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Salmonella enterica is a frequent cause of foodborne diseases, which is attributed to its adaptability. Even within a single host, expressing a gene can be beneficial in certain infection stages but neutral or even detrimental in others as previously shown for flagellins. Mutants deficient for the conserved glycerol-3-phosphate and phosphate antiporter glpT have been shown to be positively selected in nature, clinical, and laboratory settings. This suggests that different selective pressures select for the presence or absence of GlpT in a context dependent fashion, a phenomenon known as antagonistic pleiotropy. Using mutant libraries and reporters, we investigated the fitness of glpT-deficient mutants during murine orogastric infection. While glpT-deficient mutants thrive during initial growth in the gut lumen, where GlpT's capacity to import phosphate is disadvantageous, they are counter-selected by macrophages. The dichotomy showcases the need to study the spatial and temporal heterogeneity of enteric pathogens' fitness across distinct lifestyles and niches. Insights into the differential adaptation during infection may reveal opportunities for therapeutic interventions., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: As current literature does not provide sufficient data to support clear guidelines in patients with a rare adult-type granulosa cell tumor, we aim to investigate: (1) whether additional staging surgery following primary surgical treatment is necessary; (2) how long standard follow-up should be and (3) risk factors for disease recurrence., Methods: A national multicenter prospective study was initiated in April 2018. Patients with suspected or confirmed adult-type granulosa cell tumor were eligible. Data on staging, follow-up and risk factors were both retrospectively and prospectively collected from medical records, and patients were followed until April 2024 or until death. Descriptive statistical analysis and survival analysis were performed using Cox regression methods and Kaplan-Meier analyses., Results: In total, 208 patients with histopathologically confirmed adult-type granulosa cell tumor were included, with a median follow-up of 5.5 years (IQR: 2.2-12.3 years). Vaginal bleeding and abdominal pain were the most common symptoms at diagnosis. Median time until first recurrence was 4.2 years (range 2 months- 32 years). Additional staging surgery did not reduce the risk of recurrence. During follow-up, most patients had no symptoms at the time of detection of recurrence. No difference in overall survival was found between patients who were diagnosed with a recurrence during follow-up, and those who were no longer in follow-up and presented with symptoms., Conclusions: Staging surgery does not improve recurrence free survival in patients with adult-type granulosa cell tumor. Our results suggest that adult-type granulosa cell tumor patients can be discharged from follow-up of adult-type granulosa cell tumor after five years., Competing Interests: Declarations. Ethical approval and consent to participate: A national multicenter prospective study was conducted and approved by the Medical Ethics Committee of the University Medical Centre Utrecht (UMCU METC 17–868) and by the institutional review boards of all participating centers. All patients provided written informed consent. The study was registered in the Dutch Trial Register under trial number NL63786.041.17, first registered on April 17, 2018 ( https://onderzoekmetmensen.nl/en/trial/54607 ). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Consent for publication: All patients provided written informed consent. Competing interests: J.M.J. Piek received grants of the Dutch Cancer society, the Catharina research fund and the INNOsign/OPZuid grant. C.D. de Kroon received grants from ZonMW, KWF, and ZorgInstituut, and occupies chair roles for the guideline committee on endometrial cancer and the working party gynecological oncology from the NVOG. The other authors declare no conflicts of interest., (© 2025. The Author(s).)

Molecular testing for human papillomaviruses (HPV) is gradually replacing cytology in cervical cancer screening. In this longitudinal population-based cohort study, 4140 women 20 to 64 years old attending organized screening were tested at baseline by five different screening methods and followed for 9 years. To assess long-term safety, the cumulative risks of CIN2+/CIN3+ were estimated after a negative baseline result obtained by conventional cytology and four clinically validated HPV assays: Hybrid Capture 2 (hc2), RealTime High Risk HPV assay (RealTime), cobas 4800 HPV Test (cobas&#95;4800), and Alinity m HR HPV (Alinity). HPV-negative women at baseline had a substantially lower risk for CIN2+ compared to those with normal baseline cytology: 0.84% (95% CI, 0.46-1.22), 0.90% (95% CI, 0.51-1.29), 0.78% (95% CI, 0.42-1.15), and 0.75% (95% CI, 0.39-1.11) for hc2, RealTime, cobas&#95;4800, and Alinity, respectively, compared to 2.46% (95% CI, 1.88-3.03) for cytology. No differences were observed between HPV assays in longitudinal sensitivity (range: 86.21%-90.36%) and negative predictive values (range: 99.54%-99.70%) for CIN2+ in women ≥30 years, but were significantly different from cytology (p < .05). The 9-year cumulative risk of CIN2+ differed significantly between HPV genotypes, reaching 32.1% (95% CI, 14.5-46.1) for HPV16, 24.9% (95% CI, 4.7-40.8) for HPV18/45, 27.2% (95% CI, 14.6-37.8) for HPV31/33/35/52/58, and 8.1% (95% CI, 0.0-16.7) for HPV39/51/56/59. Four clinically validated HPV assays showed comparable safety and better assurance against precancerous lesions than cytology, but some important differences were identified in the performance characteristics of HPV assays impacting the referral rate. Information about the HPV genotype is valuable for guiding further clinical action in HPV-based screening programs., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Lymph node T follicular helper (Tfh) cells and germinal center (GC) B cells are critical to generate potent antibodies but are rarely possible to study in humans. To understand how Tfh/GC B-cell interactions during acute HIV-1 infection (AHI) impact the generation of HIV-specific antibodies, we performed a unique cross-sectional analysis of inguinal lymph node biopsies taken prior to antiretroviral therapy (ART) initiation in AHI. Although total Tfh and GC B cell frequencies did not change during AHI, increased frequencies of proliferating Th1-like CXCR3 + Tfh, CXCR3 + non-GC B cells, and total CXCR3 + GC B cells correlated with gp120-specific IgG antibody levels in AHI. Frequencies of proliferating CXCR3 + Tfh in AHI also correlated with gp120-specific IgG antibody levels after 48 weeks of ART, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and increased antibody binding to infected cells after ART. Importantly, while beneficial for antibody development, CXCR3 + Tfh cells were also infected by HIV-1 at higher frequencies than their CXCR3 - counterparts and may contribute to the initial dissemination of HIV-1 in follicles. Together, these data suggest that activation of CXCR3 + Tfh cells is associated with induction of the germinal center response and subsequent antibody development, making these cells an important target for future therapeutic interventions., Importance: Early initiation of antiretroviral therapy (ART) is important to limit the seeding of the long-lasting HIV-1 reservoir; however, it also precludes the development of HIV-specific antibodies that can help control the virus if ART is stopped. Antibody development occurs within germinal centers in the lymph node and requires activation of both antigen-specific B cells and T follicular helper cells (Tfh), a specialized CD4 + cell that provides B cell help. To understand how early ART initiation may prohibit antibody development, we analyzed the frequencies and activation status of Tfh and B cells in lymph node biopsies collected in the different stages of acute HIV-1 infection. Our data suggest that decreased antibody development after early ART initiation may be due to limited germinal center development at the time of treatment and that new interventions that target activation of CXCR3 + Tfh may be beneficial to increase long-term HIV-specific antibody levels.

