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Drug development; Non-alcoholic steatohepatitis; Study designs Desenvolupament de fàrmacs; Esteatohepatitis no alcohòlica; Dissenys d'estudi Desarrollo de fármacos; Esteatohepatitis no alcohólica; Diseños de estudio Background and Aims Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. Methods Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. Results Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. Conclusions PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, ‘proof-of-platform’ at a smaller scale needs to be provided. JMP reports having received consulting fees from Boehringer-Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898. NAdP works for Janssen. QMA is Coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. He reports research Grant Funding: Allergan/Tobira, AstraZeneca, Boehringer-Ingelheim, Glaxo SmithKline, Glympse Bio, Intercept, Novartis Pharma AG, Pfizer Ltd. Consultancy: 89Bio, Abbvie/Allergan, Akero, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer-Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company, Viking Therapeutics. Speaker: Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape. Royalties: Elsevier Ltd. PM works for Novartis. MSK is an employee of and a shareholder in Novo Nordisk A/S. JG has received consulting fees from Boehringer-Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. JRE has received speaking fees from Gilead. FT lab’ work has been supported by the German Research Foundation (DFG, CRC/TR 362) and research grants from Gilead, Allergan, Bristol-Myers Squibb and Inventiva. VR consults for and Intercept, Novo Nordisk, Galmed, Poxel, NGM, Madrigal, Enyo, Sagimet, 89 Bio, Prosciento, Terns, and Theratechnologies, and received grants from Intercept and Gilead.

Non-alcoholic steatohepatitis; Drug development; Non-invasive biomarkers Esteatohepatitis no alcohólica; Desarrollo de fármacos; Biomarcadores no invasivos Esteatohepatitis no alcohòlica; Desenvolupament de medicaments; Biomarcadors no invasius Non-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH. EU-PEARL has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Children’s Tumor Foundation, Global Alliance for TB Drug Development Non-profit Organisation, Springworks Therapeutics Inc.

Tendinopathy and enthesitis share clinical, anatomical, and molecular parallels. However, their relationship is complex, presenting challenges in diagnosis and treatment. The biomechanics underlying these pathologies, together with relative immune and stromal contributions to pathology, are characterised by crucial comparative elements. However, methodologies used to study enthesitis and tendinopathy have been divergent, which could account for discrepancies in how these conditions are perceived and treated. In this Review, we summarise key clinical parallels between these two common presentations in musculoskeletal medicine and address factors that currently preclude development of more effective therapeutics. Furthermore, we describe molecular similarities and disparities that govern pathological mechanisms in tendinopathy and enthesitis, thus informing translational studies and treatment strategies.

The microtubule-associated protein 7 (MAP7) is a protein involved in cargo transport along microtubules (MTs) by interacting with kinesin-1 through the C-terminal kinesin-binding domain. Moreover, the protein is reported to stabilize MT, thereby playing a key role in axonal branch development. An important element for this latter function is the 112 amino-acid long N-terminal microtubule-binding domain (MTBD) of MAP7. Here we report NMR backbone and side-chain assignments that suggest a primarily alpha-helical secondary fold of this MTBD in solution. The MTBD contains a central long α-helical segment that includes a short four-residue ‘hinge’ sequence with decreased helicity and increased flexibility. Our data represent a first step towards analysing the complex interaction of MAP7 with MTs at an atomic level via NMR spectroscopy.

This article combines qualitative and quantitative methods to examine affectivity in discussions on Twitter about the first years of a pilot programme for medicinal cannabis in Denmark. Starting in 2018, the pilot programme has been the object of much public discussion, including on social media. Drawing on data from the platform Twitter and affect theory from Sara Ahmed (2010 , 2014 ), the article uses a combination of computational methods and close readings to locate and analyse which topics in the debate are particularly affectively charged and what the implications of this affectivity are. The article argues that the circulation of affect here is rooted in wider negotiations and hierarchies of knowledge as this relates to medicine and bodies. In particular, ideas and discourses relating to evidence are circulated in the debate as an object of varying articulations of hopes, dreams, and frustration.

Background: Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer’s disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. Objective: To investigate the safety, feasibility, and exploratory measures of efficacy. Methods: This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light. Results: Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: –2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/–2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: –0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo. Conclusion: Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

Objective: To describe the development over time of the use of C-reactive protein (CRP) and rapid streptococcal detection test (RADT) point-of-care tests (POCT) in Danish general practice and to explore associations between patient characteristics and POCT use (i.e. CRP and RADT). Design and settings: A register-based study including all general practice clinic consultations in daytime and out-of-hours (OOH) settings in Denmark between 2003 and 2018. Subjects: All citizens who had at least one clinic consultation in daytime or OOH general practice within the study period. Main outcome measures: We estimated the total and relative use of CRP and RADT POCTs and described the development over time. Crude and adjusted proportion ratios (PRs) were calculated to explore associations between patient characteristics and POCT use. Results: Overall, the relative use of CRP POCTs increased. At OOH, a steep increase was noticed around 2012. The relative use of RADT decreased. Patient age 40–59 years and existing comorbidity were significantly associated with a higher use of CRP testing in both settings. A significantly lower use of CRP testing was found for patients with higher educational level. We found a significantly higher use of RADT testing for patients aged 0–19 years and with higher household educational level, whereas comorbidity was associated with a lower use of RADT testing. Conclusion: The use of CRP POCT increased over time, whereas the use of RADT POCT decreased. Perhaps the success of implementing CRP as a tool for reducing antibiotic use has reached it limit. Future studies should focus on how and when POCT are used most optimal.Key points CRP POC tests and RADT POCTs are frequently used diagnostic tools in general practice, both in daytime and in the out-of-hours setting. There was an increased use of CRP POCTs, particularly in out-of-hours general practice, whereas the use of RADT POCTs declined between 2003 and 2018. CRP POCTs were associated with age of 40–59 years and co-morbidity, while the use of RADT was mostly associated with younger age.

