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Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8 + T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8 + T cells, follicular helper T cells and shorter distances between tumor and CD8 + T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 ., (© 2024. The Author(s).)

Introduction: Interprofessional working and learning thrives with speak-up behavior. Efforts to improve speak-up have mainly focused on isolated techniques and training programs within the patient safety scope, yet sustained improvement requires a cultural shift beyond this scope. This research investigates the influence of culture elements on speak-up behavior in interprofessional teams beyond the patient safety context., Methods: An exploratory qualitative study design was used in a Dutch hospital's Obstetrics and Gynecology department. A representative sample of stakeholders was purposefully selected, resulting in semi-structured interviews with 13 professionals from different professional backgrounds (nurses, midwifes, managers, medical specialists, and residents). A speak-up pledge was developed by the research team and used to prime participants for discussion. Data analysis involved three-step coding, which led to the development of themes., Results: This study has identified six primary cultural themes that enhance speak-up behavior. These themes encompass the importance of managing a shared vision, the role of functional hierarchy, the significance of robust interpersonal relationships, the formulation of a strategy delineating when to speak up and when to exercise restraint, the promotion of an open-minded professional mindset, and the integration of cultural practices in the context of interprofessional working and learning., Conclusion: Six crucial cultural elements have been pinpointed to boost the practice of speaking up behavior in interprofessional working and learning. Remarkably, hierarchy should not be held responsible as the wrongdoer; instead, can be a great facilitator through respect and appreciation. We propose that employing transformational and humble leadership styles can provide guidance on effectively integrating the identified cultural elements into the workplace and provide an IMOI framework for effective interprofessional speak-up beyond patient safety., 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 Malik, Azar, Taimounti, Buljac-Samardžić, Hilders and Scheele.)

Introduction: Sexual health and wellbeing are significant aspects of quality of life. However, taking a sexual history is often avoided in medical practice, leaving a void in management and awareness. As the menopause can have a major impact on sexual health, it is imperative that healthcare providers are appropriately trained in sexual health and wellbeing and the aligned disciplines in order to achieve optimal care., Aim: To provide an evidence-based clinical guide for the assessment and management of sexual problems at the menopause and beyond., Materials and Methods: Review of the literature and consensus of expert opinion., Results and Conclusion: The assessment of sexual problems includes history taking, examination and laboratory investigation (if indicated), and occasionally the use of specific validated questionnaires. Management of sexual problems requires a multidimensional approach using biopsychosocial measures. Medical management and psychosexual counselling include pharmacological and non-pharmacological interventions, and sex therapy and psychoeducation. Furthermore, perimenopausal women should be advised about the need for contraception if they wish to avoid pregnancy. Also, sexually transmitted diseases can be acquired at any age. To conclude, taking a sexual history should be incorporated into medical practice and healthcare providers should be appropriately trained to assess and manage sexual problems at the menopause and beyond., Competing Interests: Declaration of competing interest Stavroula A. Paschou: none declared. Kleoniki I. Athanasiadou: none declared. Trish Hafford-Letchfield: none declared. Sharron Hinchliff: none declared. Melissa Mauskar: Medical Advisory Board: Nuvig; Grant/research support: Incyte. Margaret Rees: none declared. James A. Simon: Grant/research support: AbbVie, Inc., Bayer Healthcare LLC., Dare´ Bioscience; Ipsen, Mylan/Viatris Inc., Myovant Sciences, Sebela Pharmaceuticals Inc.; Consultant/advisory boards: Bayer HealthCare Pharmaceuticals Inc., Besins Healthcare, California Institute of Integral Studies (CIIS), Dare´ Bioscience, Femasys Inc., Khyria, Madorra Pty Ltd., Mayne Pharma, Inc., Vella Bioscience Inc.; Speaker's bureaus: Astellas Pharma, Inc., Mayne Pharma, Inc., Myovant Sciences, Inc., Pfizer Inc., Pharmavite LLC., Scynexis Inc.; Stockholder (direct purchase): Sermonix Pharmaceuticals. Eleni Armeni: none declared. C. Tamer Erel: none declared. Ivan Fistonić: none declared. Timothy Hillard: Remuneration for talks or consultancy work over the last 5 years from: Theramex, Besins, Astellas, Shionogi. Angelica Lindén Hirschberg: consulting fees from Astellas and Gedeon Richter, research support from Besins and Avia Pharma. Blazej Meczekalski: none declared. Nicolás Mendoza: consulting fees from Exeltis, Organon, Theramex and Novonordisk. Alfred Mueck: Grant/research support: Besins/Dr.Kade Company; Consultancies and/or Lectures: Abbott, Bayer, Besins/Dr.Kade, Exeltis, Gedeon Richter, Hexal, Novartis, Jenapharm, MSD, Schaper and Brümmer, Serelys. Tommaso Simoncini: consulting fees from Abbot, Astellas, Gedeon Richter, Mitsubishi Tanabe, Sojournix, Estetra, Mithra, Actavis, Medtronic, Shionogi, Applied Medical. Speakers' honoraria from Abbott, Shionogi, Gedeon Richter, Intuitive Surgical, Applied Medical, Theramex. Petra Stute: Grant/research support: Schaer Pharma, EFFIK; Consultancies: Theramex, Astellas; Membership of speakers' bureau: Theramex, Jenapharm, Labatec, Exeltis, Besins Healthcare, Astellas, Gedeon Richter, Hexal, Pierre Fabre, Zeller. Dorenda van Dijken: none declared. Irene Lambrinoudaki: research grant from ITF Hellas., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Consumption of ultra-processed foods [UPFs] may be associated with negative health outcomes. Limited data exist regarding the potential role of UPFs in the occurrence of allergic diseases. The underlying mechanisms underpinning any such associations are also poorly elucidated., Methods: We performed a systematic review and narrative evidence synthesis of the available literature to assess associations between UPF consumption and pediatric allergy outcomes (n = 26 papers), including data on the association seen with the gut microbiome (n = 16 papers) or immune system (n = 3 papers) structure and function following PRISMA guidelines., Results: Dietary exposure to fructose, carbonated soft drinks, and sugar intake was associated with an increased risk of asthma, allergic rhinitis, and food allergies in children. Commercial baby food intake was associated with childhood food allergy. Childhood intake of fructose, fruit juices, sugar-sweetened beverages, high carbohydrate UPFs, monosodium glutamate, UPFs, and advanced glycated end-products (AGEs) was associated with the occurrence of allergic diseases. Exposure to UPFs and common ingredients in UPFs seem to be associated with increased occurrence of allergic diseases such as asthma, wheezing, food allergies, atopic dermatitis, and allergic rhinitis, in many, but not all studies., Conclusion: More preclinical and clinical studies are required to better define the link between UPF consumption and the risk of allergies and asthma. These observational studies ideally require supporting data with clearly defined UPF consumption, validated dietary measures, and mechanistic assessments to definitively link UPFs with the risk of allergies and asthma., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Clozapine remains the only pharmacological treatment option for treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of clozapine is recommended, although evidence for the therapeutic range of 350-600 ng/ml is limited. In various countries including Serbia, TDM of clozapine is not routinely performed. This study evaluated the distribution of clozapine levels and their relationship with clinical outcomes in Serbian patients who had not undergone prior TDM. 140 Patients with treatment-resistant schizophrenia and schizo-affective disorder were enrolled. Clozapine levels were measured by dried blood spot (DBS) analysis. Side effects were evaluated by GASS-c, severity of symptoms and functional impairment with WHODAS, CGI-S and GAF. Of the patients, 51.2% had subtherapeutic levels, 24.8% were in the therapeutic window, and 24% had supratherapeutic levels. Clozapine levels showed no association with side effects and a weak positive association with symptom severity and functional impairment. No serious side effects were observed in patients with clozapine levels surpassing 1000 ng/ml (n = 8). Based on these findings, we propose that the upper limit of the therapeutic range should not be regarded as an absolute barrier, and guidelines should allow for a personalized approach when prescribing clozapine., 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.)

