference=-0.23, Hedge's g=0.45), after receiving XPAND. XPAND was associated with lower treatment costs (£-2642; 95% CI: -£8715 to £3873) and fewer QALYs (-0.0141; 95% CI: -0.0369 to 0.0028)., Conclusions: XPAND was associated with a lower UVR dose-to-face in XP patients and was cost-effective., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Peptidoglycan recognition proteins (PGRPs or PGLYRPs) are implicated in the control of the intestinal microbiota; however, molecular requirements for peptidoglycan (PGN) binding and receptor signaling mechanisms remain poorly understood. We identified PGLYRP-1 as a receptor for the disaccharide motif of lysine N-acetylglucosamine N-acetylmuramic tripeptide (GMTriP-K) with a newly constructed PGN microarray. Surprisingly, PGLYRP-1 was required for innate immune activation of macrophages by GMTriP-K but not N-acetylglucosamine N-acetylmuramic dipeptide (GMDiP) or muramyl dipeptide (MDP). In macrophages, intracellular PGLYRP-1 complexed with NOD2 and GEF-H1, both of which were required for GMTriP-K-regulated gene expression. PGLYRP-1 localized to the endoplasmic reticulum and interacted at the Golgi with NOD2 upon GMTriP-K stimulation. PGLYRP-1 upregulation and its dependent gene expression signatures were induced in both mouse intestinal inflammation and human ulcerative colitis. Importantly, PGLYRP-1 activation by GMTriP-K resulted in innate immune activation and protection of mice from colitis. Our results show that PGLYRPs can function as intracellular PGN pattern recognition receptors for the control of host defense responses in the intestine.

Male germ cells share a common origin across animal species, therefore they likely retain a conserved genetic program that defines their cellular identity. However, the unique evolutionary dynamics of male germ cells coupled with their widespread leaky transcription pose significant obstacles to the identification of the core spermatogenic program. Through network analysis of the spermatocyte transcriptome of vertebrate and invertebrate species, we describe the conserved evolutionary origin of metazoan male germ cells at the molecular level. We estimate the average functional requirement of a metazoan male germ cell to correspond to the expression of approximately 10,000 protein-coding genes, a third of which defines a genetic scaffold of deeply conserved genes that has been retained throughout evolution. Such scaffold contains a set of 79 functional associations between 104 gene expression regulators that represent a core component of the conserved genetic program of metazoan spermatogenesis. By genetically interfering with the acquisition and maintenance of male germ cell identity, we uncover 161 previously unknown spermatogenesis genes and three new potential genetic causes of human infertility. These findings emphasize the importance of evolutionary history on human reproductive disease and establish a cross-species analytical pipeline that can be repurposed to other cell types and pathologies., Competing Interests: RB, JA, MW, IJ, DS, CM, SD, LG, HS, NS, PP, AN, AL, JB, SL, MM, SK, MM, LR, FT, JB, PN No competing interests declared, (© 2024, Brattig-Correia, Almeida, Wyrwoll et al.)

Background: Idiopathic granulomatous mastitis (IGM) is a rare, benign inflammatory breast condition often mistaken for inflammatory breast cancer and, therefore, requires a biopsy for accurate diagnosis. Although not cancerous, IGM can cause emotional distress because of severe pain and ensuing breast deformity. Differentiating IGM from other breast inflammations caused by infections is essential. IGM mostly affects premenopausal women and is potentially associated with recent pregnancies and breastfeeding. The risk factors, including smoking and contraceptive use, have inconsistent associations. Steroid responses suggest an autoimmune component, though specific markers are lacking., Methods: We performed a narrative review on potential risk factors, diagnostics, and therapy of IGM., Results: Diagnostics and clinical management of IGM are challenging. The treatment options include NSAIDs, steroids, surgery, antibiotics, immunosuppressants, prolactin suppressants, and observation, each with varying effectiveness and side effects., Conclusions: Current IGM treatment evidence is limited, based on case reports and small series. There is no consensus on the optimal management strategy for this disease. The GRAMAREG study by the EUBREAST Study Group aims to collect comprehensive data on IGM to improve diagnostic and treatment guidelines. By enrolling patients with confirmed IGM, the study seeks to develop evidence-based recommendations, enhancing patient care and understanding of this condition.