IntroductionPregnancy is a risk factor for severe coronavirus disease 2019 (COVID-19) and adverse pregnancy outcomes. We aimed to explore maternal characteristics, pregnancy outcomes, vaccination status, and virus variants among pregnant women admitted to intensive care units (ICU) with severe COVID-19.Material and methodsWe identified pregnant women admitted to ICU in Sweden (n = 96), Norway (n = 31), and Denmark (n = 16) because of severe COVID-19, from national registers and clinical databases between March 2020 and February 2022 (Denmark), August 2022 (Sweden), or December 2022 (Norway). Their background characteristics, pregnancy outcome, and vaccination status were compared with all birthing women and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test-positive pregnant women during the same time period. We calculated the number admitted to ICU per 10 000 birthing and per 1000 SARS-CoV-2 test-positive women during the Index, Alpha, Delta, and Omicron periods.ResultsWomen admitted to ICU had a higher mean body mass index, were more often of non-Scandinavian origin, had on average lower education and income levels, had a higher proportion of chronic and pregnancy-related conditions, delivered preterm, had neonates with low Apgar scores, and had more infants admitted to neonatal care, compared with all birthing and test-positive pregnant women. Of those admitted to ICU, only 7% had been vaccinated before admission. Overall, the highest proportion of women admitted to ICU per birthing was during the Delta period (4.1 per 10 000 birthing women). In Norway, the highest proportion admitted to ICU per test-positive pregnant women was during the Delta period (17.8 per 1000 test-positive), whereas the highest proportion of admitted per test-positive in Sweden and Denmark was seen during the Index period (15.4 and 8.9 per 1000 test-positive, respectively).ConclusionsAdmission to ICU because of COVID-19 in pregnancy was a rare event in the Scandinavian countries, but women who were unvaccinated, of non-Scandinavian origin, and with lower socio-economic status were at higher risk of admission to ICU. In addition, women admitted to ICU for COVID-19 had higher risk of adverse pregnancy outcomes. INTRODUCTION: Pregnancy is a risk factor for severe coronavirus disease 2019 (COVID-19) and adverse pregnancy outcomes. We aimed to explore maternal characteristics, pregnancy outcomes, vaccination status, and virus variants among pregnant women admitted to intensive care units (ICU) with severe COVID-19.MATERIAL AND METHODS: We identified pregnant women admitted to ICU in Sweden (n = 96), Norway (n = 31), and Denmark (n = 16) because of severe COVID-19, from national registers and clinical databases between March 2020 and February 2022 (Denmark), August 2022 (Sweden), or December 2022 (Norway). Their background characteristics, pregnancy outcome, and vaccination status were compared with all birthing women and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test-positive pregnant women during the same time period. We calculated the number admitted to ICU per 10 000 birthing and per 1000 SARS-CoV-2 test-positive women during the Index, Alpha, Delta, and Omicron periods.RESULTS: Women admitted to ICU had a higher mean body mass index, were more often of non-Scandinavian origin, had on average lower education and income levels, had a higher proportion of chronic and pregnancy-related conditions, delivered preterm, had neonates with low Apgar scores, and had more infants admitted to neonatal care, compared with all birthing and test-positive pregnant women. Of those admitted to ICU, only 7% had been vaccinated before admission. Overall, the highest proportion of women admitted to ICU per birthing was during the Delta period (4.1 per 10 000 birthing women). In Norway, the highest proportion admitted to ICU per test-positive pregnant women was during the Delta period (17.8 per 1000 test-positive), whereas the highest proportion of admitted per test-positive in Sweden and Denmark was seen during the Index period (15.4 and 8.9 per 1000 test-positive, respectively).CONCLUSIONS: Admission to ICU because of COVID-19 in pregnancy was a rare event in the Scandinavian countries, but women who were unvaccinated, of non-Scandinavian origin, and with lower socio-economic status were at higher risk of admission to ICU. In addition, women admitted to ICU for COVID-19 had higher risk of adverse pregnancy outcomes.