Objectives: Previous research in the general population shows more potentially inappropriate medications (PIMs) among persons with a migration background compared with persons without a migration background. This study investigated the association between non-Western (nw) migration background (MB) and dementia-specific PIMs in older adults with dementia in the Netherlands., Design: Cohort study using routinely recorded electronic health records and administrative data., Setting and Participants: Electronic health record data of general practitioners from the NIVEL-Primary Care Database, were linked to registries managed by Statistics Netherlands (2013-2014). A total of 9055 community-dwelling older adults with dementia were included, among whom 294 persons had an nw-MB from Africa, South America, or Asia, based on their country of birth., Methods: We determined the presence of dementia-specific PIM prescriptions and compared this between persons with an nw-MB and without an MB, using logistic regression analysis adjusted for follow-up time, age, registered sex, and total number of prescriptions. Interaction effects of potentially relevant covariates were tested. The 3 largest nw-MB groups in the Netherlands were analyzed separately., Results: Dementia-specific PIMs were less frequently prescribed to persons with an nw-MB compared to persons without an MB with a dementia diagnosis [30.6% vs 34.4%, odds ratio (OR) 0.71, 95% CI 0.54-0.92], with especially less often a benzodiazepine prescription in the group with an nw-MB, compared to persons without an MB (15.0% vs 19.3%, OR 0.61, 95% CI 0.43-0.84). Dementia duration, living alone, household income, and degree of urbanization did not influence the associations., Conclusions and Implications: Among older adults with dementia in the Netherlands, persons with an nw-MB had less often a dementia-specific PIM prescription compared to persons without an MB. Whether this difference is a reflection of better quality of care, higher professional uncertainty, or less recognition of (mental) health problems in persons with an nw-MB and dementia, needs further investigation., Competing Interests: Disclosures The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To perform a cost study of pharmacist-led medication reviews in patients with an acute hospitalization for adverse drug events., Method: Emergency department pharmacists performed medication reviews in patients hospitalized after visiting the emergency department for an adverse drug event (ADE). Control patients were hospitalized after an emergency department visit not related to an ADE and received usual care. The costs of the intervention were labour costs of the junior emergency department pharmacist and the cost savings consisted of costs of medication that was stopped or reduced during six months after the intervention. Sensitivity analyses were performed to evaluate different scenarios., Results: In the intervention group (n = 104) 113 medication changes led to stopping or reducing medication, accounting for averted costs of €22,850. In the control group (n = 112) 39 medication changes led to stopping or reducing medication, accounting for averted costs of €299. The mean labour costs of the intervention were €138 per patient, resulting in saved costs of €61 per patient per six months. Sensitivity analyses showed that if the intervention would be performed by a senior clinical pharmacist, there are no cost savings (€-21), if parts of the intervention would be executed by pharmacy technicians (e.g. administrative tasks), cost savings would be augmented to €87, if outliers in costs associated with medication reduction would be excluded, there are no cost savings (€-35) and if the costs of reduced medication were extrapolated to one year, cost savings would be €260., Conclusion: In this study, medication reviews by junior emergency department pharmacists in patients hospitalized after an emergency department visit for an ADE lead to a cost reduction over a six month period., Trial Registration: The main study is registered on the ISRCTN registry with trial ID ISRCTN12506329 on 06-03-2022., (© 2024. The Author(s).)

Background and Aims: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups., Methods: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronization therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life-, clinical-, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented., Results: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were non-significant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = .03; adjusted Pinteraction = .33) and diabetics (Pinteraction = .01; adjusted Pinteraction = .06) were observed. However, these interaction effects did not persist after adjusting for multiple testing., Conclusions: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: The purpose of this study is to investigate whether retained hardware after surgical treatment for a pelvic fracture prior to pregnancy affects the choice of delivery method. The study aims to provide insights into the rates of vaginal delivery and caesarean sections, understanding whether the mode of delivery was influenced by patient preference or the recommendations of obstetricians or surgeons, and examining the rate of complications during delivery and postpartum., Methods: All women of childbearing age who underwent surgical fixation for a pelvic ring fracture between 1994 and 2021 were identified. A questionnaire was sent about their possible pregnancies and deliveries. Of the included patients, surgical data were collected and the fracture patterns were retrospectively classified. Follow-up was a minimum of 36 months., Results: A total of 168 women with a pelvic fracture were identified, of whom 13 had a pregnancy after surgical stabilization. Eleven women had combined anterior and posterior fracture patterns and two had isolated sacral fractures. Four women underwent combined anterior and posterior fixation, the others either anterior or posterior fixation. Seven women had a total of 11 vaginal deliveries, and 6 women had 6 caesarean sections. The decision for vaginal delivery was often the wish of the mother (n = 4, 57%) while the decision to opt for caesarean section was made by the surgeon or obstetrician (n = 5, 83%). One woman in the vaginal delivery group suffered a postpartum complication possibly related to her retained pelvic hardware., Conclusion: Women with retained hardware after pelvic ring fixation can have successful vaginal deliveries. Complications during labor or postpartum are rare. The rate of primary caesarean sections is high (46%) and is probably influenced by physician bias. Future research should focus on tools that can predict labor outcomes in this specific population, and larger multicenter studies are needed., Level of Evidence: Level III., (© 2024. The Author(s).)

Trauma is one of the main causes of death in younger people and ongoing disability worldwide. In Europe, while there is generally good organization of trauma reception and acute treatment, rehabilitation from major musculoskeletal injuries is less well defined and provided. This article documents the diverse approaches to rehabilitation after major injury in 6 European nations. The recognition of need is universal, but achieving a robust rehabilitation strategy is more elusive across the varying health care systems. Switzerland has the most robust service in the insured population. In the other countries, particularly where there is a reliance on public institutes, this provision is at best patchy. In the Netherlands, innovative patient-empowering strategies have gained traction with notable success, and in the United Kingdom, a recent randomized trial also showed this approach to be reproducible and robust. Overall, there is a clear need for learning across the national systems and implementation of a minimum set of standards., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

Purpose: Viral mutations and improved prevention or treatment options may have changed the association of frailty with mortality throughout the COVID-19 pandemic. We investigated how associations of frailty with in-hospital mortality changed throughout the pandemic in older people hospitalised for COVID-19., Methods: The COVID-OLD study included COVID-19 patients aged ≥ 70 years hospitalised during the first (early 2020), second (late 2020), third (late 2021) or fourth wave (early 2022). Based on the clinical frailty scale, patients were categorised as fit (1-3), pre-frail (4-5) or frail (6-9). Associations of frailty with in-hospital mortality were assessed with pairwise comparisons with fit as reference category and modelled using binary logistic regression adjusted for age and sex., Results: This study included 2362 patients (mean age 79.7 years, 60% men). In the first wave, in-hospital mortality was 46% in patients with frailty and 27% in fit patients. In-hospital mortality decreased in each subsequent wave to 25% in patients with frailty and 11% in fit patients in the fourth wave. After adjustments, an overall higher risk of in-hospital mortality was found in frail (OR 2.26, 95% CI: 1.66-3.07) and pre-frail (OR 1.73, 95% CI: 1.27-2.35) patients compared to fit patients, which did not change over time (p for interaction = 0.74)., Conclusions: Frailty remained associated with a higher risk of in-hospital mortality throughout the entire COVID-19 pandemic, although overall in-hospital mortality rates decreased. Frailty therefore remains a relevant risk factor in all stages of a pandemic and is important to consider in prevention and treatment guidelines for future pandemics., (© 2024. The Author(s).)