Introduction: Data about impact of switch to dolutegravir (DTG)-based antiretroviral therapy (ART) on estimated glomerular filtration rate (eGFR) in Asians are scarce. RV254/SEARCH010 is a prospective observational cohort in Bangkok, Thailand with ART initiation during acute HIV infection (AHI) where participants switched to DTG-based ART., Methods: Participants started Efavirenz (EFV)-based ART during AHI (n = 214) and switched to DTG-based ART after a median of 97 weeks (IQR 61-145). GFR was estimated by serum creatinine (eGFR cre ) every 24 weeks before and after switch. Estimated GFR by cystatin C (eGFR cystC ) was ordered at clinician's discretion for decreased eGFR cre after switch. Random-effect linear regression model was used to assess changes in eGFR cre over 96 weeks from starting ART, and from switching to DTG., Results: At study entry, 20 participants (9.3%) had eGFR cre  < 90 ml/min/1.73 m 2 . During EFV-based ART, an additional 17 (8%) developed eGFR cre  < 90 ml/min/1.73 m 2 , nearly all transient, while mean eGFR cre remained stable and within normal range. At switch to DTG, 21 (9.8%) had eGFR cre  < 90 ml/min/1.73 m 2 but an additional 116 (54%) developed eGFR cre  < 90 ml/min/1.73 m 2 during follow-up with eGFR cre decrease being mostly persistent. Mean eGFR cre decreased 20.8% from 117.0 to 92.4 ml/min/1.73 m 2 (p < 0.001). Among 20 post-switch participants with eGFR cystC measured within 4 weeks of eGFR cre  < 90 mL/min/1.73 m 2 , 13 (65%) had normal kidney function by eGFR cystC ., Conclusions: Persistent eGFR cre decrease to < 90 ml/min/1.73 m 2 after switch to DTG was common in this Thai population. eGFR cystC was helpful to identify individuals with clinically significant decrease in kidney function and obviate unnecessary ART modifications. Trial registration Clinical Trials Registry Number: ClininicalTrials.gov NCT00796146., Competing Interests: Declarations. Ethics approval and consent to participate: All participants signed written informed consent and participated in protocols approved by Thai (Chulalongkorn University, Faculty of Medicine, OHRP IRB00001607) and US (Walter Reed Army Institute of Research, OHRP IRB00000794) Institute Review Boards. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Aims: Both plasma levels of remnant cholesterol and low-density lipoprotein cholesterol (LDL-C) levels are independent risk factors for atherosclerotic cardiovascular disease. However, only remnant cholesterol has consistently been associated with systemic inflammation. In this study, we aimed to assess the extent to which inflammation mediates the effect of remnant and LDL cholesterol on (non)fatal major adverse cardiovascular events (MACE), comprising of coronary artery disease and ischemic stroke., Methods and Results: This prospective study included 16,445 participants without prior atherosclerotic cardiovascular disease from the EPIC-Norfolk study, with a mean age of 58.8±9.1 years, of which 9,357 (56.9%) were women. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher high-sensitivity C-reactive protein (hsCRP) levels (95% Confidence Interval (CI): 22.1, 37.4, p<0.001), whereas LDL-C was not significantly associated with hsCRP levels in the fully adjusted model. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a hazard ratio (HR) of 1.31 (95% CI: 1.14, 1.50, p<0.001) for MACE, compared to a HR of 1.21 (95% CI: 1.13, 1.31, p<0.001) for LDL-C. Mediation analysis showed that hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, p<0.001) of the effect of remnant cholesterol on MACE, whereas hsCRP did not mediate the effect of LDL-C., Conclusions: Plasma remnant cholesterol levels are independently associated with systemic inflammation and cardiovascular events. Inflammation, as measured with hsCRP, contributed minorly to the association between remnant cholesterol and MACE. This underscores the need to address both remnant cholesterol and systemic inflammation separately in the clinical management of cardiovascular disease., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Modern lifestyle risk factors, like physical inactivity and poor nutrition, contribute to rising rates of obesity and chronic diseases like type 2 diabetes and heart disease. Particularly personalized interventions have been shown to be effective for long-term behavior change. Machine learning can be used to uncover insights without predefined hypotheses, revealing complex relationships and distinct population clusters. New data-driven approaches, such as the factor probabilistic distance clustering algorithm, provide opportunities to identify potentially meaningful clusters within large and complex datasets., Objective: This study aimed to identify potential clusters and relevant variables among individuals with obesity using a data-driven and hypothesis-free machine learning approach., Methods: We used cross-sectional data from individuals with abdominal obesity from The Maastricht Study. Data (2971 variables) included demographics, lifestyle, biomedical aspects, advanced phenotyping, and social factors (cohort 2010). The factor probabilistic distance clustering algorithm was applied in order to detect clusters within this high-dimensional data. To identify a subset of distinct, minimally redundant, predictive variables, we used the statistically equivalent signature algorithm. To describe the clusters, we applied measures of central tendency and variability, and we assessed the distinctiveness of the clusters through the emerged variables using the F test for continuous variables and the chi-square test for categorical variables at a confidence level of α=.001., Results: We identified 3 distinct clusters (including 4128/9188, 44.93% of all data points) among individuals with obesity (n=4128). The most significant continuous variable for distinguishing cluster 1 (n=1458) from clusters 2 and 3 combined (n=2670) was the lower energy intake (mean 1684, SD 393 kcal/day vs mean 2358, SD 635 kcal/day; P<.001). The most significant categorical variable was occupation (P<.001). A significantly higher proportion (1236/1458, 84.77%) in cluster 1 did not work compared to clusters 2 and 3 combined (1486/2670, 55.66%; P<.001). For cluster 2 (n=1521), the most significant continuous variable was a higher energy intake (mean 2755, SD 506.2 kcal/day vs mean 1749, SD 375 kcal/day; P<.001). The most significant categorical variable was sex (P<.001). A significantly higher proportion (997/1521, 65.55%) in cluster 2 were male compared to the other 2 clusters (885/2607, 33.95%; P<.001). For cluster 3 (n=1149), the most significant continuous variable was overall higher cognitive functioning (mean 0.2349, SD 0.5702 vs mean -0.3088, SD 0.7212; P<.001), and educational level was the most significant categorical variable (P<.001). A significantly higher proportion (475/1149, 41.34%) in cluster 3 received higher vocational or university education in comparison to clusters 1 and 2 combined (729/2979, 24.47%; P<.001)., Conclusions: This study demonstrates that a hypothesis-free and fully data-driven approach can be used to identify distinguishable participant clusters in large and complex datasets and find relevant variables that differ within populations with obesity., (©Maik JM Beuken, Melanie Kleynen, Susy Braun, Kees Van Berkel, Carla van der Kallen, Annemarie Koster, Hans Bosma, Tos TJM Berendschot, Alfons JHM Houben, Nicole Dukers-Muijrers, Joop P van den Bergh, Abraham A Kroon, Maastricht Study Management, Iris M Kanera. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 05.02.2025.)

Zika virus (ZIKV) is an arbovirus associated with neurological disorders accompanying congenital infections. With no vaccine or antiviral approved, there is an urgent need for the development of effective antiviral agents against ZIKV infection. We evaluated the anti-ZIKV and immunomodulatory activity of ouabain, a Na + /K + -ATPase inhibitor known to have immunomodulatory and antiviral activities, using human neural stem and progenitor cells (hNS/PCs) and a murine model of congenital Zika syndrome (CZS). Our data demonstrated that ouabain reduces ZIKV infection in hNS/PCs, mouse placenta, yolk sac, and the fetal head. Ouabain mitigated neurogenesis impairment triggered by ZIKV in hNS/PCs and prevented ZIKV-mediated reduction of fetus and head sizes. In addition, ouabain decreased tumor necrosis factor and interleukin-1β levels in the placenta, highlighting its immunomodulatory activity in the murine model. Our findings indicate that ouabain possesses anti-ZIKV and immunomodulatory activities, suggesting that it should be investigated further as a promising treatment for CZS., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Yeast is a poikilothermic organism and adapts its lipid composition to the environmental temperature to maintain membrane physical properties. Studies addressing temperature-dependent adaptation of the lipidome have described changes in the phospholipid composition at the level of sum composition (e.g. PC 32:1) and molecular composition (e.g. PC 16:0&#95;16:1). However, there is little information at the level of positional isomers (e.g. PC 16:0/16:1 versus PC 16:1/16:0). Here, we used collision- and ozone-induced dissociation (CID/OzID) mass spectrometry to investigate homeoviscous adaptation of PC, PE and PS to determine the phospholipid acyl chains at the sn-1 and sn-2 position. Our data establish the sn-molecular species composition of PC, PE and PS in the lipidome of yeast cultured at different temperatures., (© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction: The prevalence of tobacco use among people experiencing homelessness is 70 %. Mental health and substance use disorders are associated with tobacco use and pose challenges for tobacco cessation., Methods: Between 2019 and 2024, we recruited 206 adults experiencing homelessness from three homeless shelters in San Francisco, California. Participants were enrolled in a 12-week pharmacist-linked smoking cessation program that involved pharmacist counseling and furnishing of nicotine replacement therapy (NRT) and brief cessation coaching by trained shelter staff. We examined the association of provision of tobacco cessation interventions with two outcomes-weekly cigarette consumption and quit attempts-using mixed effects Poisson and logistic regression models respectively. We ran separate models with baseline mental health conditions and substance use disorders and adjusted for age, gender, race-ethnicity, time to first cigarette after waking, and baseline cigarette consumption in all models., Results: Adjusting for baseline mental health conditions and other covariates, the use of pharmacist-furnished NRT was associated with lower weekly consumption (Incidence Rate Ratio [IRR]: 0.74, 95 % Confidence Interval [CI]: 0.71-0.76) and increased weekly quit attempts (Adjusted Odds Ratio (AOR): 1.78, 95 % CI: 1.23-2.58). After adjusting for baseline substances used and other covariates, use of pharmacist-furnished NRT was associated with lower weekly consumption (IRR: 0.74, 95 % CI: 0.73-0.76) and increased weekly quit attempts (AOR: 1.99, 95 % CI: 1.45-2.74)., Conclusions: A community pharmacist-linked cessation program in homeless shelters was associated with reduced consumption and increased weekly quit attempts, highlighting its potential for scalability among people experiencing homelessness with high rates of co-occurring behavioral health conditions., 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.)