Most cholera outbreaks in Bangladesh are seasonal, peaking in the dry and post-monsoon periods. Therefore, we investigated whether changes in water, sanitation, and hygiene (WASH) behavior in three populations in Bangladesh during the year could help explain why these two periods are particular to cholera transmission. The study used a mixed-method design, including a repeated cross-sectional study, focus group discussions, and key informant interviews. Through a repeated cross-sectional study, WASH-related variables were assessed during the dry, monsoon, and control seasons in 600 households from coastal Satkhira, inland Sirajganj, and the Dhaka slums. Seasonal behavioral changes were observed in all study areas. Dhaka and Satkhira had an increased mean distance to water sources during the dry and monsoon seasons (Dhaka: control season, 12 m [95% CI, 11–13]; dry season, 36 m [95% CI, 18–55]; and monsoon season, 180 m [95% CI, 118–243]; Satkhira: control season, 334 m [95% CI, 258–411]; dry season, 669 m [95% CI, 515–822]; and monsoon season, 2,437 m [95% CI, 1,665–3,209]). The participants attributed this to pollution of the usual water source. Perceived water quantity was lowest during the dry season in Dhaka and Sirajganj, and during the monsoon season in Satkhira. Handwashing with soap declined in all areas during the dry and monsoon seasons. Open defecation was frequent among children younger than 5 years, increasing during seasonal climate hazards. Results show that WASH-related behavior changed seasonally, increasing the risk of cholera transmission through multiple hygiene-related transmission pathways. Future research would benefit by ensuring that the length of studies covers all seasons throughout the year and also by looking in more detail at people’s behavior and hygiene practices.

Elisabeth Kjær Jensen,1,* Thomas K Ringsted,1,* Joakim M Bischoff,1 Morten A Petersen,2 Kirsten Møller,3,4 Henrik Kehlet,5 Mads U Werner1,6 1Department of Anaesthesia, Pain and Respiratory Support, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 2Statistical Research Unit, Department of Palliative Care, Bispebjerg Hospital, Copenhagen, Denmark; 3Department of Neuroanaesthesiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 4Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Section for Surgical Pathophysiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 6Department of Clinical Sciences, Lund University, Lund, Sweden*These authors contributed equally to this workCorrespondence: Elisabeth Kjær Jensen, Multidisciplinary Pain Center 7612, Department of Anesthesia, Pain and Respiratory Support, Neuroscience Center, Rigshospitalet, Ole Maaløes Vej 26, Copenhagen N, 2200, Denmark, Tel +45 3545 7612, Email elisabeth.kjaer@live.dkPurpose: After groin hernia repair (globally more than 20 million/year) 2– 4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy.Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory “component” indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8– 11.5) months before and 4.0 (3.5– 4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed.Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of − 2.0, − 2.5, and − 2.0 NRS (0/10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function (“deafferentation”). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001).Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep “pain generator”. The QST-analyses are useful adjuncts in mechanism-based somatosensory research.Keywords: groin, hernia repair, chronic post-surgical pain, reoperation, sensory thresholds

BackgroundLong-term cognitive impairment occurs in up to 60% of intensive care unit (ICU) survivors. Early use of functional and cognitive rehabilitation interventions, while patients are still in ICU, may reduce cognitive decline. We aim to describe the functional and cognitive interventions used during the ICU stay, the healthcare professionals providing interventions, and the potential impact on functional and cognitive rehabilitation.MethodIn this integrative systematic review, we will include empirical qualitative, quantitative, mixed- and multiple-methods studies assessing the use of functional and cognitive rehabilitation provided in ICU. We will identify studies in relevant electronic databases from 2012 to 2022, which will be screened for eligibility by at least two reviewers. Literature reported as narrative reviews and editorials will be excluded. We will assess the impact of interventions evaluating a cognitive and functional function, quality of life, and all-cause mortality at 6–12 months after ICU discharge. The Revised Cochrane risk-of-bias Tool will be used for assessing risk of bias in clinical trials. For observational studies, we will use the National Institutes of Health Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. Furthermore, we will use the critical appraisal skills programme for qualitative studies and the mixed methods appraisal tool for mixed methods studies. We will construct four matrices, including results describing which ICU patients and healthcare professionals were engaged in rehabilitation, which interventions were included in early rehabilitation in ICU, the potential impact on patient outcomes of rehabilitation interventions provided in ICU and a narrative synthesis of themes. A summary of the main results will be reported using modified GRADE methodology.ImpactThis integrative review will inform the feasibility randomised clinical trial testing the development of a complex intervention targeting functional and cognitive rehabilitation for patients in ICU. Background: Long-term cognitive impairment occurs in up to 60% of intensive care unit (ICU) survivors. Early use of functional and cognitive rehabilitation interventions, while patients are still in ICU, may reduce cognitive decline. We aim to describe the functional and cognitive interventions used during the ICU stay, the healthcare professionals providing interventions, and the potential impact on functional and cognitive rehabilitation. Method: In this integrative systematic review, we will include empirical qualitative, quantitative, mixed- and multiple-methods studies assessing the use of functional and cognitive rehabilitation provided in ICU. We will identify studies in relevant electronic databases from 2012 to 2022, which will be screened for eligibility by at least two reviewers. Literature reported as narrative reviews and editorials will be excluded. We will assess the impact of interventions evaluating a cognitive and functional function, quality of life, and all-cause mortality at 6–12 months after ICU discharge. The Revised Cochrane risk-of-bias Tool will be used for assessing risk of bias in clinical trials. For observational studies, we will use the National Institutes of Health Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. Furthermore, we will use the critical appraisal skills programme for qualitative studies and the mixed methods appraisal tool for mixed methods studies. We will construct four matrices, including results describing which ICU patients and healthcare professionals were engaged in rehabilitation, which interventions were included in early rehabilitation in ICU, the potential impact on patient outcomes of rehabilitation interventions provided in ICU and a narrative synthesis of themes. A summary of the main results will be reported using modified GRADE methodology. Impact: This integrative review will inform the feasibility randomised clinical trial testing the development of a complex intervention targeting functional and cognitive rehabilitation for patients in ICU.