Purpose: The focus of measuring success in obesity treatment is shifting from weight loss to patients' health and quality of life. The objective of this study was to select a core set of patient-reported outcomes and patient-reported outcome measures to be used in clinical obesity care., Materials and Methods: The Standardizing Quality of Life in Obesity Treatment III, face-to-face hybrid consensus meeting, including people living with obesity as well as healthcare providers, was held in Maastricht, the Netherlands, in 2022. It was preceded by two prior multinational consensus meetings and a systematic review., Results: The meeting was attended by 27 participants, representing twelve countries from five continents. The participants included healthcare providers, such as surgeons, endocrinologists, dietitians, psychologists, researchers, and people living with obesity, most of whom were involved in patient representative networks. Three patient-reported outcome measures (patient-reported outcomes) were selected: the Impact of Weight on Quality of Life-Lite (self-esteem) measure, the BODY-Q (physical function, physical symptoms, psychological function, social function, eating behavior, and body image), and the Quality of Life for Obesity Surgery questionnaire (excess skin). No patient-reported outcome measure was selected for stigma., Conclusion: A core set of patient-reported outcomes and patient-reported outcome measures for measuring quality of life in clinical obesity care is established incorporating patients' and experts' opinions. This set should be used as a minimum for measuring quality of life in routine clinical practice. It is essential that individual patient-reported outcome measure scores are shared with people living with obesity in order to enhance patient engagement and shared decision-making., (© 2024. The Author(s).)

Purpose: The aim of this study is to assess cost-effectiveness of general practitioner (GP) versus surgeon-led colon cancer survivorship care from a societal perspective., Methods: We performed an economic evaluation alongside the I CARE study, which included 303 cancer patients (stages I-III) who were randomised to survivorship care by a GP or surgeon. Questionnaires were administered at baseline, 3-, 6-, 12-, 24- and 36-months. Costs included healthcare costs (measured by iMTA MCQ) and lost productivity costs (SF-HLQ). Disease-specific quality of life (QoL) was measured using EORTC QLQ-C30 summary score and general QoL using EQ-5D-3L quality-adjusted life years (QALYs). Missing data were imputed. Incremental cost-effectiveness ratios (ICERs) were calculated to relate costs to effects on QoL. Statistical uncertainty was estimated using bootstrapping., Results: Total societal costs of GP-led care were significantly lower compared to surgeon-led care (mean difference of - €3895; 95% CI - €6113; - €1712). Lost productivity was the main contributor to the difference in societal costs (- €3305; 95% CI - €5028; - €1739). The difference in QLQ-C30 summary score over time between groups was 1.33 (95% CI - 0.049; 3.15). The ICER for QLQ-C30 was - 2073, indicating that GP-led care is dominant over surgeon-led care. The difference in QALYs was - 0.021 (95% CI - 0.083; 0.040) resulting in an ICER of 129,164., Conclusions: GP-led care is likely to be cost-effective for disease-specific QoL, but not for general QoL., Implications for Cancer Survivors: With a growing number of cancer survivors, GP-led survivorship care could help to alleviate some of the burden on more expensive secondary healthcare services., (© 2023. The Author(s).)

Introduction: Same-day discharge (SDD) after laparoscopic Roux-en-Y gastric bypass (RYGB) is a safe and effective healthcare pathway. However, there is limited understanding of the patient perspective on SDD. The aim of this study was to explore patient satisfaction and experience with SDD after RYGB., Methods: A mixed-methods study with a concurrent design was conducted in a Dutch teaching hospital, using questionnaires and interviews. Patients who underwent RYGB and were discharged on the day of the surgery completed four questionnaires of the BODY-Q (satisfaction with the surgeon, satisfaction with the medical team, satisfaction with the office staff, and satisfaction with information provision) ± 4 months postoperative. The results of the questionnaires were compared with pre-existing data from a cohort of patients who stayed overnight after surgery (i.e., control group). A subset of patients was individually interviewed for an in-depth understanding of the patient perspective on SDD., Results: In the questionnaires, median scores for the control group (n = 158) versus the present group of patients (n = 51) were as follows: 92/100 vs. 92/100 (p = 0.331) for the surgeon, 100/100 vs. 92/100 (p = 0.775) for the medical team, 100/100 vs. 100/100 (p = 0.616) for the office staff, and 90/100 vs. 73/100 (p = 0.015) for information provision. Interviews with 14 patients revealed seven themes, describing high satisfaction, along with several points of interest., Conclusions: Patient satisfaction with SDD after RYGB is high, although information provision regarding the day of surgery could be improved. However, not every medically eligible patient might be suitable for this healthcare pathway, as responsibilities are shifted., (© 2024. The Author(s).)