Purpose: To compare the cost-effectiveness of a nurse-led sexual rehabilitation intervention with standard care in women treated with external beam radiotherapy, with or without brachytherapy, for gynaecological cancers., Methods: Eligible women were randomly assigned to the intervention (n = 112) or standard care (n = 117). Primary endpoint was sexual functioning at 12-months post-radiotherapy, assessed by the Female Sexual Function Index (FSFI). Nurses documented frequency and duration of intervention sessions, patients reported sexual healthcare and functioning at 1, 3, 6, and 12-months. Costs were related to quality-adjusted-life-years (QALYs) using the EuroQol-5 Dimensions and visual analogue scale, and to sexual functioning improvement at 12-months. T-tests compared mean QALYs and costs, with multiple imputation for missing data., Results: The nurse-led intervention added €172 per patient, including training costs and 4-5 sessions. Other sexual rehabilitation costs were higher in the standard care group (€107 versus €141, p = 0.02). Total costs were €478 for the intervention group and €357 for standard care (p = 0.03). Valued at €20.000 per QALY, the intervention was 60 %-70 % likely to be cost-effective and less than 50 % likely to be cost-effective in terms of improved sexual functioning., Conclusion: The nurse-led sexual rehabilitation intervention is not more cost-effective than standard care, however with low costs in both groups. Since costs for standard care were slightly lower, it is preferred from a health-economic perspective. It includes detailed patient education and a dedicated sexual rehabilitation session within the first three months post-radiotherapy, which is better provided at lower cost by a trained nurse., 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 B.V. All rights reserved.)

Food waste is a global challenge that needs to be mitigated in the development of more sustainable societies. From manufacturers to customers, food biosensors could effectively reduce the amount of discarded food and provide more precise predictions of freshness with respect to pre-decided expiration dates. In this study, we developed a novel organic electrochemical transistor (OECT)-based xanthine biosensor. The OECT-based biosensor is based on the p-type conjugated polymer, p(g 4 2T-TT) as the channel, and incorporated xanthine oxidase (XOD) as the biorecognition element. The OECT thus acts as a transducer and amplifier of the enzymatic oxidation of xanthine. Real-time monitoring of xanthine using the OECT-based biosensor led to a linear range between 5 and 98 μM (R 2 =0.989), 3.28 μM limit of detection, and high sensitivity up to 21.8 mA/mM. Real sample tests showed that the biosensor can detect the accumulation of xanthine in fish meat from 0 to 6 days of degradation. Interference tests with ascorbic acid and uric acid and spike-and-recovery tests with fish samples indicated that as-designed biosensors have good selectivity and accuracy. The developed biosensors show great potential for point-of-care testing applied to food monitoring., 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 B.V.)

Fundamental and translational research in ovarian cancer aims to enhance understanding of disease mechanisms and improve treatment and survival outcomes. To support this, we established the Dutch multicenter, interdisciplinary Archipelago of Ovarian Cancer Research (AOCR) infrastructure, which includes a nationwide biobank. In this study, we share our experiences in establishing the infrastructure, offer guidance for similar initiatives, and evaluate the AOCR patient cohort. Key challenges included obtaining Data Protection Impact Assessment (DPIA) clearance, drafting the consortium agreement, and securing ethical approval from all hospitals. Over three years, 1093 patients were enrolled across 17 hospitals, resulting in the collection of 1339 tissue samples and 2280 blood samples. Of the 523 patients with currently available clinical and pathological data, 74 % (n = 387) had primary ovarian cancer. Among these patients, 73.4 % was diagnosed with high-grade serous ovarian carcinoma, and 80.9 % presented with advanced-stage disease. Surgery was performed on 93 % of patients with primary ovarian cancer, and chemotherapy was administered to 90.4 % of these patients. In conclusion, the AOCR biobank has established a robust foundation for future fundamental and translational ovarian cancer research. This manuscript provides valuable insights and guidance for developing future research infrastructures and biobanks, and contains detailed information about the AOCR patient cohort to date., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Hypothesis: Point-of-care ultrasound (PoCUS) can be used as a non-invasive and radiation free adjunct in the triage of patients with clavicle injuries. However, the diagnostic accuracy of PoCUS performed by non-radiologists for this purpose is not yet sufficiently established., Methods: A multicentre, prospective cohort study was conducted in 8 emergency departments (EDs) to establish the diagnostic accuracy of PoCUS of the clavicle in patients ≥4 years of age who presented with a clavicle injury. PoCUS was performed by trained emergency physicians, and results were compared with X-ray outcomes (gold standard)., Results: A total of 167 patients were included, of which 127 (76 %) patients had a fracture on X-ray, and 121 (72 %) on PoCUS. PoCUS of the clavicle had a sensitivity of 93 % (95 %CI 87-97 %), a specificity of 93 % (95 %CI 80-98 %), a negative likelihood ratio of 0.09 (95 %CI 0.04-0.14), and a positive likelihood ratio of 12.39 (95 %CI 4.17-36.82) for the presence of a clavicle fracture. Stratified based on age, specificity of PoCUS was lower in children compared to adults, whereas sensitivity was not affected. The agreement between X-ray and PoCUS for fracture displacement was substantial (κ = 0.771)., Conclusions: PoCUS of the clavicle is a useful adjunct in the triage of patients with clavicle injuries and can help to distinguish which patients need further diagnostic workup., Trial Registration Number: Netherlands Trial Register, registration code: NL9236., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Recent success of human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug-conjugate trastuzumab-deruxtecan in HER2-low and HER2-positive tumors has sparked interest in examining the HER2 status of tumors not traditionally associated with HER2 amplification. Despite the increasing number of systemic treatment options, patients with advanced endometrial cancer (EC) still face a poor prognosis. This study evaluates HER2-low status in over 800 EC, correlating HER2 with both molecular and clinical features., Methods: HER2 status was determined by immunohistochemistry (IHC) and dual in situ hybridization (DISH) on four studies of previously classified high-risk EC (PORTEC-3 and Medical Spectrum Twente cohort), recurrent or metastatic EC (DOMEC), and a primary stage IV cohort. EC was classified as HER2-negative (IHC 0), HER2-low (IHC 1+/2+ without amplification), or HER2-positive (IHC 3+ or DISH-confirmed amplification). Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models assessed the independence of any prognostic impact of HER2 status., Results: HER2 status was determined in 806 EC: 74.8% were HER2-negative, 17.2% HER2-low, and 7.9% HER2-positive. HER2-low was found across all molecular classes and histotypes. The highest rates of HER2-low and HER2-positive tumors were in recurrent or metastatic EC (35.6% and 15.6%), followed by primary stage IV EC (29.9% and 12.4%) and high-risk EC (14.2% and 6.8%). HER2 status had no independent prognostic value., Conclusion: A quarter of high-risk, metastatic, or recurrent EC exhibited HER2 overexpression. The presence of HER2 overexpression in all clinical and molecular categories highlights the need for broad testing and offers treatment options for a wide range of patients.

Aim: To determine the impact of the COVID-19 pandemic on depression, anxiety and stress of dental students by way of a systematic review., Materials and Methods: This review was conducted following the Cochrane Handbook for Systematic Reviews. An electronic search was conducted for the period January 2020 to February 2023. Quality assessment was evaluated in accordance with the Newcastle-Ottawa Scale. Frequency distribution was calculated for stress, anxiety and depression associated with students' gender, year of study and living circumstances., Results: Twenty-three studies were eligible for inclusion in the final review. Variables contributing to stress, anxiety and depression of dental students include gender, year of study and living circumstances. Being female is the most significant factor impacting on mental health., Conclusions: Results emphasise the need for dental institutions to develop targeted intervention programmes for more vulnerable students. Failure to act in a future pandemic event could result in ongoing psychological issues that persist following graduation, resulting in unfit dentists who may potentially affect the quality of the dental workforce., (© 2024 The Author(s). European Journal of Dental Education published by John Wiley & Sons Ltd.)