The high performance of platinum-tin catalysts for oxidation reactions has been linked to the formation of tin oxides at the metal surface, but little is known about the structure of these oxides or the chemical behavior that determines their catalytic properties. We show here how surface oxides on Pt3Sn(111) incorporate oxygen at the metal interface, which may be subsequently removed by reaction with CO. The storage mechanism, where oxygen uptake occurs without loss of interfacial Pt-Sn bonds, is enabled by the peculiar asymmetrical coordination state of Sn2+. O atoms are bound at pocket sites in the 2D oxide sheet between these outward-buckled Sn atoms and metallic Sn in the alloy surface below.

Background: The increasing aging population and limited health care resources have placed new demands on the healthcare sector. Reducing the number of hospitalizations has become a political priority in many countries, and special focus has been directed at potentially preventable hospitalizations. Objectives: We aimed to develop an artificial intelligence (AI) prediction model for potentially preventable hospitalizations in the coming year, and to apply explainable AI to identify predictors of hospitalization and their interaction. Methods: We used the Danish CROSS-TRACKS cohort and included citizens in 2016-2017. We predicted potentially preventable hospitalizations within the following year using the citizens' sociodemographic characteristics, clinical characteristics, and health care utilization as predictors. Extreme gradient boosting was used to predict potentially preventable hospitalizations with Shapley additive explanations values serving to explain the impact of each predictor. We reported the area under the receiver operating characteristic curve, the area under the precision-recall curve, and 95% confidence intervals (CI) based on five-fold cross-validation. Results: The best performing prediction model showed an area under the receiver operating characteristic curve of 0.789 (CI: 0.782-0.795) and an area under the precision-recall curve of 0.232 (CI: 0.219-0.246). The predictors with the highest impact on the prediction model were age, prescription drugs for obstructive airway diseases, antibiotics, and use of municipality services. We found an interaction between age and use of municipality services, suggesting that citizens aged 75+ years receiving municipality services had a lower risk of potentially preventable hospitalization. Conclusion: AI is suitable for predicting potentially preventable hospitalizations. The municipality-based health services seem to have a preventive effect on potentially preventable hospitalizations.

BackgroundVolunteer responder (VR) programs for activation of laypersons in out-of-hospital cardiac arrest (OHCA) have been deployed worldwide, but the optimal number of VRs to dispatch is unknown.ObjectivesThe purpose of this study was to investigate the association between the number of VRs arriving before Emergency Medical Services (EMS) and the proportion of bystander cardiopulmonary resuscitation (CPR) and defibrillation.MethodsWe included OHCAs not witnessed by EMS with VR activation from the Capital Region (September 2, 2017, to May 14, 2019) and the Central Region of Denmark (November 5, 2018, to December 31, 2019). We created 4 groups according to the number of VRs arriving before EMS: 0, 1, 2, and 3 or more. Using a logistic regression model adjusted for EMS response time, we examined associations between the number of VRs arriving before EMS and bystander CPR and defibrillation.ResultsWe included 906 OHCAs. The adjusted ORs for bystander CPR were 2.40 (95% CI: 1.42-4.05), 3.18 (95% CI: 1.39-7.26), and 2.70 (95% CI: 1.32-5.52) when 1, 2, or 3 or more VRs arrived before EMS (reference), respectively. The adjusted OR for bystander defibrillation increased when 1 (1.97 [95% CI: 1.12-3.52]), 2 (2.88 [95% CI: 1.48-5.58]), or 3 or more (3.85 [95% CI: 2.11-7.01]) VRs arrived before EMS (reference). The adjusted OR of bystander defibrillation increased to 1.95 (95% CI: 1.18-3.22) when ≥3 VRs arrived first compared with 1 VR arriving first (reference).ConclusionsWe found an association of increased bystander CPR and defibrillation when 1 or more VRs arrived before the EMS with a trend toward increased bystander defibrillation with increasing number of VRs arriving first. BACKGROUND Volunteer responder (VR) programs for activation of laypersons in out-of-hospital cardiac arrest (OHCA) have been deployed worldwide, but the optimal number of VRs to dispatch is unknown.OBJECTIVES The purpose of this study was to investigate the association between the number of VRs arriving before Emergency Medical Services (EMS) and the proportion of bystander cardiopulmonary resuscitation (CPR) and defibrillation.METHODS We included OHCAs not witnessed by EMS with VR activation from the Capital Region (September 2, 2017, to May 14, 2019) and the Central Region of Denmark (November 5, 2018, to December 31, 2019). We created 4 groups according to the number of VRs arriving before EMS: 0,1, 2, and 3 or more. Using a logistic regression model adjusted for EMS response time, we examined associations between the number of VRs arriving before EMS and bystander CPR and defibrillation.RESULTS We included 906 OHCAs. The adjusted ORs for bystander CPR were 2.40 (95% CI: 1.42-4.05), 3.18 (95% CI: 1.39-7.26), and 2.70 (95% CI: 1.32-5.52) when 1, 2, or 3 or more VRs arrived before EMS (reference), respectively. The adjusted OR for bystander defibrillation increased when 1 (1.97 [95% CI: 1.12-3.52]), 2 (2.88 [95% CI: 1.48-5.58]), or 3 or more (3.85 [95% CI: 2.11-7.01]) VRs arrived before EMS (reference). The adjusted OR of bystander defibrillation increased to 1.95 (95% CI: 1.18-3.22) when $3 VRs arrived first compared with 1 VR arriving first (reference).CONCLUSIONS We found an association of increased bystander CPR and defibrillation when 1 or more VRs arrived before the EMS with a trend toward increased bystander defibrillation with increasing number of VRs arriving first. (J Am Coll Cardiol 2023;81:668-680)(c) 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/