Aims: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms., Methods: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death., Conclusion: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: This study aimed to assess the prognostic value of total tumor volume (TTV) for early recurrence (within 6 months) and overall survival (OS) in patients with colorectal liver metastases (CRLM), treated with induction systemic therapy followed by complete local treatment., Methods: Patients with initially unresectable CRLM from the multicenter randomized phase 3 CAIRO5 trial (NCT02162563) who received induction systemic therapy followed by local treatment were included. Baseline TTV and change in TTV as response to systemic therapy were calculated using the CT scan before and the first after systemic treatment, and were assessed for their added prognostic value. The findings were validated in an external cohort of patients treated at a tertiary center., Results: In total, 215 CAIRO5 patients were included. Baseline TTV and absolute change in TTV were significantly associated with early recurrence (P = 0.005 and P = 0.040, respectively) and OS in multivariable analyses (P = 0.024 and P = 0.006, respectively), whereas RECIST1.1 was not prognostic for early recurrence (P = 0.88) and OS (P = 0.35). In the validation cohort (n = 85), baseline TTV and absolute change in TTV remained prognostic for early recurrence (P = 0.041 and P = 0.021, respectively) and OS in multivariable analyses (P < 0.0001 and P = 0.012, respectively), and showed added prognostic value over conventional clinicopathological variables (increase C-statistic, 0.06; 95 % CI, 0.02 to 0.14; P = 0.008)., Conclusion: Total tumor volume is strongly prognostic for early recurrence and OS in patients who underwent complete local treatment of initially unresectable CRLM, both in the CAIRO5 trial and the validation cohort. In contrast, RECIST1.1 did not show prognostic value for neither early recurrence nor OS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors of this manuscript declare relationships with the following companies: C.J.A.P. has an advisory role for Nordic Pharma; SAS Analytics paid for traveling expenses G. Kazemier. This funding is not related to the current research. The remaining authors declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: HIV treating physicians in the Netherlands follow the guidelines of the Department of Health and Human Services (DHHS). Most of these recommended initial regimens are single-tablet regimens (STRs), which incur higher costs. By the end of 2017, generic NRTI backbones had become widely available, offering a potentially cheaper multi-tablet regimen. This study aimed to evaluate guideline compliance in people with HIV who started antiretroviral therapy (ART), the uptake of generic multi-tablet regimens (gMTRs), and associated medication costs., Methods: This retrospective cohort study used data from the Dutch HIV Monitoring Foundation to determine the proportion of treatment-naïve people entering care who initiated ART according to the DHHS and type of ART regimens prescribed between January 2016 and December 2020. We analyzed ART prescriptions, both at the national level and per individual HIV treatment centers. We calculated the monthly ART costs based on Dutch medicine prices listed on www.medicijnkosten.nl for each calendar year., Results: In 2016, an integrase inhibitor-containing regimen was initiated in 77.3% which increased to 87.8% in 2020. The compliance rate to DHHS-recommended initial regimens ranged from 82.8% in 2016 to 90.9% in 2020. Most patients received single-tablet regimens, 81.3% in 2016 to 60.3% in 2020. After the introduction the gMTRs showed a steady increase from 17.8% in 2018 to 37.8% in 2020. The cost of the first-line regimen per patient decreased by 22.9% in 2020 compared with 2017. The decrease was larger in centers where treatment-naïve individuals with HIV were preferentially initiated on a gMTR., Conclusions: There was a high compliance to the "DHHS-recommended initial regimens for most people with HIV" in the Netherlands. Most people who initiated ART received STRs, although the percentage of people who started on STRs gradually decreased over time. The use of gMTRs increased over time and was associated with lower medication costs., Competing Interests: PO received personal consulting fees from ViiV Healthcare, Gilead, Merck Sharp, and Dohme. FW has been served on scientific advisory boards for ViiV Healthcare and Gilead Sciences. MvdV has served on advisory boards for Gilead Sciences (Merck, Sharp, & Dohme) and ViiV Healthcare. MvdV received independent scientific grant support from Gilead Sciences, Merck, Sharp, & Dohme, and ViiV Healthcare, all of which were paid to his institution (Amsterdam University Medical Centers, Amsterdam, Netherlands). KB received personal consultation fees from Merck, Gilead, and ViiV. KB has received a writing honorarium from UpToDate. The remaining authors declare that they have no conflicts of interest.” I confirm that this not alter my adherence to all PLOS ONE policies. And thereby: This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Oosterhof et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In many parts of the world, goat milk has been part of the human diet for millennia. Allergy to goat's milk, not associated with allergy to cow's milk, is a rare disorder, although some cases have been described. Goat milk proteins have substantial homology with cow's milk proteins and even show cross-reactivity; therefore, they are not advised as an alternative to cow's milk for infants with IgE-mediated cow's milk allergies. However, there are indications that, due to the composition of the goat milk proteins, goat milk proteins show lower allergenicity than cow's milk due to a lower αS1-casein content. For this reason, goat milk might be a better choice over cow's milk as a first source of protein when breastfeeding is not possible or after the breastfeeding period. Additionally, some studies show that goat milk could play a role in specific types of non-IgE-mediated cow milk allergy or even in the prevention of sensitization to cow's milk proteins. This review discusses a possible role of goat milk in non-IgE mediated allergy and the prevention or oral tolerance induction of milk allergy.

Although widely used in follow-up treatment protocols, the added value of routine radiographs to clinical decision-making in nonoperative treatment of patients with metatarsal fractures is unclear. This retrospective cohort study aimed to determine whether routine follow-up radiographs contributed to changes in treatment strategies in nonoperative treatment of patients with a metatarsal fracture. Adult (aged ≥ 18 years) patients who received nonoperative follow-up treatment for a metatarsal fracture between May first, 2020 and May second, 2022 were included. All relevant data were extracted from patient records. Radiographs without a documented clinical indication were classified as routine. Outcomes included changes in treatment strategies based on routine radiographs during follow-up treatment and secondarily, changes in treatment strategy based on clinically indicated radiographs. A total of 168 patients were included, with 135 single and 33 multiple metatarsal fractures. During follow-up, 223 radiographs were performed, of which 154 (69%) were routine and 69 (31%) were on clinical indication. Of routine radiographs, 9 (6%) led to a change in treatment which only included additional imaging. No switch to operative treatment or prolonging of immobilization was observed based on routine radiographs. Of clinically indicated radiographs, 16 (23%) led to a change of treatment, including prolonged immobilization (n = 2), additional follow-up appointments (n = 1) and additional imaging (n = 12). Our results show routinely performed radiographs seldom affect treatment strategies in nonoperative treatment of metatarsal fractures, indicating minimal added value to clinical decision-making. Omitting routine radiographs from treatment protocols may contribute to the reduction of unnecessary healthcare resource utilization in clinical practice., (Copyright © 2024 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: We evaluated the immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV (PWH)., Design: Prospective observational cohort study., Methods: PWH aged ≥45 years received Wuhan-BA.1 mRNA-1273.214 and those <45 years Wuhan-BA.1 BNT162b2. Participants were propensity score-matched 1 : 2 to people without HIV (non-PWH) by age, primary vaccine platform (mRNA-based or vector-based), number of prior COVID-19 boosters and SARS-CoV-2 infections, and spike (S1)-specific antibodies on the day of booster administration. The primary endpoint was the geometric mean ratio (GMR) of ancestral S1-specific antibodies from day 0 to 28 in PWH compared to non-PWH. Secondary endpoints included humoral responses, T-cell responses and cytokine responses up to 180 days post-vaccination., Results: Forty PWH received mRNA-1273.214 ( N  = 35) or BNT162b2 ( N  = 5) following mRNA-based ( N  = 29) or vector-based ( N  = 11) primary vaccination. PWH were predominantly male (87% vs. 26% of non-PWH) and median 57 years [interquartile range (IQR) 53-59]. Their median CD4 + T-cell count was 775 (IQR 511-965) and the plasma HIV-RNA load was <50 copies/ml in 39/40. The GMR of S1-specific antibodies by 28 days post-vaccination was comparable between PWH [4.48, 95% confidence interval (CI) 3.24-6.19] and non-PWH (4.07, 95% CI 3.42-4.83). S1-specific antibody responses were comparable between PWH and non-PWH up to 180 days, and T-cell responses up to 90 days post-vaccination. Interferon-γ, interleukin (IL)-2, and IL-4 cytokine concentrations increased 28 days post-vaccination in PWH., Conclusion: A bivalent BA.1 booster vaccine was immunogenic in well treated PWH, eliciting comparable humoral responses to non-PWH. However, T-cell responses waned faster after 90 days in PWH compared to non-PWH., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Clinical guidelines are evidence-based recommendations developed by healthcare organizations or expert panels to assist healthcare providers and patients in making appropriate and reliable decisions regarding specific health conditions, aiming to enhance the quality of healthcare by promoting best practices, reducing variations in care, and at the same time, allowing tailored clinical decision-making. European Hernia Society (EHS) guidelines aim to provide surgeons a reliable set of answers to their pertinent clinical questions and a tool to base their activity as experts in the management of abdominal wall defects. The traditional approach to guideline production is based on gathering key opinion leader in a particular field, to address a number of key questions, appraising papers, presenting evidence and produce final recommendations based on the literature and consensus. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) method offers a transparent and structured process for developing and presenting evidence summaries and for carrying out the steps involved in developing recommendations. Its main strength lies in guiding complex judgments that balance the need for simplicity with the requirement for complete and transparent consideration of all important issues. EHS guidelines are of overall good quality but the application of GRADE method, began with EHS guidelines on open abdomen, and the increasing adherence to the process, has greatly improved the reliability of our guidelines. Currently, the need to application of this methodology and the creation of stable and dedicated group of researchers interested in following GRADE in the production of guidelines has been outlined in the literature. Considering that the production of clinical guidelines is a complex process, this paper aim to highlights the primary features of guideline production, GRADE methodology, the challenges associated with their adoption in the field of hernia surgery and the project of the EHS to establish a stable guidelines committee to provide technical and methodological support in update of previously published guideline or the creation of new ones., 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 Stabilini, Antoniou, Berrevoet, Boermeester, Bracale, de Beaux, East, Gök, Lopez Cano, Muysoms, Capoccia Giovannini and Simons.)