Background: SARS-CoV-2 has been associated with a higher proportion of asymptomatic infections and lower mortality in sub-Saharan Africa than high-income countries. However, there is currently a lack of data on cellular immune responses to SARS-CoV-2 in people living in Africa compared with people in high-income regions of the world. We aimed to assess geographical variation in peripheral and mucosal immune responses., Methods: In this retrospective, population-based, cross-sectional study, we analysed peripheral blood and nasal curettage samples from seven clinical studies involving individuals from Senegal (Senegalese cohort), the Netherlands, and Germany (European cohort). Samples were collected between Nov 1, 2018, and Dec 20, 2021. We included samples from individuals with no, mild, or severe COVID-19. A validation cohort of individuals from Senegal and Gabon (n=64) was used to validate key findings from the main cohort. Matching of individuals between geographical regions by age, sex, viral load, and infection severity and duration was used to address confounding factors. We examined the cellular, humoral, and cytokine immune responses using cytometry by time of flight, spectral flow cytometry, ELISA, and Luminex., Findings: We included 133 individuals (59 from the Senegalese cohort and 74 from the European cohort). In contrast to the European cohort, mild COVID-19 in the Senegalese cohort was not associated with any statistically significant perturbations in blood or nasal immune cell profiles, nor with increased pro-inflammatory cytokines, although SARS-CoV-2-specific adaptive immunity was readily induced, as seen in Europeans. In severe COVID-19, both the Senegalese and European cohorts showed lymphopenia (Senegal: 2·9-times decrease, p=0·0010 vs Europe: 1·6-times decrease, p=0·0046) and increased neutrophil frequencies in blood (Senegal: 2·0-times increase, p=0·0044 vs Europe: 1·3-times increase, p=0·026) and the nasal mucosa CD66b + CD16 low neutrophils (Senegal: 9·9-times increase, p=0·045 vs Europe: 392-times increase, p<0·0001). However, in contrast to Europeans, the Senegalese cohort had no significant expansion of immature immune populations, inflammasome activation, or monocyte recruitment to the nasal mucosa., Interpretation: The observed divergent immunological trajectories during SARS-CoV-2 infection offer a potential explanation for the reported attenuated disease course in sub-Saharan Africa and highlight the need to further investigate immune responses to SARS-CoV-2 in understudied populations., Funding: European and Developing Countries Clinical Trials Partnership 2 programme (AIDCO), LUMC Gisela Thier Fellowship, Dutch Research Council (NWO), European Research Council, and Leids Universitair Fonds., Competing Interests: Declaration of interests FE reports research grants from ZonMw (a Dutch governmental agency) for vaccination-induced immunity against SARS-CoV-2 in patients with immune-mediated diseases. SPJ reports grants from ZonMw, BMGF, the EU, and the Dutch Research Council; and travel fees covered by the Dutch Lung Foundation for attending advisory board meetings. TPV is a member of PAN-ASEAN Coalition for Epidemic and Outbreak Preparedness (PACE-UP; German Academic Exchange Service [DAAD] Project ID: 57592343). All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Glucocorticoids and androgens affect each other in several ways. In metabolic organs, such as adipose tissue and the liver, androgens enhance glucocorticoid-induced insulin resistance and promote fat accumulation in male mice. However, the direct contribution of the androgen receptor (AR) to these effects is unknown. Furthermore, it is unclear whether the potentiating effect of androgens on glucocorticoid signaling in fat extends to other tissues, such as skeletal muscle and bone. In this study, we used two complementary models for androgen deprivation (orchidectomy and chemical castration) to investigate the effects of dihydrotestosterone (DHT) on corticosterone (CORT). We found that after 2 weeks of intervention, DHT alone did not affect fat mass but increased lean mass, while CORT increased fat mass and decreased lean mass. Co-supplementation with DHT counteracted the CORT effect on lean mass but enhanced its effect on adiposity. Glucocorticoid induction of Gilz, Fkbp5 and Mt2a in gonadal white adipose tissue depended on the presence of androgens, while in interscapular brown adipose tissue, these genes responded to glucocorticoids also without androgens. To directly assess the impact of the AR on the glucocorticoid response, male global AR knock-out mice were exposed to CORT and compared to WT littermates. CORT exposure resulted in an increase in fat mass and a decrease in lean mass in both genotypes. In conclusion, functional AR signaling is dispensable for the metabolic response to glucocorticoids. However, androgen signaling in WT mice modulates glucocorticoid response in a tissue-dependent manner, by counteracting lean mass and potentiating fat mass effects.

Adenomyosis is characterized by abnormal uterine bleeding, dysmenorrhea and subfertility. Increased expression of angiogenesis markers in adenomyosis presents a treatment opportunity and was studied in an adenomyosis mouse model. Mice were administered tamoxifen (1 mg/kg) on neonatal days 2-5. At six weeks of age, mice received oral treatment with axitinib 3 mg/kg ('dose I/AX3', n = 34), axitinib 25 mg/kg ('dose II/AX25' n = 34), or with vehicle-only ('placebo', n = 34). The prevalence and severity of adenomyosis were assessed. An adenomyosis severity index was calculated by multiplying mean grade/mouse by the percentage affected surface area. Angiogenesis-related gene expression was evaluated using real-time quantitative PCR. 101 mice completed adenomyosis induction and could be analyzed. The prevalence of adenomyosis was 30/33 (90.0%) in dose I, 29/34 (85.3%) in dose II, and 30/34 (88.2%) in placebo treated mice (p = 0.78). High grade (2/3) adenomyosis was significantly less prevalent in mice treated with axitinib dose II (n = 19, 55.9%) than in the placebo group (n = 27, 79.4%, p < 0.05). The adenomyosis severity index was reduced by 48% in the axitinib-treated groups (dose I, p < 0.05). The expression of angiogenic growth factors was reduced in the dose I and II axitinib-treated groups compared to the placebo-treated group. Following these promising first results, further research should focus on commonality among different angiostatic drugs, potential side effects, as well as the method and timing of application., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Introduction: While the World Health Organization (WHO) advocates organizing maternity care and preventive child healthcare (PCHC) as people-centred, integrated healthcare services, globally these services are often established separately, causing discontinuity of care. Our aim is to synthesize the evidence concerning what impacts parents' experience of continuity of care, and how to promote it., Methods: Qualitative systematic review. Embase, Medline, Web of Science, Cochrane, CINAHL and Google Scholar were searched for studies on parents' perspectives on integrated care. Helpful practices and issues regarding continuity of care were identified., Results: We found that parents valued easily accessible, tailored, family-centred care that is a display of interprofessional collaboration and is geared towards supporting and empowering parents., Discussion: Study strengths are its qualitative nature, allowing for in-depth patient views and experiences, and the multidisciplinary research team, which ensured a multidimensional view of the issue., Conclusion: Ideally, (a) parents enter the postnatal period well-prepared, and well-informed about self-care, PCHC and possible postnatal carepathways, (b) number of caretransfers is limited, (c) by overlapping maternity care and PCHC, parents are provided with an opportunity to maintain meaningful relationships with their care providers, and (d) information is consistent, family-centred, and tailored., Competing Interests: The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright: © 2025 The Author(s).)

Fibro-osseous tumors of the craniofacial bones are a heterogeneous group of lesions comprising cemento-osseous dysplasia (COD), cemento-ossifying fibroma (COF), juvenile trabecular ossifying fibroma (JTOF), psammomatoid ossifying fibroma (PsOF), fibrous dysplasia (FD), and low-grade osteosarcoma (LGOS) with overlapping clinicopathological features. However, their clinical behavior and treatment differ significantly, underlining the need for accurate diagnosis. Molecular diagnostic markers exist for subsets of these tumors, including GNAS mutations in FD, SATB2 fusions in PsOF, mutations involving the RAS-MAPK signaling pathway in COD, and MDM2 amplification in LGOS. Because DNA methylation and copy number profiling are well established for the classification of central nervous system tumors, we aimed to investigate whether this tool might be used as well for classifying fibro-osseous tumors in the craniofacial bones. We collected a well-characterized, multicenter cohort with available molecular data, including COD (n = 20), COF (n = 13), JTOF (n = 10), PsOF (n = 25), FD (n = 23), LGOS (n = 4), and high-grade osteosarcoma (HGOS; n = 11). Genome-wide DNA methylation and copy number variation data were generated using the Illumina Infinium Methylation EPIC array interrogating >850 000 CpG sites. DNA methylation profiling yielded evaluable results in 73/106 tumors, including 6 CODs, 12 COFs, 6 JTOFs, 19 PsOFs, 18 FDs, 2 LGOSs, and 10 HGOSs. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) revealed that FD, extragnatic PsOF, and HGOS formed distinct clusters. Surprisingly, COD, COF, JTOF, and mandibular PsOF clustered together, apart from other craniofacial bone tumors. LGOS did not form a distinct cluster, likely due to the low number of cases. Copy number analysis revealed that FD, COD, COF, JTOF, and PsOF were typically characterized by flat copy number profiles compared with LGOS with gains of chromosome 12 and HGOS with multiple heterogeneous copy number alterations. In conclusion, using DNA methylation and copy number profiles, benign fibro-osseous tumors can be separated from low-grade and HGOSs in the craniofacial bones, which is of diagnostic value in challenging cases with overlapping clinicopathological features., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Pain in hand osteoarthritis (OA) is evaluated with repeated pain questionnaires. It is unclear whether these questionnaires adequately capture changes in pain recalled by patients. This study investigated whether changes on pain questionnaires (real-time evaluation) correspond to recalled pain., Methods: Data from hand OA patients from the HOSTAS cohort (four one-yearly) and HOPE trial (one six-week interval) were used. Pain was measured with the Australian/Canadian hand Osteoarthritis Index (AUSCAN, range 0-20) and a recall question (how is the pain compared with your last visit). Changes in AUSCAN pain were categorized into improved (≤-1), stable or worsened pain (≥1) and compared with the recall question using Cohen's kappa and percentage agreement. We determined concordance between measurement methods, and investigated associations of mental wellbeing and illness perceptions with concordance using GEE., Results: Of 708 intervals from HOSTAS (307 patients, 82% women, mean age 61.0 years, mean AUSCAN 9.1), AUSCAN changes and recall were concordant in 42% (Cohen's kappa 0.13). There was concordance in 47% of 86 intervals (Cohen's kappa 0.14) from the HOPE trial (86 patients, 80% women, mean age 63.5, mean AUSCAN 10.7). The most frequent recall answer was worsened pain in the HOSTAS (60%), improved pain in the HOPE trial (76%). In both studies, AUSCAN pain most frequently improved. Depression and anxiety showed no association with concordance., Conclusion: Changes in repeatedly measured AUSCAN pain often differ from the recalled course of pain over the same period. This has profound implications for evaluating patient reported pain in clinical trials., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background and Objective: Intravesical instillation of chemotherapy (IIC) after radical surgery for upper urinary tract urothelial carcinoma (UTUC) reduces the risk of intravesical recurrence (IVR). However, compliance is low because of possible extravesical leakage after bladder cuff excision. The aim of this study was to evaluate the efficacy of preoperative IIC in reducing the risk of IVR., Methods: In this prospective, single-arm, multi-institutional, phase 2 clinical trial, 190 chemonaïve patients with primary UTUC without prior or concurrent bladder cancer received a single intravesical instillation of mitomycin C for 1-2 hr within 3 h before surgery. The primary endpoint was the 2-yr histologically confirmed IVR rate, with a target reduction of >40% (from 33.2% according to literature data to <20%). A historical cohort of 247 patients with UTUC who did not receive perioperative IIC served as the reference. Secondary endpoints included compliance, toxicity, and IVR-free survival, which was analyzed via multivariable Cox regression and stratified by previous diagnostic ureteroscopy (d-URS)., Key Findings and Limitations: The 2-yr IVR rate was 24% (95% confidence interval [CI] 18-31%) on intention-to-treat analysis and 23% (95% CI 13-32%) on per-protocol analysis. Multivariable analysis revealed that d-URS was associated with higher IVR risk. In the REBACARE cohort, patients without d-URS had threefold lower IVR risk (hazard ratio 0.33, 95% CI 0.12-0.87) in comparison to the reference cohort. Compliance with preoperative instillation was 96% and no grade >2 toxicity occurred., Conclusions and Clinical Implications: Preoperative IIC with mitomycin C was feasible and well tolerated and significantly reduced IVR risk for patients without d-URS. These findings suggest that preoperative IIC is a viable strategy for this subset of UTUC patients and that d-URS should be performed judiciously., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Natural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained. We performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were TST & IGRA positive (called LTBI) and 6 who were persistently TST & IGRA negative (called resisters). Alveolar macrophages (AM) from resisters displayed a baseline M1 macrophage phenotype while AM from LTBI did not. Resisters displayed alveolar lymphocytosis, with enrichment of all T cell subpopulations including IFNG-expressing cells. In both groups, mycobactericidal granulysin was expressed almost exclusively by a T cell subtype that co-expressed granzyme B, perforin and NK cell receptors. These poly-cytotoxic T lymphocytes (CTL) over-expressed activating NK cell receptors and were increased in resister BAL. Following challenge with Mtb, only Intraepithelial Lymphocytes-like cells from LTBI participants responded with increased transcription of IFNG. AM from resisters responded with a stronger TNF signature at 6h post-infection while at 24h post-infection AM from LTBI displayed a stronger IFN-γ signature. Conversely, at 24h post-infection only AM from resisters displayed a significant upregulation of MICA transcripts which encode an activating ligand for poly-CTL. These results suggest that poly-CTL and AM mediate the resister phenotype in PWH.