Iridium nanoparticles are important catalysts for several chemical and energy conversion reactions. Studies of iridium nanoparticles have also been a key for the development of kinetic models of nanomaterial formation. However, compared to other metals such as gold or platinum, knowledge on the nature of prenucleation species and structural insights into the resultant nanoparticles are missing, especially for nanoparticles obtained from IrxCly precursors investigated here. We use in situ X-ray total scattering (TS) experiments with pair distribution function (PDF) analysis to study a simple, surfactant-free synthesis of colloidal iridium nanoparticles. The reaction is performed in methanol at 50 °C with only a base and an iridium salt as precursor. From different precursor salts─IrCl3, IrCl4, H2IrCl6, or Na2IrCl6─colloidal nanoparticles as small as Ir∼55 are obtained as the final product. The nanoparticles do not show the bulk iridium face-centered cubic (fcc) structure but show decahedral and icosahedral structures. The formation route is highly dependent on the precursor salt used. Using IrCl3 or IrCl4, metallic iridium nanoparticles form rapidly from IrxClyn- complexes, whereas using H2IrCl6 or Na2IrCl6, the iridium nanoparticle formation follows a sudden growth after an induction period and the brief appearance of a crystalline phase. With H2IrCl6, the formation of different Irn (n = 55, 55, 85, and 116) nanoparticles depends on the nature of the cation in the base (LiOH, NaOH, KOH, or CsOH, respectively) and larger particles are obtained with larger cations. As the particles grow, the nanoparticle structure changes from partly icosahedral to decahedral. The results show that the synthesis of iridium nanoparticles from IrxCly is a valuable iridium nanoparticle model system, which can provide new compositional and structural insights into iridium nanoparticle formation and growth.

Constant current charging and discharging is widely used nowadays for commercial lithium (Li) ion batteries (LIBs) in applications of portable electronic devices and electric vehicles. However, the main battery degradation mechanism during constant current cycling remains unclear. In this work, electrochemical cycling, real-time temperature monitoring, and operando electrochemical impedance spectroscopy of a fresh and an aged battery have been carried out to unveil the aging mechanism during constant current cycling. The results of the incremental capacity analysis (ICA) indicate that polarization is the main reason for the capacity fading during operation. Besides, post-mortem analysis of the electrodes reveals that the formation of a solid-electrolyte interphase (SEI) and cathode-electrolyte interphase (CEI) is the leading cause of electrode degradation. The interface formation and evolution over cycling (including thickening and chemical variation) leads to continuous loss of active materials. The presence of a SEI and CEI also increases the impedance for charge transfer and transport and reduces the kinetics of electrochemical Li-ion redox on the electrodes. Moreover, the irreversible Li loss due to Li plating and SEI formation has been quantified, which accounts for 16.8% of the total Li in the battery. This work provides a mechanistic understanding of the degradation mechanism of commercial LIBs, guides the rational design of commercial batteries and inspires the design of charging and discharging protocols toward enhanced cycling stability and prolonged cycle life.

Pretargeting imaging has gained a lot of prominence, due to its excellent bioorthogonality and improved imaging contrast compared to conventional imaging. A new iodo tetrazine (Tz) derivative has been synthesized and further developed into the corresponding iodine-125 ( 125 I) analog (12), via the trimethylstannane precursor. Radiolabeling with either N-chlorosuccinimide or chloramine-T, in either MeCN or MeOH proceeded with a radiochemical conversion (RCC) of >80%. Subsequent deprotection only proved successful, among the tested conditions, when the radiolabeled Tz was stirred in 6-M HCl (aq.) at 60°C for 2.5 h. To the best of our knowledge, this is the first H-tetrazine labeled with iodine. In vivo investigations on the pretargeting ability of 12 are currently under way.