Contact with the hospital is usually limited for patients after day care surgery. Dedicated smartphone applications can improve communication and possibly enhance outcomes. The objective of this retrospective study was to evaluate patients' self-reported pain and nausea and assess the success of routine implementation of a smartphone application for outcome reporting. During preoperative assessment, patients were instructed to download and activate the smartphone application to report pain, nausea and to be in contact with the hospital after discharge. Main outcome was the number of patients actively using the smartphone application and the incidence of pain and nausea on postoperative day 1 to 7. In total, 4952 patients were included in the study. A total of 592 (12%) participants downloaded the application, of whom 351 (7%) were active users. A total of 4360 (88%) participants refrained from downloading the application. 56% (2,769) were female, the median age was 46 (18-92), and 4286 (87%) were classified as 1 or 2 American Society of Anesthesiologists Physical Status (ASA). Postoperative pain was experienced by 174 (76%) of 229 active users on postoperative day (POD) 1 and decreased to 44 (44%) of 100 active users on POD7. Postoperative nausea was experienced by 63 (28%) of 229 active users on POD1 and decreased to 12 (12%) of 100 active users on POD7. Female sex (p .000), socioeconomic status (p .001), and surgical severity (p .001) showed statistically significant differences between active users, non-active users, and non-downloaders. Most patients active with the application experienced pain and nausea on the first and second day after discharge. Only a minority of the patients used the application. Those who used it were satisfied with the possibilities offered to them. Future research should focus on increasing the uptake and effect of this application on the quality of recovery., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Thiel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Bariatric surgery with same-day discharge (SDD) is becoming increasingly common. Nevertheless, there is limited data available comparing gastric bypass patients with SDD to those with overnight hospitalization., Objective: The aim of this study was to investigate the short-term outcomes of gastric bypass with SDD compared to overnight hospitalization in The Netherlands., Setting: Retrospective database study with the use of the Dutch national registry., Methods: Patients who underwent gastric bypass surgery in 2022 were included and propensity score matching was performed to compare SDD with patients discharged on postoperative days (POD) 1-4. The primary outcome was the occurrence of severe complications within 30 days postoperative., Results: A total of 775 SDD patients were matched with 1550 patients discharged on POD 1-4. The occurrence of severe complications was .9% in both groups (P = 1.000), and there were no significant differences in reoperations or mortality. A significant difference was observed in the readmission rate, with 3.9% in the SDD group compared to 1.6% in the other group (P = .001). A proportionally small, yet statistically significant difference favored the control group regarding anastomotic leakages (.6% versus 0%, P = .004) and unspecified surgical complications (1.4% versus .5%, P = .028)., Conclusion: Gastric bypass with SDD is safe, with no increased risk of short-term severe complications, reoperations, or mortality. However, SDD is associated with a higher 30-day readmission rate compared to patients who stay overnight in the hospital after surgery., (Copyright © 2024 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Currently, there is no marker of efficacy of red blood cell (RBC) transfusion. This study describes the impact of RBC transfusion on mitochondrial oxygen tension (mitoPO 2 ) and mitochondrial oxygen consumption (mitoVO 2 ) in critically ill patients with anemia., Methods: Critically ill patients with a hemoglobin concentration < 10 g/dL, for whom a single RBC unit had been ordered, were included. MitoPO 2 was measured with the COMET device immediately before RBC transfusion, 0.5 h, 1 h, 3 h, and 24 h after RBC transfusion. MitoVO 2 was calculated from dynamic mitoPO 2 measurements during cessation of local oxygen supply., Results: Sixty-three patients participated, median age 64.0 (interquartile range (IQR) 52.3-72.8) years, median hemoglobin concentration before transfusion 7.4 (IQR 7.1-7.7) g/dL. Median mitoPO 2 values were 55.0 (IQR 49.6-63.0) mmHg before RBC transfusion, 51.0 (IQR 41.5-61.2) directly after and 67.3 (IQR 41.6-83.7) at 24 h after RBC transfusion. Median mitoVO 2 values were 3.3 (IQR 2.1-5.9) mmHg/s before RBC transfusion, 3.7 (IQR 2.0-5.1) mmHg/s directly after, and 3.1 (IQR 2.5-4.8) mmHg/s 24 h after RBC transfusion. In the higher Hb concentration group (> 7 g/dL), we saw a dissociation of the effect of RBC transfusion on mitoPO 2 versus on mitoVO 2 values. MitoPO 2 and mitoVO 2 values were not associated with commonly used parameters of tissue perfusion and oxygenation., Conclusion: RBC transfusion did not alter mitoPO 2 and mitoVO 2 in critically ill patients with anemia. MitoPO 2 and mitoVO 2 values were not notably associated with Hb concentrations, parameters of severity of illness and markers of tissue perfusion or oxygenation. Given the high baseline value, it cannot be excluded nor confirmed whether RBC can improve low mitoPO 2 . Trial registration number NCT03092297 (registered 27 March 2017)., (© 2024. The Author(s).)

