Swiss National Science Foundation Research Articles

Decompressive craniectomy plus best medical treatment versus best medical treatment alone for spontaneous severe deep supratentorial intracerebral haemorrhage: a randomised controlled clinical trial.

It is unknown whether decompressive craniectomy improves clinical outcome for people with spontaneous severe deep intracerebral haemorrhage. The SWITCH trial aimed to assess whether decompressive craniectomy plus best medical treatment in these patients improves outcome at 6 months compared to best medical treatment alone. In this multicentre, randomised, open-label, assessor-blinded trial conducted in 42 stroke centres in Austria, Belgium, Finland, France, Germany, the Netherlands, Spain, Sweden, and Switzerland, adults (18-75 years) with a severe intracerebral haemorrhage involving the basal ganglia or thalamus were randomly assigned to receive either decompressive craniectomy plus best medical treatment or best medical treatment alone. The primary outcome was a score of 5-6 on the modified Rankin Scale (mRS) at 180 days, analysed in the intention-to-treat population. This trial is registered with ClincalTrials.gov, NCT02258919, and is completed. SWITCH had to be stopped early due to lack of funding. Between Oct 6, 2014, and April 4, 2023, 201 individuals were randomly assigned and 197 gave delayed informed consent (96 decompressive craniectomy plus best medical treatment, 101 best medical treatment). 63 (32%) were women and 134 (68%) men, the median age was 61 years (IQR 51-68), and the median haematoma volume 57 mL (IQR 44-74). 42 (44%) of 95 participants assigned to decompressive craniectomy plus best medical treatment and 55 (58%) assigned to best medical treatment alone had an mRS of 5-6 at 180 days (adjusted risk ratio [aRR] 0·77, 95% CI 0·59 to 1·01, adjusted risk difference [aRD] -13%, 95% CI -26 to 0, p=0·057). In the per-protocol analysis, 36 (47%) of 77 participants in the decompressive craniectomy plus best medical treatment group and 44 (60%) of 73 in the best medical treatment alone group had an mRS of 5-6 (aRR 0·76, 95% CI 0·58 to 1·00, aRD -15%, 95% CI -28 to 0). Severe adverse events occurred in 42 (41%) of 103 participants receiving decompressive craniectomy plus best medical treatment and 41 (44%) of 94 receiving best medical treatment. SWITCH provides weak evidence that decompressive craniectomy plus best medical treatment might be superior to best medical treatment alone in people with severe deep intracerebral haemorrhage. The results do not apply to intracerebral haemorrhage in other locations, and survival is associated with severe disability in both groups. Swiss National Science Foundation, Swiss Heart Foundation, Inselspital Stiftung, and Boehringer Ingelheim.

Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines—an exploratory sub-study of the BRACE trial

The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E.coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children's. BRACE trial funding is detailed in acknowledgements.

Hepatocellular carcinoma surveillance among people living with hepatitis B in Senegal (SEN-B): insights from a prospective cohort study

Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma in west Africa, yet data on the incidence of HBV-related hepatocellular carcinoma remain scarce. We aimed to describe the uptake and early outcomes of systematic ultrasound-based hepatocellular carcinoma screening in SEN-B, which is a prospective HBV cohort in Senegal. In this prospective cohort study, we included treatment-naive, HBsAg-positive individuals who were referred to the two infectious diseases clinics (the Department of Tropical and Infectious Diseases and Ambulatory Treatment Center) at Fann University Hospital of Dakar, Senegal, between Oct 1, 2019, and Oct 31, 2022. All participants resided within the Dakar region. Participants underwent abdominal ultrasound, transient elastography, and clinical and virological assessments at inclusion and every 6 months. Liver lesions at least 1 cm in diameter on ultrasound were assessed using four-phase CT, MRI, or liver biopsy. Adherence to hepatocellular carcinoma surveillance was measured using the proportion of time covered, calculated by dividing the cumulative months covered by abdominal ultrasound examinations by the overall follow-up time, defined as the number of months from the date of cohort entry until the last recorded visit, hepatocellular carcinoma diagnosis, or death. Optimal adherence was defined as a proportion of time covered of 100%. Overall, 755 (99·6%) of 758 participants had at least one abdominal ultrasound performed. The median age of the enrolled participants was 31 years (IQR 25-39), 355 (47·0%) of 755 participants were women, and 82 (10·9%) had a family history of hepatocellular carcinoma. 15 (2·0%) of 755 individuals were HBeAg positive, 206 (27·3%) of 755 individuals had HBV DNA of more than 2000 IU/mL, and 27 (3·6%) of 755 had elastography-defined liver cirrhosis. Of ten (1·3%) participants with a focal lesion at least 1 cm at initial assessment, CT or MRI ruled out hepatocellular carcinoma in nine, whereas imaging and subsequent liver biopsy confirmed one patient with hepatocellular carcinoma. Two further patients with hepatocellular carcinoma were diagnosed at study presentation due to the presence of portal thrombosis on ultrasound. Excluding the three participants with hepatocellular carcinoma identified at baseline, 752 participants were eligible for screening every 6 months. Median follow-up time was 12 months (IQR 6-18) and the median number of ultrasounds per patient was 3 (2-4). During 809·5 person-years of follow-up, one incident hepatocellular carcinoma was reported, resulting in an incidence rate of 1·24 cases per 1000 person-years (95% CI 0·18-8·80). Overall, 702 (93·0%) of 755 participants showed optimal hepatocellular carcinoma surveillance, but this proportion decreased to 77·8% (42 of 54 participants) after 24 months. Hepatocellular carcinoma screening is feasible in HBV research cohorts in west Africa, but its longer-term acceptability needs to be evaluated. Long-term hepatocellular carcinoma incidence data are crucial for shaping tailored screening recommendations. Swiss National Science Foundation, the Swiss Cancer Research Foundation, the National Cancer Institute, and Roche Diagnostics. For the French translation of the abstract see Supplementary Materials section.