BACKGROUND: Patient and public involvement in randomised clinical trials has received increased focus, including in intensive care trials, but the frequency, method and extent is unknown. This meta-epidemiological study investigated patient and public involvement in contemporary, large ICU trials.METHODS: We systematically searched PubMed for large (≥225 randomised patients), contemporary trials (published between 1 January 2019 and 31 January 2022) assessing interventions in adult patients in ICU settings. Abstracts and full-text articles were assessed independently and in duplicate. Data were extracted using a pre-defined, pilot-tested data extraction form with details on trials, patient and public involvement including categories and numbers of individuals involved, methods of involvement, and trial stage(s) with involvement. Trials authors were contacted as necessary.RESULTS: We included 100 trials, with 18 using patient and public involvement; these were larger and conducted in more centres than trials without patient and public involvement. Among trials with patient and public involvement, patients (in 14/18 trials), clinicians (13 trials), and family members (12 trials) were primarily involved, mainly in the development of research design (15 trials) and development of research focus (13 trials) stages and mostly by discussion (12 trials) and solo interviews (10 trials). A median of 65 individuals (range 1-6894) were involved.CONCLUSIONS: We found patient and public involvement in a fifth of large, contemporary ICU trials. Primarily patients, families, and clinicians were included, particularly in the trial planning stages and mostly through interviews and discussions. Increased patient and public involvement in ICU trials is warranted.

Aims Emerging data show that complete revascularization (CR) reduces cardiovascular death and recurrent myocardial infarction in ST-segment elevation myocardial infarction (STEMI). However, the influence of revascularization status on development of arrhythmia in the long-term post-STEMI phase is poorly described. We hypothesized that incomplete revascularization (ICR) compared with CR in STEMI is associated with an increased long-term risk of new-onset arrhythmia. Methods and results Patients with STEMI treated with primary percutaneous coronary intervention (PPCI) at Copenhagen University Hospital, Rigshospitalet, Denmark, with CR or ICR were identified via the Eastern Danish Heart registry from 2009 to 2016. Using unique Danish administrative registries, the outcomes were assessed. The primary outcome was new-onset arrhythmia defined as a composite of atrial fibrillation/flutter (AF), sinoatrial block, advanced second- or third-degree atrioventricular block, ventricular tachycardia/fibrillation (VT), or cardiac arrest (CA), with presentation >7 days post-PPCI. Secondary outcomes were the components of the primary outcome and all-cause mortality. A total of 5103 patients (median age: 62.0 years; 76% men) were included, of whom 4009 (79%) and 1094 (21%) patients underwent CR and ICR, respectively. Compared with CR, ICR was associated with a higher risk of new-onset arrhythmia [hazard ratio (HR), 1.33; 95% confidence interval (CI), 1.07–1.66; P = 0.01], AF (HR, 1.29; 95% CI, 1.00–1.66; P = 0.05), a combined outcome of VT and CA (HR, 1.77; 95% CI, 1.10–2.84; P = 0.02) and all-cause mortality (HR, 1.27; 95% CI, 1.05–1.53; P = 0.01). All HRs adjusted. Conclusion Among patients with STEMI, ICR was associated with an increased long-term risk of new-onset arrhythmia and all-cause mortality compared with CR.

To determine if prior HPV vaccination contributes to preterm birth risk.Population-based retrospective cohort study.Denmark.243 136 primiparous females born 1961-2004 who had a singleton delivery at22 weeks' gestation occurring in October 2006 to December 2018.High-quality nationwide registries were linked to provide information on demographics, birth outcomes, HPV vaccination status, smoking, BMI, and cervical lesions and treatment history.We assessed the association between HPV vaccination status and spontaneous preterm birth using logistic regression. To address age at vaccination, we performed a stratified analysis by vaccination before and after 17 years old.In age-adjusted and fully-adjusted models, there was a non-significant difference in the odds of spontaneous preterm birth between vaccinated and unvaccinated women (OR: 1.05 [95% CI: 0.99-1.12] and 1.04 [95% CI: 0.98-1.10], respectively). There was no difference in the odds of spontaneous preterm birth in relation to time between vaccination and pregnancy. In contrast, compared to unvaccinated women, the odds of preterm birth were lower among women vaccinated before age 17 (fully-adjusted OR: 0.87, 95% CI: 0.75-1.00). This association was not present for women vaccinated at age17.In this large, population-based cohort, we found reduced odds of spontaneous preterm birth among women HPV vaccinated at an early age compared to those unvaccinated. It seems conceivable that HPV vaccination may not only reduce the incidence of cervical cancer and severe precursors, but also the risk of preterm birth related to HPV infection.