Objectives: Antiretroviral therapy (ART) accounts for a considerable proportion of HIV care expenses. In June 2021, a Dutch healthcare insurer implemented a mandatory policy to de-simplify branded RPV/TDF/FTC (Eviplera) into a two-tablet regimen containing rilpivirine (Edurant) and generic TDF/FTC as part of cost-saving measures. The objectives of this study were to evaluate the acceptance of this policy, the trends in ART dispensation, and cost developments., Design: A retrospective database study., Methods: In this study, medication dispensation data were obtained from the Dutch Foundation for Pharmaceutical Statistics (SFK). This database covers 98% of all medication dispensations from Dutch pharmacies including people with HIV who receive ART. We received pseudonymized data exclusively from individuals insured by the insurer for the years 2020-2022. Costs were calculated using Dutch drug prices for each year., Results: In June 2021, 128 people with HIV were on branded RPV/TDF/FTC. Following the policy implementation, 59 (46%) had switched to RPV + generic TDF/FTC, but after 1.5 years, only 17 of 128 individuals (13%) used the proposed two-tablet regimen. The other 111/128 used RPV/TDF/FTC with prescriptions for 'medical necessity' ( n  = 29), switched to RPV/TAF/FTC ( n  = 51), or other ART ( n  = 31). Despite expectations of cost-savings, costs increased from €72 988 in May 2021 to €75 649 in May 2022., Conclusion: A mandatory switch from an STR to a TTR in people with HIV proved unsuccessful, marked by low acceptance, and increased costs after 1 year. This underscores the necessity of incorporating patient and prescriber involvement in changing medication policies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Cytochrome P450 (CYP) enzymes play a central role in the elimination of approximately 80% of all clinically used drugs. Differences in CYP enzyme activity between individuals can contribute to interindividual variability in exposure and, therefore, treatment outcome. In vivo CYP enzyme activity could be determined with phenotyping. Currently, (sub)therapeutic doses are used for in vivo phenotyping, which can lead to side effects. The use of microdoses (100 µg) for in vivo phenotyping for CYP enzymes could overcome the limitations associated with the use of (sub)therapeutic doses of substrates. The aim of this review is to provide a critical overview of the application of microdosing for in vivo phenotyping of CYP enzymes. A literature search was performed to find drug-drug interaction studies of CYP enzyme substrates that used microdoses of the respective substrates. A substrate was deemed sensitive to changes in CYP enzyme activity when the pharmacokinetics of the substrate significantly changed during inhibition and induction of the enzyme. On the basis of the currently available evidence, the use of microdosing for in vivo phenotyping for subtypes CYP1A2, CYP2C9, CYP2D6, and CYP2E1 is not recommended. Microdosing can be used for the in vivo phenotyping of CYP2C19 and CYP3A. The recommended microdose phenotyping test for CYP2C19 is measuring the omeprazole area-under-the-concentration-time curve over 24 h (AUC 0-24 ) after administration of a single 100 µg dose. CYP3A activity could be best determined with a 0.1-75 µg dose of midazolam, and subsequently measuring AUC extrapolated to infinity (AUC ∞ ) or clearance. Moreover, there are two metrics available for midazolam using a limited sampling strategy: AUC over 10 h (AUC 0-10 ) and AUC from 2 to 4 h (AUC 2-4 )., (© 2024. The Author(s).)

Acute respiratory infections are a major cause of morbidity and mortality in children worldwide. Dietary and nutritional interventions, including minerals and vitamin supplementation, have been explored as potential treatments for these infections. However, the evidence on their efficacy is limited and inconclusive. This systematic review and meta-analysis aim to provide a comprehensive summary of the available evidence on the effectiveness of dietary and nutritional interventions for treating acute respiratory tract infections in children. A systematic review was conducted according to the PRISMA 2020 guidelines in April 2022 and updated in April 2023. Clinical trials focusing on dietary or nutritional interventions, including supplementations, in children with acute respiratory tract infections were included. The selection of interventions and outcomes was based on biological plausibility. Data were extracted using a standardized form, and the risk of bias was assessed using the Cochrane Risk of Bias Tool. Meta-analysis was performed using random-effect models. A total of 50 studies were included in the review. Four trials were conducted in low, 32 in lower-middle, 12 in upper-middle, and only two in high-income countries. The studies evaluated various dietary interventions, including zinc, vitamin A, vitamin E, vitamin D, and probiotics. The results of individual studies on the efficacy of these interventions were mixed, with some showing positive effects on clinical outcomes such as duration of symptoms, while others showed no significant impact. Meta-analysis was conducted for zinc supplementation in children with pneumonia, and the pooled results suggested a potential limited benefit in terms of reduced hospital length of stay but not time to recovery. Meta-analyses on vitamin D did not show any effect in children with pneumonia. This systematic review fills a critical gap in the literature by synthesizing the available evidence on the efficacy and safety of nutritional or dietary interventions for acute respiratory tract infections in children. The findings indicate no dietary or nutritional intervention can currently be recommended for the routine treatment of respiratory tract infections in children based on single supplement studies. The metanalysis suggests that zinc supplementation might have a beneficial effect on length of hospitalization in children with pneumonia. New studies are needed to establish more conclusive evidence for pediatric acute respiratory diseases especially for children living in a context of high-income countries., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: Thyroid diseases are common in women in their late reproductive years; therefore, thyroid disease and menopause may co-exist. Both conditions may present with a wide range of symptoms, leading to diagnostic challenges and delayed diagnosis. Aim To construct the first European Menopause and Andropause Society (EMAS) statement on thyroid diseases and menopause., Materials and Methods: Literature review and consensus of expert opinion (EMAS executive board members/experts on menopause and thyroid disease)., Summary Recommendations: This position paper highlights the diagnostic and therapeutic dilemmas in managing women with thyroid disease during the menopausal transition, aiming to increase healthcare professionals' awareness of thyroid disorders and menopause-related symptoms. Clinical decisions regarding the treatment of both conditions should be made with caution and attention to the specific characteristics of this age group while adopting a personalized patient approach. The latter must include the family history, involvement of the woman in the decision-making, and respect for her preferences, to achieve overall well-being., Competing Interests: Declaration of competing interest, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Increasing life expectancy in high-income countries has been linked to a rise in fall mortality. In the Netherlands, mortality rates from falls have increased gradually from the 1950s, with some indication of stabilisation in the 1990s. For population health and clinical practice, it is important to foresee the future fall mortality trajectories., Methods: A graphical approach was used to explore trends in mortality by age, calendar period and cohorts born in the periods of 1915-1945. Population data and the numbers of people with accidental fall fatality as underlying cause of death from 1990 to 2021 were derived from Statistics Netherlands. Age-standardised mortality rates of unintentional falls per 100 000 population were calculated by year and sex. A log-linear model was used to examine the separate effects of age, period and cohort on the trend in mortality and to produce estimates of future numbers of fall deaths until 2045., Results: While the total population increased by 17% between 1990 and 2021, absolute numbers of fall-related deaths rose by 230% (from 1584 to 5234), which was 251% (an increase of 576 deaths in 1990 to 2021 deaths in 2020) for men and 219% (from 1008 to 3213) for women. Age-standardised figures were higher for women than men and increased more over time. In 2020, 79% of those with death due to falls were over the age of 80, and 35% were 90 years or older. From 2020 to 2045, the observed and projected numbers of fall deaths were 2021 and 7073 for men (250% increase) and 3213 and 12 575 for women (291% increase)., Conclusion: Mortality due to falls has increased in the past decades and will continue to rise sharply, mainly caused by growing numbers of older adults, especially those in their 80s and 90s. Contributing risk factors are well known, implementation of preventive measures is a much needed next step. An effective approach to managing elderly people after falls is warranted to reduce crowding in the emergency care and reduce unnecessary long hospital stays., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cocaine was the drug of choice in 4.7 % of all recreational drug-related emergency department visits. Of these patients, 40 % present with cocaine-associated chest pain, of whom 4.7 % develop an acute coronary syndrome. The American Heart Association recommends a 12-hour observation period for these patients., Objective: This study primarily aimed to ascertain whether the European Society of Cardiology non-ST-elevation myocardial infarction guidelines can be safely applied to rule-out acute coronary syndrome in low-risk patients with cocaine-associated chest pain., Methods: For this prospective observational cohort study, patients, aged 18-45 years old, who presented with cocaine-associated chest pain and were risk stratified as low risk according to the European Society of Cardiology non-ST-elevation myocardial infarction guidelines and therefore discharged home without prolonged observation period, were included. They were followed to assess major adverse cardiac events four weeks after presentation to the emergency department or chest pain unit. Cocaine use was confirmed with urine toxicology screening., Results: A total of 107 patients were included and analysed. The accuracy of the self-reported history of recent cocaine use was 94 %. Post-discharge cocaine use persisted among 32 % of patients. None of the included 107 patients died and major adverse cardiac event within four weeks did not occur among 97 patients with available data regarding MACE., Conclusion: Ruling out an acute coronary syndrome using the European Society of Cardiology non-ST-elevation myocardial infarction guidelines is likely to be safe for patients with cocaine-associated chest pain, however this study was underpowered to reach definitive conclusions., Competing Interests: 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., (© 2024 The Authors.)