Real-world data on anatomically localized psoriasis and its response to systemic therapy across different age-groups and sexes is limited. This study aimed to evaluate the severity and distribution of psoriasis over time in female and male patients receiving systemic therapies, categorized by age within the Swiss psoriasis registry (SDNTT). Patient-data was obtained over 11 years through the SDNTT. The localized Psoriasis Area and Severity Index (locPASI) of the head, trunk, upper and lower extremities was analyzed over two years following the start of systemic non-/biologic treatment. A total of 316 female and 517 male patients were analyzed. Male patients had a higher baseline locPASI for legs, trunk and arms (p < 0.001), but not for the head (p = 0.961). The locPASI for the head in younger female patients (18-40 years) had a higher score than those aged 55 + (p = 0.022) and after two years, middle aged (41-54) showed a lower score compared to younger patients (p = 0.045). Younger male patients revealed a lower score after two years of therapy in the leg- and arm-area compared to older (p = 0.018 and p = 0.048, respectively). Female patients on non-biologics had a fast initial response, converging with male patients' scores over 24 months. Over 75% locPASI reduction was observed for female head-area (81.4%), male trunk (82.7%) and legs (76.1%). Absolute locPASI ≤ 2 was achieved 3-6 months for all locations with interleukin (IL)-17, IL-12/23 and IL-23-inhibitors, except for the legs of male patients on anti-IL-17 and female patients on anti-IL-12/23 and -IL-23. After two years, male patients did not achieve a locPASI ≤ 2 for any biologic-treatment in the legs, nor for the arms on anti-TNF-α. Significant disparities in localized PASI were observed between female and male patients. The age, sex and severity of distinct localizations should be considered to optimize treatment goals., (© 2024. The Author(s).)

Background: Penicillin may be administered enterally or intravenously for the treatment of bacterial infections within the oropharynx and the frontal sinuses. We aimed to assess and compare penicillin concentrations in oropharyngeal and frontal sinus tissues following enteral and intravenous administration in a porcine model., Method: Twelve pigs were randomized to receive either enteral (0.8 g Penicillin V) or intravenous (1.2 g Penicillin G) penicillin. Microdialysis was used for sampling in oropharyngeal and frontal sinus tissues during a six-hour dosing interval. In addition, plasma samples were collected. The primary endpoints were time with drug concentration above the minimal inhibitory concentration (T>MIC) for two MIC targets: 0.125 (low target) and 0.5 (high target) μg/mL (covering Group A Streptococci, Fusobactarium necrophorum, Streptococcus pneumoniae and Hemophilus influenza) and attainment of these treatment targets for ≥50 % T>MIC., Results: For both the low and high MIC targets, intravenous administration resulted in higher T>MIC in oropharyngeal and frontal sinus tissues compared to enteral administration. In oropharyngeal tissue, the treatment target (≥50 % T>MIC) was achieved for both the low target (96 %) and high target (68 %) when penicillin was administrated intravenously. In frontal sinus tissue, the treatment target was reached for the low target (70 %), but not the high target (35 %) when administered intravenously. None of the two tissues reached the treatment targets when penicillin was administered enterally., Conclusion: Intravenous administrated penicillin in standard dosage is superior to enteral administration of penicillin in standard dosage in achieving clinically important T>MIC as the majority of targets were achieved following intravenously administration, while none of the targets were achieved following enteral administration. These results support the general notion of higher tissue concentrations following intravenous compared to enteral administration., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier B.V.)

Bombesin receptor-activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin-induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004 -/- ). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high-fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004 +/+ mice. Compared to control mice, BC004004 -/- mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004 +/+ mice after UUO surgery showed a more significant decrease in E-cadherin expression and a more significant increase in both α smooth muscle actin (α-SMA) and vimentin expression compared to BC004004 -/- mice. Additionally, stimulation with transforming growth factor-β1 (TGF-β1) led to a more significant decrease in E-cadherin expression and a more significant increase in α-SMA and vimentin expression in isolated TECs from BC004004 +/+ than in those from BC004004 -/- mice. These results suggest that an enhanced epithelial-mesenchymal transition (EMT) process occurred in TECs in BC004004 +/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004 -/- mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury., (© 2024 John Wiley & Sons Australia, Ltd.)