Objective: To describe the use and nationwide variation of red blood cell (RBC) transfusions in neonatal intensive care units (NICUs) following the introduction of the revised national transfusion guideline in 2019., Design and Patients: We randomly selected neonates born below 32 weeks' gestation admitted to any NICU in the Netherlands in 2020 to include in our retrospective observational cohort study., Main Outcome Measures: Main outcome measures were the number of neonates receiving at least one transfusion, and the number of transfusions per transfused neonate., Results: Of 762 neonates included, 34% (257/762) received at least one RBC transfusion, varying between centres from 20% (12/61) to 50% (39/77). Median phlebotomy loss during admission was 8.2 mL/kg (IQR 4.5-17.3 mL/kg), equating to 54.3% of the median transfusion volume. Of 770 transfusions, 358 (47%) were administered above the recommended threshold, and the proportion of transfusions given above the threshold varied between centres from 15% to 719%. Median transfusion dosage and mean infusion duration were 15.1 mL/kg (IQR 15.0-16.7 mL/kg) and 3.9 hours (SD 1.1 hour) and varied from 14.8 mL/kg to 18.9 mL/kg and from 2.5 hours to 5.5 hours between centres. Blood transfusion volume was positively correlated with cumulative volume of blood draws (Pearson correlation coefficient 0.84, 95% CI 0.82 to 0.86) and lower gestation., Conclusions: Large variation in transfusion practice remains between Dutch NICUs despite a national guideline. Extreme prematurity and cumulative blood draws were associated with increased use of RBC transfusions. Benchmarking will yield leverage points to understand and potentially prevent unwarranted variation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objectives: Rumination syndrome (RS) is diagnosed based on clinical criteria with or without diagnostic testing showing characteristic findings on antroduodenal manometry (ADM), high-resolution esophageal manometry (HREM), and multichannel intraluminal impedance-pH testing (MII-pH). The objective of this study was to evaluate the correlation between diagnostic testing and clinical outcomes., Methods: We conducted a retrospective review of children with RS evaluated at our institution. Patients were divided into two groups: those with confirmatory diagnostic testing for rumination based on ADM, HREM, and/or MII-pH, and those without. We compared response to treatment based on the proportion no longer having vomiting at follow-up and no longer needing supplemental nutrition., Results: We included 152 children (60% female, median age of diagnosis 13 years, interquartile range 8-15 years) with RS. 22 patients (14%) had diagnostic testing that confirmed RS. At baseline, there was no statistical difference in the percentage of patients who had overt vomiting (p = 0.311), however, the confirmatory testing group was more likely to need supplemental nutrition (p ≤ 0.001) and to receive intensive treatment (p < 0.001). After treatment, the proportion of patients without vomiting increased in both groups without a statistically significant difference between the two groups. There were also no significant differences in likelihood of reporting improvement in symptoms or needing supplemental nutrition., Conclusions: Children with RS who had confirmatory diagnostic testing were equally likely to no longer have vomiting after treatment when compared to those without confirmatory testing. Future studies are needed to account for potential differences in baseline severity between groups., (© 2025 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

The endothelium is the gatekeeper of vessel health, and its dysfunction is pivotal in driving atherogenesis. Here, we present a protocol to replicate endothelial-macrophage crosstalk during atherogenesis, called the "atherogenesis-on-chip" model, based on the Emulate dual-channel perfusion system. We describe a model for studying endothelial-macrophage interactions during atherogenesis in human aortic endothelial cells and human macrophages using qPCR and secretome analysis, fluorescence microscopy, and flow cytometry. This protocol could be adapted toward more complex plaque microenvironment or other disease settings., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Simple hysterectomy and pelvic node assessment (SHAPE) is a phase III randomized trial (ClinicalTrials.gov identifier: NCT01658930) reporting noninferiority of simple compared with radical hysterectomy for oncologic outcomes in low-risk cervical cancer. This study presents secondary outcomes of sexual health and quality of life (QOL) of the SHAPE trial., Methods: Participants were randomly assigned to receive either radical or simple hysterectomy. Sexual health was assessed up to 36 months postoperatively using the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale-Revised and QOL using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Cervical Cancer-Specific Module (QLQ-CX24) questionnaires., Results: Among participants with at least one QOL measure, clinical and pathologic characteristics were balanced and with no differences in preoperative baseline scores for sexual health or QOL between groups. FSFI total score met the cutoff for dysfunction up to 6 months ( P = .02) in the radical hysterectomy group. Group differences favored simple hysterectomy for FSFI subscales: desire and arousal at 3 months ( P ≤ .001) and pain and lubrication up to 12 months ( P ≤ .018). Both groups met the cutoff for sexual distress but was higher in radical hysterectomy at 3 months ( P = .018). For QLQ-CX24, symptom experience was significantly better up to 24 months ( P = .031) and body image better at 3, 24, and 36 months ( P ≤ .01) for simple hysterectomy. Sexual-vaginal functioning was significantly better up to 24 months ( P ≤ .022) and more sexual activity up to 36 months ( P = .024) in the simple hysterectomy arm. Global health status was significantly higher at 36 months for simple hysterectomy ( P = .025)., Conclusion: Simple hysterectomy was associated with lower rates of sexual dysfunction than radical hysterectomy, with a lower proportion of women having sustained sexual-vaginal dysfunction. These results further support the benefit of surgical de-escalation for low-risk cervical cancer.