Purpose: The demand for trauma care in the Netherlands is increasing due to a rising incidence of injuries. To provide adequate trauma care amidst this increasing pressure, a Virtual Fracture Care (VFC) review protocol was introduced for treatment of musculoskeletal injuries to the extremities (MIE). This study aimed to assess the influence of the Dutch VFC review protocol on secondary healthcare utilization (i.e., follow-up appointments and imaging) in adult trauma patients (aged ≥18 years) who underwent semi-acute surgery (2-14 days after initial presentation) for MIE, compared to traditional workflows. We hypothesized utilization of VFC review would lead to reduced secondary healthcare utilization., Methods: This retrospective cohort study assessed the influence of VFC review on secondary healthcare utilization in adult trauma patients (aged ≥18 years) who underwent semi-acute surgery for a MIE. Patients treated before VFC review and the COVID-19 pandemic, from 1st of July 2018 to 31st of December 2019, formed a pre-VFC group. Patients treated after VFC review implementation from January 1st 2021 to June 30th 2022, partially during and after the COVID-19 pandemic (including distancing measures), formed a VFC group. Outcomes were follow-up appointments, radiographic imaging, time to surgery, emergency department reattendances, and complications. The study was approved by the local ethical research committee approved this study (WO 23.073)., Results: In total, 2,682 patients were included, consisting of 1,277 pre-VFC patients, and 1,405 VFC patients. Following VFC review, the total number of follow-up appointments reduced by 21% and a shift from face-to-face towards telephone consultations occurred with 19% of follow-up appointments performed by telephone in the VFC group vs. 4% in the pre-VFC group. Additionally, VFC review resulted in a 7% reduction of radiographs, improved time scheduling of surgery, and a 56% reduction of emergency department reattendances. Registered complication rates remained similar., Conclusion: The utilization of VFC review for management of adult patients with a MIE requiring semi-acute surgery improves efficiency compared to traditional workflows. It results in a 21% follow-up appointment reduction, a shift from face-to-face to remote delivery of care, fewer radiographs, improved time scheduling of surgery, and reduces emergency department reattendances by 56%., 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., (© 2024 Willinge, Spierings, Geerdink, Twigt, Goslings and van Veen.)

The Latarjet procedure is a frequently used stabilization procedure in case of anterior shoulder instability with critical glenoid bone loss and/or off-track Hill Sachs lesions. Although uncommon, intra-operative graft fractures do occur. When confronted with this potentially challenging intra-operative complication, having a secondary solution is paramount to achieve a successful outcome. This technical note provides a treatment algorithm that may function as a useful guideline to assist surgeons that experience this potentially complex unintended event during a Latarjet procedure. LEVEL OF EVIDENCE: Level IV, therapeutic case series., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited., Methods: We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses., Results: Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease., Conclusions: In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.)., (Copyright © 2024 Massachusetts Medical Society.)

Objectives: Participation in an external (interlaboratory) quality control (QC) programme is an essential part of quality assurance as it provides laboratories with valuable insights into their analytical performance. We describe the 10 year results of an international QC programme for the measurement of anti-tuberculosis (TB) drugs., Methods: Each year, two rounds were organized in which serum (or plasma) samples, spiked with known concentrations of anti-TB drugs, were provided to participating laboratories for analysis. Reported measurements within 80%-120% of weighed-in concentrations were considered accurate. Mixed model linear regression was performed to assess the effect of the measured drug, concentration level, analytical technique and performing laboratory on the absolute inaccuracy., Results: By 2022, 31 laboratories had participated in the QC programme and 13 anti-TB drugs and metabolites were included. In total 1407 measurements were reported. First-line TB drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) represented 58% of all measurements. Overall, 83.2% of 1407 measurements were accurate, and the median absolute inaccuracy was 7.3% (IQR, 3.3%-15.1%). The absolute inaccuracy was related to the measured anti-TB drug and to the performing laboratory, but not to the concentration level or to the analytical technique used. The median absolute inaccuracies of rifampicin and isoniazid were relatively high (10.2% and 10.9%, respectively)., Conclusions: The 10 year results of this external QC programme illustrate the need for continuous external QC for the measurement of anti-TB drugs for research and patient care purposes, because one in six measurements was inaccurate. Participation in the programme alerts laboratories to previously undetected analytical problems., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: Describing mitochondrial oxygenation (mitoPO2) and its within- and between-subject variability over time after 5-aminolevulinic acid (ALA) plaster application in healthy volunteers., Design: Prospective cohort study., Setting: Measurements were performed in Leiden University Medical Center, the Netherlands., Participants: Healthy volunteers enrolled from July to September 2020., Interventions: Two ALA plasters were placed parasternal left and right, with a 3-hour time interval, to examine the influence of the calendar time on the value of mitoPO2. We measured mitoPO2 at 4, 5, 7, 10, 28, and 31 hours after ALA plaster 1 application, and at 4, 5, 7, 25, and 28 hours after ALA plaster 2 application., Primary and Secondary Outcome Measures: At each time point, five mitoPO2 measurements were performed. Within-subject variability was defined as the standard deviation (SD) of the mean of five measurements per timepoint of a study participant. The between-subject variability was the SD of the mean mitoPO2 value of the study population per timepoint., Results: In 16 completed inclusions, median mitoPO2 values and within-subject variability were relatively similar over time at all time points for both plasters. An increase in overall between-subject variability was seen after 25 hours ALA plaster time (19.6 mm Hg vs 23.9 mm Hg after respectively 10 and 25 hours ALA plaster time)., Conclusions: The mitoPO2 values and within-subject variability remained relatively stable over time in healthy volunteers. An increase in between-subject variability was seen after 25 hours ALA plaster time warranting replacement of the ALA plaster one day after its application., Trial Registration: ClinicalTrials.gov with trial number NCT04626661., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: E.G. Mik is a founder and shareholder of Photonics Healthcare B.V. (Utrecht, The Netherlands). Photonics Healthcare develops and commercializes the COMET measuring system for mitochondrial oxygen measurements. The other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Baysan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Cannabis is the most common recreational drug worldwide and synthetic cannabinoid receptor agonists are currently the largest group of new psychoactive substances. The aim of this study was to compare the clinical features and outcomes of lone acute cannabis toxicity with lone acute synthetic cannabinoid receptor agonist toxicity in a large series of presentations to European emergency departments between 2013-2020., Methods: Self-reported drug exposure, clinical, and outcome data were extracted from the European Drug Emergencies Network Plus which is a surveillance network that records data on drug-related emergency department presentations to 36 centres in 24 European countries. Cannabis exposure was considered the control in all analyses. To compare the lone cannabis and lone synthetic cannabinoid receptor agonist groups, univariate analysis using chi squared testing was used for categorical variables and non-parametric Mann-Whitney U- testing for continuous variables. Statistical significance was defined as a P value of <0.05., Results: Between 2013-2020 there were 54,314 drug related presentations of which 2,657 were lone cannabis exposures and 503 lone synthetic cannabinoid receptor agonist exposures. Synthetic cannabinoid receptor agonist presentations had statistically significantly higher rates of drowsiness, coma, agitation, seizures and bradycardia at the time of presentation. Cannabis presentations were significantly more likely to have palpitations, chest pain, hypertension, tachycardia, anxiety, vomiting and headache., Discussion: Emergency department presentations involving lone synthetic cannabinoid receptor agonist exposures were more likely to have neuropsychiatric features and be admitted to a psychiatric ward, and lone cannabis exposures were more likely to have cardiovascular features. Previous studies have shown variability in the acute toxicity of synthetic cannabinoid receptor agonists compared with cannabis but there is little comparative data available on lone exposures. There is limited direct comparison in the current literature between lone synthetic cannabinoid receptor agonist and lone cannabis exposure, with only two previous poison centre series and two clinical series. Whilst this study is limited by self-report being used to identify the drug(s) involved in the presentations, previous studies have demonstrated that self-report is reliable in emergency department presentations with acute drug toxicity., Conclusion: This study directly compares presentations with acute drug toxicity related to the lone use of cannabis or synthetic cannabinoid receptor agonists. It supports previous findings of increased neuropsychiatric toxicity from synthetic cannabinoid receptor agonists compared to cannabis and provides further data on cardiovascular toxicity in lone cannabis use.