Biological drug substance (DS) is typically stored frozen to increase stability. However, freezing and thawing (F/T) of DS can impact product quality and therefore F/T processes need to be controlled. Because active F/T systems for DS bottles are lacking, freezing is often performed uncontrolled in conventional freezers, and thawing at ambient temperature or using water baths. In this study, we evaluated a novel device for F/T of DS in bottles, which can be operated in conventional freezers, generating a directed air stream around bottles. We characterized the F/T geometry and process performance in comparison to passive F/T using temperature mapping and analysis of concentration gradients. The device was able to better control the F/T process by inducing directional bottom-up F/T. As a result, it reduced cryo-concentration during freezing as well as ice mound formation. However, freezing with the device was dependent on freezer performance, i.e. prolonged process times in a highly loaded freezer were accompanied by increased cryo-concentrations. Thawing was faster compared to without the device, but had no impact on concentration gradients and was slower compared to thawing in a water bath. High-performance freezers might be required to fully exploit the potential of directional freezing with this device and allow F/T process harmonization and scaling across sites., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

The ecosystem of brain tumors is considered immunosuppressed, but our current knowledge may be incomplete. Here we analyzed clinical cell and tissue specimens derived from patients presenting with glioblastoma or nonmalignant intracranial disease to report that the cranial bone (CB) marrow, in juxtaposition to treatment-naive glioblastoma tumors, harbors active lymphoid populations at the time of initial diagnosis. Clinical and anatomical imaging, single-cell molecular and immune cell profiling and quantification of tumor reactivity identified CD8 + T cell clonotypes in the CB that were also found in the tumor. These were characterized by acute and durable antitumor response rooted in the entire T cell developmental spectrum. In contrast to distal bone marrow, the CB niche proximal to the tumor showed increased frequencies of tumor-reactive CD8 + effector types expressing the lymphoid egress marker S1PR1. In line with this, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker indicating focal association with improved progression-free survival. The data of this study advocate preservation and further exploitation of these cranioencephalic units for the clinical care of glioblastoma., (© 2024. The Author(s).)

Background: The SYNCHRONOUS-study investigates simultaneous ASV-ablation with great saphenous vein (GSV) treatment in endovenous laser ablation (EVLA) for preventing varicose vein recurrence. This sub-study examines complication rates associated with prophylactic ASV-ablation., Methods: Among 1173 patients with refluxing GSV, 604 underwent GSV-ablation only, and 569 received additional ASV-ablation. Complication rates were compared over 6 months., Results: Approximately 80% of patients were complication-free with minor bruising and dysesthesia being most common complications. After 6 months, additional prophylactic ASV-ablation did not increase the rate of complications compared to GSV-only treatment., Conclusion: The 6-months follow-up data suggests that prophylactic ASV-closure, alongside GSV-treatment, is safe, with similar complication rates to GSV-only EVLA., 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.

Background: Local infiltration analgesia is commonly used for postoperative pain control after several surgical procedures including intra- and peri-articular as well as wound infiltration. Even though, various adjuvants injected with the local anesthetic have been studied in pairwise comparison or compared to peripheral nerve blocks, the question which adjuvant or combination of adjuvants is the most effective in prolonging the duration of different types of local infiltration analgesia (LIA) has not been answered conclusively., Objective: The objective of this network meta-analysis was to determine the analgesic effectiveness and safety of adjuvants in local infiltration analgesia., Design: Systematic review of randomized controlled trials with network meta-analyses., Data Sources: A comprehensive literature search in Embase, CENTRAL, MEDLINE and Web of Science was performed up to March 2023., Results: The best interventions to prolong the duration of analgesia were dexamethasone (Ratio of Means (ROM) 3.33) followed by the combinations of clonidine + morphine (ROM 3.35) and morphine + magnesium sulfate (ROM 2.92), fentanyl (ROM 2.27), ketorolac (ROM 2.26), buprenorphine (ROM 2.04), morphine (ROM 1.93), magnesium sulfate (ROM 1.91), clonidine (ROM 1.89), dexmedetomidine (ROM 1.74) and tramadol (ROM 1.58). Serious adverse events were not reported with either investigated adjuvant., Conclusion: There is moderate evidence that dexamethasone is the most effective adjuvant to prolong the duration of analgesia in LIA. The evidence for the alpha-2 agonists dexmedetomidine and clonidine is also moderate, but their effectivity to prolong analgesia stays behind dexamethasone. Clonidine and dexmedetomidine had a small detectable effect on pain scores, yet below clinical relevance, but the largest effect on MEQ consumption. The effects of different opioids were homogenous for all endpoints. The prespecified subgroup analysis of LIA of the knee did not show significantly different results than the pooled analysis., Study Registration: PROSPERO 2020 CRD42020176154 (28.04.2020)., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