Background: We aimed to update the 2018 systematic literature review on the efficacy and safety of treatments for hand osteoarthritis (OA), which was based on 126 studies., Methods: We performed a systematic literature search on randomised controlled trials from June 2017 up to 31 December 2023. Risk of bias was assessed using the RoB2 tool. Meta-analyses of previous and new studies regarding the efficacy for pain, function, grip strength and OMERACT/OARSI responders were performed. Certainty of evidence was judged using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) tool., Results: Sixty-five new studies were included. For non-pharmacological interventions, there was low-certainty evidence for a small long-term effect of hand exercises and a moderate long-term effect of thumb orthoses for pain, and moderate-certainty evidence that assistive devices had a moderate long-term effect on function. Concerning pharmacological interventions, there was low-certainty evidence for a moderate short-term effect of oral non-steroidal anti-inflammatory drugs (NSAIDs) on pain, high- and moderate-certainty evidence for a small short-term effect of topical NSAIDs and oral glucocorticoids on function, respectively, and low-certainty evidence that oral glucocorticoids had a small short-term effect on function. Further, there was low-certainty evidence that methotrexate had a small long-term effect on pain. The heterogeneity of studies did not allow for any meta-analyses on surgery., Conclusion: The results largely support current treatment recommendations. However, there is a lack of interventions that efficiently improve grip strength, and the evidence for most current treatments is still limited. To better understand action mechanism of different treatments, future trials should include hand OA subtyping and be powered for subgroup analyses., Competing Interests: Competing interests: This study had no competing financial interests. Interests disclosed in the international Committee of Medical Journal Editors (ICMJE) conflict of interest forms are as follows: IKH has received consulting fees from Novartis and GSK and is a member of the OARSI executive committee. MK has received grants from IMI APPROACH and the Dutch Arthritis Society, royalties/licences from Wolters Kluwer and Springer Verlag, and consulting fees from AbbVie, Pfizer, Kiniksa Flexion, Galapagos, CHDR, Novartis and UCB, and she is a member of the OARSI board, the EULAR council and President of the Dutch Society for Rheumatology., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Vascular and bleeding complications remain a concern after transfemoral transcatheter aortic valve replacement (TAVR). The impact of the sheath type on these complications remains unclear., Methods: The prospective MARVEL registry study analyzed enrolled 500 patients undergoing large-bore transfemoral procedures and arteriotomy closure with the MANTA vascular closure device from 10 hospitals in Europe and Canada. We stratified these patients according to type of sheath used (expandable or conventional). A propensity-matched analysis was performed using VARC-2 major or minor vascular and bleeding complications as the primary endpoint. The secondary endpoint was time to hemostasis., Results: We identified 196 propensity-matched pairs. Major vascular complications occurred in 3.6% in the expandable sheath group and 4.1% in the conventional sheath group (p = 1.0). Minor vascular complications occurred in 5.6% in the expandable sheath group and 4.6% in the conventional sheath group (p = 0.819). There were no significant differences in bleeding complications between groups. Time to hemostasis after MANTA closure was significantly shorter in the expandable sheath group (30 vs. 60 s, p < 0.001)., Conclusions: A propensity-matched analysis demonstrated no significant differences in vascular complication rates with MANTA arteriotomy closure after removal of large bore expandable or conventional sheaths. Time to hemostasis was significantly shorter in the expandable sheath group., (© 2025 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: The HIV epidemic in Indonesia is one of the fastest growing in Southeast Asia and is characterised by a number of geographic and sociocultural challenges. Can large language models (LLMs) be integrated with telehealth (TH) to address cost and quality of care? Methods: A literature review was performed using the PRISMA-ScR (2018) guidelines between Jan 2017 and June 2024 using the PubMed, ArXiv and semantic scholar databases. Results: Of the 694 records identified, 12 studies met the inclusion criteria. Although the role of eHealth interventions as well as telehealth in HIV management appears well established, there is a significant literature gap on the integration of telehealth and LLM technology. To address this, we provide a blueprint for the safe and ethical integration of LLM-TH into triage, history taking, patient education highlighting opportunities for reduced consultation time and improved quality of care. Conclusions: Variable access to mobile technology and the need for empirical validation stand out as limitations for LLM-TH. However, we argue that the current evidence base suggests the benefits far outweigh the challenges in applying LLM-TH for HIV care in Indonesia. We also argue this novel therapeutic modality is broadly applicable to the subacute general practice setting., 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.

New conduction disorders remain a frequent complication in current transcatheter aortic valve replacement (TAVR) era. Left bundle branch block (LBBB) occurs early in about 20-30 % of TAVR-patients, persists at 1 month in about 35-45 % of cases and will likely remain thereafter. Third-degree atrioventricular block (AV3B) affects approximately 15 % of patients. Pacemaker dependency gradually decreases throughout follow-up and approximately 25-35 % of patients remain pacemaker dependent at one year. We aimed to review what is currently known about the dynamics of acquired conduction disorders, including extraction of predictors, and how to interpret these dynamics in light of an early discharge policy., Competing Interests: Declaration of competing interest RN: received research grant support from Vifor Pharma and consulting fees from Edwards Lifesciences, Abbott, Boston Scientific NVM: received research grant support from Abbott Vascular, Boston Scientific, Edwards Lifesciences, Medtronic, Daiichi Sankyo and also advisory fees from JenaValve, Anteris, Luma Vision, Pie Medical, Siemens, Abbott Vascular, Boston Scientific, PulseCath BV, Abiomed, Amgen, Medtronic All other authors have no conflicts of interest to report., (Copyright © 2024. Published by Elsevier Inc.)

Background: Inflammation is increasingly recognised as a treatment target in hand osteoarthritis, and therefore correct measurement of local inflammation is essential. This study aimed to assess ultrasound scoring of synovitis and the additional value of the Global OMERACT/EULAR Ultrasound Synovitis Score (GLOESS) in hand osteoarthritis., Methods: Data from the randomised, double-blinded Hand Osteoarthritis Prednisolone Efficacy (HOPE) trial were used. The HOPE trial included patients with painful, inflammatory hand OA, treated with prednisolone or placebo (1:1). Ultrasound was performed in 30 hand joints at weeks 0, 6 and 14. Effusion, synovial thickening and Doppler signal were measured, the GLOESS was calculated from the latter two. Joint tenderness on palpation was assessed semiquantitatively (0-3), soft swelling as present/absent. Changes in ultrasound scores, and their association with change in joint tenderness or soft swelling, were investigated using generalised estimating equations. Effect sizes were calculated., Results: Of 92 included patients 79% were women, with mean (SD) age 63.9 (8.8) and body mass index 27.2 (4.6). Synovial thickening was the most prevalent. All ultrasound scores were strongly associated with joint tenderness and soft swelling cross-sectionally. There was no association of change in ultrasound scores with change in tenderness, but there was with change in soft tissue swelling. Synovial thickening and the GLOESS responded to treatment (effect size -0.39 (-0.72 to -0.07), -0.39 (-0.71 to -0.07), respectively)., Discussion: Various ultrasound scores were associated with joint tenderness and soft swelling. The GLOESS and synovial thickening were both responsive to treatment, but GLOESS was not superior to synovial thickening alone., Competing Interests: Competing interests: MK reports the following, all outside the current study. Grant from IMI-APPROACH. Royalties or licences from Wolters Kluwer and Springer Verlag, paid to the institution. Fees for consulting/advisory boards by Pfizer, UCB, CHDR, GSK, Novartis and Peptinov, all paid to the institution. Payment or honoraria for lectures or presentations from Novartis, paid to the institution. Roles on the OARSI board (member), EULAR council (member advocacy committee EULAR) and presidency of the Dutch Society for Rheumatology. For the current study, MK reports funding from the Dutch Arthritis Society, paid to the institution. The other authors report no competing interests., (© 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.)

The global number of COVID-19 deaths has reached 7 million, with 4% of these deaths occurring in children and adolescents. In Brazil, around 1500 children up to 11 years old died from the disease. The most common symptoms in children are respiratory, potentially progressing to severe illnesses, such as severe acute respiratory syndrome (SARS) and MIS-C. Studies indicate that comorbidities and genetic factors, such as polymorphisms in immune response genes, can influence the severity of COVID-19. This study investigates the occurrence of single-nucleotide polymorphisms (SNPs) in innate immune response genes in children with COVID-19. Seventy-three samples were analyzed from children under 13 years old hospitalized at João Paulo II Children's Hospital due to COVID-19. The evaluated SNPs were tlr8 (1) (rs3764879), tlr8 (2) (rs2407992), tlr7 (rs179008), tlr3 (rs3775291), tirap (rs8177374), and mcp-1 (rs1024611), considering four categories of severity: mild, moderate, severe, and critical COVID-19. To identify the SNPs, PCR and sequencing were performed. The frequencies of the SNPs obtained were not discrepant when compared to the frequencies described in the Global ALFA, Global 1000 Genomes, Global gnomAD, American 1000 Genomes, and American gnomAD databases, except for the SNP in TLR7. Comparing severe and critical cases to mild and moderate cases, we found a higher relative risk associated with mutations in tlr8 (1) , tlr7 , tlr3 , and tirap ( p < 0.05). No association was found for SNPs in tlr8 (2) and mcp-1 . Our analyses suggest an association between SNPs in innate immune response genes and severity of symptoms in children with COVID-19 (or SARS-CoV-2 infected children).

Since its first report in Brazil in 1999, outbreaks of exanthematous diseases caused by vaccinia virus (VACV) have been a recurring concern, particularly impacting rural regions. Minas Gerais (MG) State, Brazil, has emerged as the epicenter of bovine vaccinia (BV) outbreaks. This study presents a comprehensive overview of VACV circulation in MG State over the past two decades, examining the occurrence and distribution of poxvirus cases and outbreaks and the demographic characteristics of affected populations. Analysis of secondary databases from 2000 to 2023 revealed VACV circulation in at least 149 municipalities, particularly expanding in dairy regions. The study underscores BV as an occupational disease, predominantly affecting rural men involved in dairy cattle activities. Laboratory findings indicate high levels of anti-OPXV antibodies in most individuals, with some showing acute infections confirmed by qPCR testing. This analysis informs public health policies, emphasizing the need for enhanced surveillance of and preventive measures for dairy farming communities.