BACKGROUND: Previous studies have reported that epileptiform activity may be detectible in nearly half of patients with Alzheimer's disease (AD) on long-term electroencephalographic (EEG) recordings. However, such recordings can be uncomfortable, expensive, and difficult. Ear-EEG has shown promising results for long-term EEG monitoring, but it has not been used in patients with AD.OBJECTIVE: To investigate if ear-EEG is a feasible method for long-term EEG monitoring in patients with AD.METHODS: In this longitudinal, single-group feasibility study, ten patients with mild to moderate AD were recruited. A total of three ear-EEG recordings of up to 48 hours three months apart for six months were planned.RESULTS: All patients managed to wear the ear-EEG for at least 24 hours and at least one full night. A total of 19 ear-EEG recordings were performed (self-reported recording, mean: 37.15 hours (SD: 8.96 hours)). After automatic pre-processing, a mean of 27.37 hours (SD: 7.19 hours) of data with acceptable quality in at least one electrode in each ear was found. Seven out of ten participants experienced mild adverse events. Six of the patients did not complete the study with three patients not wanting to wear the ear-EEG anymore due to adverse events.CONCLUSION: It is feasible and safe to use ear-EEG for long-term EEG monitoring in patients with AD. Minor adjustments to the equipment may improve the comfort for the participants.

Days Alive and Out of Hospital (DAOH) is a recently introduced, readily obtainable postoperative outcome measure method that expresses procedure and disease-associated morbidity and mortality. In this study, we evaluated DAOH with 30- and 365-days follow-up periods after primary surgery (DAOHThis retrospective cohort study from a prospective collected database represents patients from Eastern Denmark surgically treated for primary OSCC in the period 2000-2014. DAOHWe included 867 patients (63% males, median age: 63 years (IQR 56-70 years)). Median DAOHIn this population-based study in OSCC patients treated with primary surgery, we found that DAOH after 30 days was 25 days (83%), while DAOH after 365 days was 356 days (98%). Advanced T-stage acts as a predictor for significant DAOH

In the western context, law has two functions. It upholds normative expectations and it transforms social phenomena. The latter is expressed through the form-giving function of law, as law designates particular social phenomena, such as, for example, economic, political or religious. Inside such overarching categories, further subcategories can moreover be observed. In relation to economic processes, the legal institutions of competition, contract, corporation and property are, for example, classical examples of the form-giving function of law. The dual function of law is briefly illustrated through a genealogy of imaginaries of law distinguishing between four historically dominant types of law: ‘Law as purpose’; ‘law as a tool’; ‘law as an obstacle’; and ‘law as reflexivity-initiation’. On this background, ten core dimensions of what might become a new episteme of transformative law are fleshed out with the aim of answering the question to what extent it can act as an alternative to the previous four types of law.

The functionality of industrial refrigeration systems is important for environment-friendly companies and organizations, since faulty systems can impact human health by lowering food quality, cause pollution, and even lead to increased global warming. Therefore, in this industry, there is a high demand among manufacturers for early and automatic fault diagnosis. In this paper, different machine learning classifiers are tested to find the best solution for diagnosing twenty faults possibly encountered in such systems. All sensor faults and some relevant component faults are simulated in a high fidelity Matlab/Simscape model of the system, which has previously been used for controller development and verification. In this work, Convolutional Neural Networks, Support Vector Machines (SVM), Principal Components Analysis-SVM, Linear Discriminant Analysis-SVM, and Linear Discriminant Analysis classifiers are compared. The results indicate that the fault detection reliability of the algorithms highly depends on how well the training data covers the operation regime. Furthermore, it is found that a well-trained SVM can simultaneously classify twenty types of fault with 95% accuracy when the verification data is taken from different system configurations.

BACKGROUND: The functional status of immune cells in the tumor microenvironment and tumor characteristics may explain bacillus Calmette-Guérin (BCG) failure in high-risk non-muscle-invasive bladder cancer (NMIBC).OBJECTIVE: To characterize molecular correlates of post-BCG high-grade (HG) recurrence using multiomics analysis.DESIGN, SETTING, AND PARTICIPANTS: Patients with BCG-treated NMIBC (n = 156) were included in the study. Metachronous tumors were analyzed using RNA sequencing (n = 170) and whole-exome sequencing (n = 195). Urine samples were analyzed for immuno-oncology-related proteins (n = 190) and tumor-derived DNA (tdDNA; n = 187).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was post-BCG HG recurrence. Cox regression and Wilcoxon rank-sum, t, and Fisher's exact tests were used for analyses.RESULTS AND LIMITATIONS: BCG induced activation of the immune system regardless of clinical response; however, immunoinhibitory proteins were observed in the urine of patients with post-BCG HG recurrence (CD70, PD1, CD5). Post-BCG HG recurrence was associated with post-BCG T-cell exhaustion (p = 0.002). Pre-BCG tumors from patients with post-BCG T-cell exhaustion had high expression of genes related to cell division and immune function. A high predicted post-BCG exhaustion score for pre-BCG tumors was associated with worse post-BCG HG recurrence-free survival (HGRFS; p = 0.002). This was validated in independent cohorts. Pre-BCG class 2a and 2b tumors (UROMOL2021 scheme) were associated with worse post-BCG HGRFS (p = 0.015). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p = 0.017) and MUC4 mutations (p = 0.002). Finally, the absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p = 0.018). The retrospective design and partial overlap for analyses are study limitations.CONCLUSIONS: Post-BCG HG recurrence may be caused by T-cell exhaustion. Tumor subtype and pre-BCG tumor characteristics may identify patients at high risk of post-BCG HG recurrence. Urinary measurements have potential for real-time assessment of treatment response.PATIENT SUMMARY: A dysfunctional immune response to bacillus Calmette-Guérin (BCG) therapy may explain high-grade recurrences of bladder cancer.