To evaluate tumour necrosis factor inhibitor (TNFi) drug-levels and presence of anti-drug antibodies (ADAb) in patients with inflammatory arthritis who taper TNFi compared to TNFi continuation. Patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis on stable TNFi dose and in low disease activity ≥ 12 months were randomised (2:1) to disease activity-guided tapering or control. Blood samples at baseline, 12- and 18-months were evaluated for TNFi drug-levels and ADAb. In total, 129 patients were randomised to tapering (n = 88) or control (n = 41). Between baseline and month 18, a significant shift in TNFi drug-levels were observed in the tapering group resulting in fewer patients with high drug-levels (change: - 14% [95% CI - 27 to - 1%]) and more with low drug-levels (change: 18% [95% CI 5-31%]). Disease activity was equivalent between groups at 18 months, mean difference: RA - 0.06 (95% CI - 0.44 to 0.33), PsA 0.03 (95% CI - 0.36 to 0.42), and axSpA 0.16 (- 0.17 to 0.49), equivalence margins ± 0.5 disease activity points. ADAb were detected in eight patients, all from the tapering group. TNFi drug-level category or ADAb were not predictive for achieving successful tapering at 18 months. TNFi drug-levels decreased during tapering which indicate adherence to the tapering algorithm. Despite the difference in TNFi drug-levels at 18 months, disease activity remained equivalent, and only few tapering patients had detectable ADAb. These data do not support using TNFi drug-level and/or ADAb to guide the tapering decision but future research with larger trials is needed.Trial registration: EudraCT: 2017-001970-41, December 21, 2017., (© 2024. The Author(s).)

Background: Ablation is an effective, parenchymal-sparing treatment for primary liver cancer and liver metastases. The purpose of this study was to report our initial experience with laparoscopic microwave ablation regarding postoperative complications, rate of conversions to open procedure, and technical efficacy., Methods: This was a quality improvement project carried out at a tertiary care center in Denmark. Patients ≥ 18 years old with liver malignancies, not available for percutaneous ablation, and treated with ultrasound-guided laparoscopic ablation were included., Results: From March 2023 to December 2023, 39 patients were referred for laparoscopic ablation after a multidisciplinary team conference. Of these, two procedures were converted to open procedures due to adhesion and tumor progression. Three patients rejected the sharing of medical information, two procedures were canceled and in one case the strategy was changed perioperatively. Therefore, 32 procedures in 31 patients were available for analysis. Complete ablation was evaluated after 1 month and was achieved in 100% of the procedures. None of the patients died, and no complications were reported in 21 cases (65.6%). Most patients with complications had a grade 1 complication based on the Clavien-Dindo classification, which among others included abdominal and shoulder pain, atrial fibrillation, and subcutaneous hematoma. Two patients had a complication grade 2 (wound infection and decompensated cirrhosis) and one had a grade 4b (sepsis due to pneumonia and urinary tract infection). The median Comprehensive Complication Index was 12.2 (interquartile range 8.7-24.2). Furthermore, univariable logistic regression showed that ≥ 2 tumors treated were associated with a higher risk of complications (odds ratio 6.37, 95% confidence interval [1.20;33.85], p-value = 0.0297)., Conclusion: Ultrasound-guided laparoscopic microwave ablation of liver malignancies is feasible and safe with little risk for complications, a high technical efficacy, and a low rate of conversions to open procedures., (© 2024. The Author(s).)