Background and Objective: A standardized intraoperative frozen section analysis of the prostate resection margin adjacent to the neurovascular bundle according to the NeuroSAFE technique is performed to maximize nerve sparing during radical prostatectomy (RP) for prostate cancer (PCa). The aim of this review was to analyze oncological and functional outcomes of NeuroSAFE., Methods: A systematic search of the Medline, Embase, and Web of Science databases until July 2024 was performed. Studies were eligible if these included men undergoing RP with NeuroSAFE for PCa, and reported on oncological and/or functional outcomes. A cumulative analysis with random-effect models for oncological outcomes was conducted using Review Manager software, together with a narrative analysis of the procedure and functional outcomes., Key Findings and Limitations: We analyzed 14 studies with nine distinct patient populations; 7505 out of 15 446 patients underwent NeuroSAFE. The number of nerve-sparing procedures was higher for patients with NeuroSAFE than for controls in all studies. Cumulative analyses showed a statistically significantly lower risk of positive surgical margins (PSMs) in favor of NeuroSAFE (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.51-0.91, I 2  = 79%) and no difference in 2-yr biochemical recurrence (BCR; OR 0.79, 95% CI 0.53-1.18, I 2  = 63%). All studies with control groups showed higher potency rates in the NeuroSAFE group; none reported significant difference in continence rates. Adverse events were scarce. Limitations of the studies include a lack of randomization resulting in a selection bias; the overall risk of bias judgment ranged from low to serious., Conclusions and Clinical Implications: We present the first systematic review on NeuroSAFE during RP. The level of evidence is weak. The increased rate of nerve-sparing surgery, reduced PSMs, similar BCR, and low adverse event rates imply that NeuroSAFE is an oncologically safe technique. NeuroSAFE seems to improve functional outcomes, especially potency, but results of randomized trials are awaited., Patient Summary: We know that for patients with prostate cancer who undergo an operation to remove the prostate, sparing the nerve bundles next to each side of the prostate improves continence and erectile function. In this literature review, we evaluated a technique (NeuroSAFE) that aids surgeons in deciding whether they can spare these nerve bundles safely while still operating radically, for example, remove all cancer. We found that the technique is oncologically safe. Furthermore, the impact on potency appears promising but needs further study., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The 3D micro- and nanostructure of wood has extensively been employed as a template for cost-effective and renewable electronic technologies. However, other electroactive components, in particular native lignin, have been overlooked due to the absence of an approach that allows access of the lignin through the cell wall. In this study, we introduce an approach that focuses on establishing conjugated-polymer-based electrical connections at various length scales within the wood structure, aiming to leverage the charge storage capacity of native lignin in wood-based energy storage electrodes. We demonstrate that poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) PEDOT/PSS, integrated within the cell wall lumen, can be interfaced with native lignin through the wood cell wall through in situ polymerization of a water-soluble S-EDOT monomer. This approach increases the capacitance of the conductive wood to 315 mF cm -2 at a scan rate of 5 mV s -1 , which is seven and, respectively, two times higher compared to the capacitance of conductive wood made with the single components PEDOT/PSS or S-PEDOT. Moreover, we show that the capacitance is contributed by both the electroactive polymers and native lignin, with native lignin accounting for over 70% of the total charge storage capacity. We show that accessing native lignin through in situ creation of electrical interconnections within the wood structure offers a pathway toward sustainable, wood-based electrodes with improved charge-storage capacity for applications in electronics and energy storage.

Background: The existence of sociodemographic disparities in pancreatic cancer has been well-studied but how these disparities have changed over time is unclear. The purpose of this study was to longitudinally assess patient management in the context of sociodemographic factors to identify persisting disparities in pancreatic cancer care., Methods: Using the National Cancer Database, patients diagnosed with pancreatic ductal adenocarcinoma from 2010 to 2017 were identified. The primary outcomes were surgical resection and/or receipt of chemotherapy. Outcome measures included changes in associations between sociodemographic factors (i.e., sex, age, race, comorbidity index, SES, and insurance type) and treatment-related factors (i.e., clinical stage at diagnosis, surgical resection, and receipt of chemotherapy). For each year, associations were assessed via univariate and multivariate analyses., Results: Of 75,801 studied patients, the majority were female (51%), White (83%), and had government insurance (65%). Older age (range of OR 2010-2017 [range-OR]:0.19-0.29), Black race (range-OR: 0.61-0.78), lower SES (range-OR: 0.52-0.94), and uninsured status (range-OR: 0.46-0.71) were associated with lower odds of surgical resection (all p < 0.005), with minimal fluctuations over the study period. Older age (range-OR: 0.11-0.84), lower SES (range-OR: 0.41-0.63), and uninsured status (range-OR: 0.38-0.61) were associated with largely stable lower odds of receiving chemotherapy (all p < 0.005)., Conclusions: Throughout the study period, age, SES, and insurance type were associated with stable lower odds for both surgery and chemotherapy. Black patients exhibited stable lower odds of resection underscoring the continued importance of mitigating racial disparities in surgery. Investigation of mechanisms driving sociodemographic disparities are needed to promote equitable care., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Following the description of an illustrative case of a 70-year-old female patient with longstanding active acromegaly and invalidating, progressive joint complaints, current insights regarding diagnosis, treatment, and long-term management of acromegalic arthropathy are summarized. Since clinical trials on this topic are lacking, the reported recommendations are based on extensive clinical and research experience with this clinical entity, and on established diagnostics and interventions in patients with other rheumatic diseases. The cornerstones of the management of acromegalic arthropathy remains normalization of growth hormone and insulin growth factor-1 levels. However, patients with severe or progressive acromegalic arthropathy require a multidisciplinary approach to determine adequate diagnostics and treatment options. Because of the high prevalence and invalidating character of acromegalic arthropathy, developing evidence-based effective prevention and treatment strategies, preferably by international collaboration within rare disease networks, e.g., Endo-ERN, is a clear unmet need., Competing Interests: Declarations. Conflict of interest: The authors have no conflicts of interest or funding details to disclose., (© 2024. The Author(s).)

This paper introduces a comprehensive protocol leveraging open-access techniques to create small- to medium-scale 3D representations of the environment by using iPhone and iPad light detection and ranging (LiDAR). The protocol focuses on two capabilities of the iPhone LiDAR. The first capability is 3D modeling: iPhone LiDAR rapidly generates detailed indoor and outdoor 3D models, providing insights into object size, volume and geometry. The second capability is change detection: the 3D models created by the LiDAR sensor can be used for precise measurement of changes over time. Compared to other 3D topographic surveying methods, this method is rapid, high resolution, low cost and easy to use. The protocol outlines iPhone LiDAR scanning practices, model export and change detection. The expected results after executing the protocol are (i) a detailed 3D model of a small- to medium-sized object or area of interest and (ii) a distance point cloud revealing change between two point clouds of the same object or area between different times. The entire protocol can be conducted within 2 h by anyone with an iPhone with the LiDAR sensor and a computer. This protocol empowers scientists, students and community members conducting research with a cheap, easy-to-use method for addressing a range of questions and challenges, thus benefiting experts and the broader community., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)

Objective: Biobanks play a crucial role in fundamental and translational research by storing valuable biomaterials and data for future analyses. However, the design of their information technology (IT) infrastructures is often customized to specific requirements, thereby lacking the ability to be used for biobanks comprising other (types of) diseases. This results in substantial costs, time, and efforts for each new biobank project. The Dutch multicenter Archipelago of Ovarian Cancer Research (AOCR) biobank has developed an innovative, reusable IT infrastructure capable of adaptation to various biobanks, thereby enabling cost-effective and efficient implementation and management of biobank IT systems. Methods and Results: The AOCR IT infrastructure incorporates preexisting biobank software, mainly managed by Health-RI. The web-based registration tool Ldot is used for secure storage and pseudonymization of patient data. Clinicopathological data are retrieved from the Netherlands Cancer Registry and the Dutch nationwide pathology databank (Palga), both established repositories, reducing administrative workload and ensuring high data quality. Metadata of collected biomaterials are stored in the OpenSpecimen system. For digital pathology research, a hematoxylin and eosin-stained slide from each patient's tumor is digitized and uploaded to Slide Score. Furthermore, adhering to the Findable, Accessible, Interoperable, and Reusable (FAIR) principles, genomic data derived from the AOCR samples are stored in cBioPortal. Conclusion: The IT infrastructure of the AOCR biobank represents a new standard for biobanks, offering flexibility to handle diverse diseases and types of biomaterials. This infrastructure bypasses the need for disease-specific, custom-built software, thereby being cost- and time-effective while ensuring data quality and legislative compliance. The adaptability of this infrastructure highlights its potential to serve as a blueprint for the development of IT infrastructures in both new and existing biobanks.