Evidence regarding cancer risk after borderline ovarian tumors (BOTs) is limited. We conducted a nationwide cohort study examining the incidence of nonovarian cancers in women with serous or mucinous BOTs compared with the general female population with up to 41 years of follow-up. Through the nationwide Pathology Registry, we identified nearly 5000 women with BOTs (2506 serous and 2493 mucinous) in Denmark, 1978 to 2018. We computed standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) as relative risk estimates of specific nonovarian cancers. Compared with general female population rates, women with serous BOTs had increased rates of particularly malignant melanoma (SIR = 1.9; 95% CI: 1.3-2.6), thyroid cancer (SIR = 3.0; 95% CI: 1.4-5.4) and myeloid leukemia (SIR = 3.2; 95% CI: 1.5-5.8), and women with mucinous BOTs had elevated rates of lung cancer (SIR = 1.7; 95% CI: 1.3-2.1), pancreatic cancer (SIR = 1.9; 95% CI: 1.2-2.9) and myeloid leukemia (SIR = 2.3; 95% CI: 0.9-4.7). We found no convincing association with neither breast nor colorectal cancer in women with BOTs. This is the first large nationwide study showing that women with specific types of BOTs have increased risks of several nonovarian cancers, likely due to some shared risk factors or genetic characteristics.

Despite structural and cultural similarities across the Nordic countries, differences in cancer survival remain. With a focus on similarities and differences between the Nordic countries, we investigated the association between socioeconomic position (SEP) and stage at diagnosis, anticancer treatment and cancer survival to describe patterns, explore underlying mechanisms and identify knowledge gaps in the Nordic countries.We conducted a systematic review of population based observational studies. A systematic search in PubMed, EMBASE and Medline up till May 2021 was performed, and titles, abstracts and full texts were screened for eligibility by two investigators independently. We extracted estimates of the association between SEP defined as education or income and cancer stage at diagnosis, received anticancer treatment or survival for adult patients with cancer in the Nordic countries. Further, we extracted information on study characteristics, confounding variables, cancer type and results in the available measurements with corresponding confidence intervals (CI) and/or p-values. Results were synthesized in forest plots.From the systematic literature search, we retrieved 3629 studies, which were screened for eligibility, and could include 98 studies for data extraction. Results showed a clear pattern across the Nordic countries of socioeconomic inequality in terms of advanced stage at diagnosis, less favorable treatment and lower cause-specific and overall survival among people with lower SEP, regardless of whether SEP was measured as education or income.Despite gaps in the literature, the consistency in results across cancer types, countries and cancer outcomes shows a clear pattern of systematic socioeconomic inequality in cancer stage, treatment and survival in the Nordic countries. Stage and anticancer treatment explain some, but not all of the observed inequality in overall and cause-specific survival. The need for further studies describing this association may therefore be limited, warranting next step research into interventions to reduce inequality in cancer outcomes.Prospero protocol no: CRD42020166296.

ContextSupraphysiological serum insulin-like growth factor-I (IGF-I) concentrations have been a matter of concern in children treated with GH because high IGF-I levels were associated with risk of later disease in former epidemiological studies.ObjectiveTo determine whether a single IGF-I measurement reliably reflects lifetime IGF-I exposure we evaluated intraindividual longitudinal tracking of IGF-I and IGF-binding protein-3 (IGFBP-3) levels and we estimated cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals.MethodsWe included 6459 healthy participants (cross-sectional = 5326; longitudinal = 1133) aged 0-76 years (9963 serum samples) and 9 patients born small-for-gestational-age (SGA) with 238 serum samples during GH treatment. Intraindividual tracking of IGF-I and IGFBP-3 (SD score [SDS]) was determined by intraclass correlation coefficients (ICCs). Cumulative lifetime IGF-I exposure was estimated by area under the curve of the predicted SDS trajectory from 0 to 76 years.ResultsFor IGF-I (SDS), ICCs were 0.50 (95% CI, 0.47-0.53) for male and 0.53 (0.50-0.56) for female participants. Lifetime IGF-I exposure was significantly higher in female (mean 12 723 ± 3691 SD) than in male participants (12 563 ± 3393); P = 0.02. In SGA children, treatment with GH increased the lifetime exposure to IGF-I from 9512 ± 1889 to 11 271 ± 1689, corresponding to an increase in lifetime IGF-I trajectory from −0.89 SD ± 0.57 to −0.35 SD ± 0.49.ConclusionBecause IGF-I and IGFBP-3 levels track throughout life, a single measurement reliably reflects lifetime exposure. GH therapy increased the lifetime exposure to IGF-I only slightly and it remained below the average lifetime exposure in the reference population.