Objectives: Many studies on educational interventions to enhance residents' shared decision-making (SDM) skills show limited improvement in SDM skills and clinical outcomes. One plausible explanation for these suboptimal results is the insufficient emphasis on the educational quality of training interventions., Methods: This review evaluates interventions' educational quality using an evaluation framework based on a previous study on effective skills transfer and a well-known SDM model. A systematic review was conducted, searching three databases until December 13, 2022. We assessed study quality by calculating MERSQI scores, examined the levels of study effects based on Kirkpatrick's model, and applied our evaluation framework to assess the interventions' educational quality. Given the heterogeneity among the studies, a meta-analysis was not feasible., Results: Twenty-six studies were included. Role-play and feedback were common training characteristics (65% and 54% of interventions). Only four studies (15%) met our framework's high educational quality threshold. No correlation was found between MERSQI scores and educational quality., Conclusions: This review is a valuable attempt to assess the educational quality of SDM interventions beyond measuring study outcomes., Practice Implications: Future evaluation frameworks should consider study results, training characteristics, and training content. Our framework offers a sound basis for such an evaluation framework., 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.)

Background: Acute respiratory distress syndrome (ARDS) is characterized by alveolar edema that can progress to septal fibrosis. Mechanical ventilation can augment lung injury, termed ventilator-induced lung injury (VILI). Connective tissue growth factor (CTGF), a mediator of fibrosis, is increased in ARDS patients. Blocking CTGF inhibits fibrosis and possibly vascular leakage. This study investigated whether neutralizing CTGF reduces pulmonary edema in VILI., Methods: Following LPS administration, rats were mechanically ventilated for 6 h with low (6 mL/kg; low V T ) or moderate (10 mL/kg; mod V T ) tidal volume and treated with a neutralizing CTGF antibody (FG-3154) or placebo lgG (vehicle). Control rats without LPS were ventilated for 6 h with low V T . Lung wet-to-dry weight ratio, FITC-labeled dextran permeability, histopathology, and soluble RAGE were determined., Results: VILI was characterized by reduced PaO 2 /FiO 2 ratio (low V T : 540 [381-661] vs. control: 693 [620-754], p < 0.05), increased wet-to-dry weight ratio (low V T : 4.8 [4.6-4.9] vs. control: 4.5 [4.4-4.6], p < 0.05), pneumonia (low V T : 30 [0-58] vs. control: 0 [0-0]%, p < 0.05) and interstitial inflammation (low V T : 2 [1-3] vs. control: 1 [0-1], p < 0.05). FG-3154 did not affect wet-to-dry weight ratio (mod V T  + FG-3154: 4.8 [4.7-5.0] vs. mod V T  + vehicle: 4.8 [4.8-5.0], p > 0.99), extravasated dextrans (mod V T  + FG-3154: 0.06 [0.04-0.09] vs. mod V T  + vehicle: 0.04 [0.03-0.09] µg/mg tissue, p > 0.99), sRAGE (mod V T  + FG-3154: 1865 [1628-2252] vs. mod V T  + vehicle: 1885 [1695-2159] pg/mL, p > 0.99) or histopathology., Conclusions: 'Double hit' VILI was characterized by inflammation, impaired oxygenation, pulmonary edema and histopathological lung injury. Blocking CTGF does not improve oxygenation nor reduce pulmonary edema in rats with VILI., (© 2024. The Author(s).)

Background: The EXPLORE (Evaluating Xience and Left Ventricular Function in PCI on Occlusions After STEMI) trial was the first and only randomized trial investigating chronic total occlusion (CTO) percutaneous coronary intervention (PCI) early after primary PCI for ST-segment-elevation myocardial infarction, compared with medical therapy for the CTO. We performed a 10-year follow-up of EXPLORE to investigate long-term safety and clinical impact of CTO PCI after ST-segment-elevation myocardial infarction, compared with no-CTO PCI., Methods and Results: In EXPLORE, 302 patients post-ST-segment-elevation myocardial infarction with concurrent CTO were randomized to CTO PCI within ≈1 week or no-CTO PCI. We performed an extended clinical follow-up for the primary end point of major adverse cardiac events, consisting of cardiovascular death, coronary artery bypass grafting, or myocardial infarction. Secondary end points included all-cause death, angina, and dyspnea. Median follow-up was 10 years (interquartile range, 8-11 years). The primary end point occurred in 25% of patients with CTO PCI and in 24% of patients with no-CTO PCI (hazard ratio [HR], 1.11 [95% CI, 0.70-1.76]). Cardiovascular mortality was higher in the CTO PCI group (HR, 2.09 [95% CI, 1.10-2.50]), but all-cause death was similar (HR, 1.53 [95% CI, 0.93-2.50]). Dyspnea relief was more frequent after CTO PCI (83% versus 65%, P =0.005), with no significant difference in angina., Conclusions: This 10-year follow-up of patients post-ST-segment-elevation myocardial infarction randomized to CTO PCI or no-CTO PCI demonstrated no clinical benefit of CTO PCI in major adverse cardiac events or overall mortality. However, CTO PCI was associated with a higher cardiovascular mortality compared with no-CTO PCI. Our long-term data support a careful weighing of effective symptom relief against an elevated cardiovascular mortality risk in CTO PCI decisions., Registration: URL: https://www.trialregister.nl; Unique identifier: NTR1108.