Objectives: To assess the association of early and late postpartum maternal mental health with infants' health related quality of life (HRQoL)., Methods: The study was embedded within the POST-UP trial (n = 1843). Infants' HRQoL was assessed with the Infant and Toddler Quality of Life Questionnaire Short Form-47 at ages 1 month (1 m), and 12 m. Maternal mental health regarded postpartum depression (PPD), measured with the Edinburgh Postnatal Depression Scale at 1 m and 6 m (early/late), and postpartum anxiety (PPA) with the short version of the state form of the Spielberger State-Trait Anxiety inventory at 1 m and 12 m (early/late). We used linear regression analyses., Results: Early and late PPD and PPA were negatively associated with infants' HRQoL at ages 1 m and 12 m. The negative associations with infants' HRQoL at 1 m were most pronounced for the domain infant temperament (standardized regression coefficient, (95% confidence interval)): -0.30 (-0.34; -0.25), and -0.37 (-0.41; -0.32) for PPD and PPA respectively, and weakest for the domain bodily pain: -0.14 (-0.19; -0.09), and -0.22 (-0.26; -0.17) for PPD and PPA respectively. The negative associations of early postpartum maternal health with infants' HRQoL at age 12 months were less pronounced. Moreover, associations with infants' HRQol were weaker for late than for early PPD and PPA., Limitation: Usage of maternal proxy reports for assessing infant HRQoL., Conclusion: Postpartum maternal mental health is negatively associated with infants' HRQoL at age 1 m and 12 m. This confirms the need for regular screening of maternal mental health in the postpartum period., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Magda M. Boere-Boonekamp reports financial support was provided by the Netherlands Organization for Health Research and Development. 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 © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This article describes the implementation of preemptive clinical pharmacogenomics (PGx) testing linked to an automated clinical decision support (CDS) system delivering actionable PGx information to clinicians at the point of care at UCSF Health, a large Academic Medical Center., Methods: A multidisciplinary team developed the strategic vision for the PGx program. Drug-gene interactions of interest were compiled, and actionable alleles identified. A genotyping platform was selected and validated in-house. Following HIPAA protocols, genotype results were electronically transferred and stored in electronic health records (EHRs). CDS was developed and integrated with electronic prescribing., Results: We developed a customized PGx program for 56 medications and 15 genes. Two hundred thirty-three pharmacogenomic prescribing alerts and 15 pharmacogenomic testing prompts, approved by clinicians, were built into EHR to deliver actionable clinical PGx information to clinicians., Conclusions: Our multidisciplinary team successfully implemented preemptive PGx testing linked to point-of-care CDS to guide clinicians with precise medication decision-making., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

High-risk HPV (hrHPV)-based screening has led to many unnecessary colposcopy referrals, mainly because of direct referral after low-grade cytology (ASC-US/LSIL). DNA methylation and genotyping tests on ASC-US/LSIL samples have the potential to significantly improve the efficiency of screening. In this study, 12 triage strategies were constructed from FAM19A4/miR124-2 or ASCL1/LHX8 methylation, HPV16/18 or HPV16/18/31/33/45 genotyping and 1-year repeat cytology. The performance was evaluated on 215 hrHPV-positive ASC-US/LSIL samples from the IMPROVE trial (NTR5078). Performance was measured by colposcopy referral rate, positive predictive value (PPV) for detecting precancer (CIN3), and negative predictive value (NPV). To evaluate efficiency, strategies were ordered by the cumulative colposcopy referral rate after 1-year cytology and compared by the marginal PPV to detect one additional CIN3 (mPPV). The most conservative strategy (referral when HPV16/18 and FAM19A4/miR124 methylation results are positive) had a direct referral rate of 5.2%, a cumulative referral rate after 1-year cytology of 54.1%, and mPPV of 19.3%. Replacing HPV16/18 by HPV16/18/31/33/45 increased the cumulative 1-year referral rate to 54.6%, and yielded an mPPV of 10.0%. Similar results were obtained for strategies with ASCL1/LHX8 methylation. Of all strategies, referral after an HPV16/18/31/33/45 positive, ASCL1/LHX8 methylation-positive, and/or 1-year cytology-positive result yielded the highest direct and cumulative 1-year colposcopy referral rates of 64.4% and 79.1%, respectively. The NPVs after 1-year cytology varied between 98.1% and 99.4%, warranting a return to routine screening. Altogether, DNA methylation-based triage strategies are recommended as they are discriminative for CIN3 and control the number of immediate colposcopy referrals., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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.

Background: Chronic inguinal pain (CIP) can be caused by musculoskeletal or neurological pathologies and by surgical trauma after inguinal hernia repair among other. The aim of this prospective cohort observational study was to find the incidence and causes of CIP unrelated to surgical trauma 12 months after inguinal hernia repair., Methods: During sixteen months patients consulting a hernia center for groin-related symptoms were included in the study. Patients were evaluated by surgeons and filled out preoperatively the Inguinal Pain Questionnaires and a Numerical Rating Scale pain-questionnaire. For patients undergoing inguinal hernia repair, postoperative questionnaires similar to the pre-operative ones were sent out at 12 months. Patients scoring pain on pain questionnaires were evaluated by phone and physical examination., Results: 289 patients (78.1%) of 370 repaired patients filled in the postoperative questionnaires. 62 (21.4%) patients scored pain, of these patients 5 (1.7%, 5/289) answered incorrectly in the pain questionnaires and 14 (4.8%, 14/289) had non-surgical trauma causes of pain: 5 musculoskeletal, 4 neurological and 3 other medical pathologies., Conclusions: This cohort study found CIP unrelated to surgical trauma in 4.8% of patients undergoing a groin hernia repair. Most causes of pain unrelated to surgical trauma were musculoskeletal and neurological pathologies. Nearly a third of patients scoring inguinal pain on pain-questionnaires did not have chronic post-surgical pain (CPSP), therefore incidence of CPSP should not be based solely on pain questionnaires. Clinical assessment of patients with pain is necessary to excluded CIP unrelated to the surgical trauma., Competing Interests: Declarations Previous presentation of the study Part of the paper has previously been presented as abstracts at the EHS-AHS joint congress Hernia 2021 in Copenhagen, at the EHS-2022 congress in Manchester, at the AHS-22 congress in Charlotte, USA and at the BJS prize of the EHS-24 congress in Prag, therefore the abstract was published as a supplement of BJS (https://doi.org/10.1093/bjs/znae122.001). The original paper has not been published and will not be simultaneously submitted or published elsewhere. Disclosure The authors have nothing to disclose., (© 2024. The Author(s).)

Objective: Endogenous glucocorticoid levels display a strong circadian rhythm, which is often not considered when synthetic glucocorticoids are prescribed as anti-inflammatory drugs. In this study we evaluated the effect timing of glucocorticoid administration, i.e. in-phase (administered when endogenous glucocorticoid levels are high) versus out-of-phase (administered when endogenous glucocorticoid levels are low). We investigated the synthetic glucocorticoid betamethasone - which is extensively used in the clinic - and monitored the development of common metabolic side effects in mice upon prolonged treatment, with a particular focus on glucose metabolism., Methods: Male and female C57BL/6J mice were treated with the synthetic glucocorticoid betamethasone in-phase and out-of-phase, and the development of metabolic side effects was monitored., Results: We observed that, compared with in-phase treatment, out-of-phase treatment with betamethasone results in hyperinsulinemia in both male and female C57BL/6J mice. We additionally found that out-of-phase betamethasone treatment strongly reduced insulin sensitivity as compared to in-phase administration during morning measurements. Our study shows that the adverse effects of betamethasone are dependent on the time of treatment with generally less side effects on glucose metabolism with in-phase treatment., Conclusions: This study highlights differences in glucocorticoid outcome based on the time of measurement, advocating that potential circadian variation should be taken into account when studying glucocorticoid biology., Competing Interests: Declaration of competing interest OM received research funding from Corcept Therapeutics. JK is seconded to Corcept Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Coronary heart disease is a major global health threat, with acute myocardial ischemia-reperfusion injury (IRI) being a major contributor to myocardial damage following an ischemic event. IRI occurs when blood flow to ischemic tissues is restored and exacerbates the cellular damage caused by ischemia/hypoxia. Although animal studies investigating IRI have provided valuable insights, their translation into clinical outcomes has been limited, and translation into medical practice remains cumbersome. Recent advancements in engineered three-dimensional human in vitro models could offer a promising avenue to bridge the "therapeutic valley of death" from bench to bedside, enhancing the understanding of IRI pathology. This review summarizes the current state-of-the-art cardiovascular 3D models, including spheroids, organoids, engineered cardiac microtissues, and organ-on-a-chip systems. We provide an overview of their advantages and limitations in the context of IRI, with a particular emphasis on the crucial roles of cell-cell communication and the multi-omics approaches to enhance our understanding of the pathophysiological processes involved in IRI and its treatment. Finally, we discuss currently available multicellular human 3D models of IRI., 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 Peletier, Zhang, Klein and Kroon.)