Cognitive enrichment through art: a randomized controlled trial on the effect of music or visual arts group practice on cognitive and brain development of young children

BackgroundThe optimal stimulation for brain development in the early academic years remains unclear. Current research suggests that musical training has a more profound impact on children's executive functions (EF) compared to other art forms. What is crucially lacking is a large-scale, long-term genuine randomized controlled trial (RCT) in cognitive neuroscience, comparing musical instrumental training (MIP) to another art form, and a control group (CG). This study aims to fill this gap by using machine learning to develop a multivariate model that tracks the interconnected brain and EF development during the academic years, with or without music or other art training.MethodsThe study plans to enroll 150 children aged 6-8 years and randomly assign them to three groups: Orchestra in Class (OC), Visual Arts (VA), and a control group (CG). Anticipating a 30% attrition rate, each group aims to retain at least 35 participants. The research consists of three analytical stages: 1) baseline analysis correlating EF, brain data, age, gender, and socioeconomic status, 2) comparison between groups and over time of EF brain and behavioral development and their interactions, including hypothesis testing, and 3) exploratory analysis combining behavioral and brain data. The intervention includes intensive art classes once a week, and incremental home training over two years, with the CG receiving six annual cultural outings.DiscussionThis study examines the potential benefits of intensive group arts education, especially contrasting music with visual arts, on EF development in children. It will investigate how artistic enrichment potentially influences the presumed typical transition from a more unified to a more multifaceted EF structure around age eight, comparing these findings against a minimally enriched active control group. This research could significantly influence the incorporation of intensive art interventions in standard curricula.Trial registrationThe project was accepted after peer-review by the Swiss National Science Foundation (SNSF no. 100014_214977) on March 29, 2023. The study protocol received approval from the Cantonal Commission for Ethics in Human Research of Geneva (CCER, BASEC-ID 2023-01016), which is part of Swiss ethics, on October 25, 2023. The study is registered at clinicaltrials.gov (NCT05912270).

Twin study dissects CXCR3+ memory B cells as non-heritable feature in multiple sclerosis

In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets. In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals. The frequencies of CXCR3+ memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3+ memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their invitro propensity to develop into antibody-secreting cells. Circulating CXCR3+ memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3+ memory B cells mature into antibody-secreting cells to drive MS. This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement no.882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478).

Point-of-care testing and treatment of sexually transmitted and genital infections to improve birth outcomes in high-burden, low-resource settings (WANTAIM): a pragmatic cluster randomised crossover trial in Papua New Guinea

Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and bacterial vaginosis have been associated with adverse maternal and perinatal outcomes, but there is conflicting evidence on the benefits of antenatal screening and treatment for these conditions. We aimed to determine the effect of antenatal point-of-care testing and immediate treatment of C trachomatis, N gonorrhoeae, T vaginalis, and bacterial vaginosis on preterm birth, low birthweight, and other adverse maternal and perinatal outcomes compared with current standard of care, which included symptom-based treatment without laboratory confirmation. In this pragmatic cluster randomised crossover trial, we enrolled women (aged ≥16 years) attending an antenatal clinic at 26 weeks' gestation or earlier (confirmed by obstetric ultrasound), living within approximately 1 h drive of a study clinic, and able to provide reliable contact details at ten primary health facilities and their catchment communities (clusters) in Papua New Guinea. Clusters were randomly allocated 1:1 to receive either the intervention or control (standard care) in the first phase of the trial. Following an interval (washout period) of 2-3 months at the end of the first phase, each cluster crossed over to the other group. Randomisation was stratified by province. Individual participants were informed about trial group allocation only after completing informed consent procedures. The primary outcome was a composite of preterm birth (livebirth before 37 weeks' gestation), low birthweight (<2500 g), or both, analysed according to the intention-to-treat population. This study is registered with ISRCTN Registry, ISRCTN37134032, and is completed. Between July 26, 2017, and Aug 30, 2021, 4526 women were enrolled (2210 [63·3%] of 3492 women in the intervention group and 2316 [62·8%] of 3687 in the control group). Primary outcome data were available for 4297 (94·9%) newborn babies of 4526 women. The proportion of preterm birth, low birthweight, or both, in the intervention group, expressed as the mean of crude proportions across clusters, was 18·8% (SD 4·7%) compared with 17·8% in the control group (risk ratio [RR] 1·06, 95% CI 0·78-1·42; p=0·67). There were 1052 serious adverse events reported (566 in the intervention group and 486 in the control group) among 929 trial participants, and no differences by trial group. Point-of-care testing and treatment of C trachomatis, N gonorrhoeae, T vaginalis, and bacterial vaginosis did not reduce preterm birth or low birthweight compared with standard care. Within the subgroup of women with N gonorrhoeae, there was a substantial reduction in the primary outcome. UK Department of Health and Social Care; UK Foreign, Commonwealth and Development Office; UK Medical Research Council; the Wellcome Trust; the Australian National Health and Medical Research Council; and Swiss National Science Foundation.

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study.

Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on the administration of sulfadoxine-pyrimethamine plus amodiaquine. However, poor regimen adherence and the increased frequency of parasite mutations conferring sulfadoxine-pyrimethamine resistance might threaten the effectiveness of SMC. Guidance is needed to de-risk the development of drug compounds for malaria prevention. We aimed to provide guidance for the early prioritisation of new and alternative SMC drugs and their target product profiles. In this modelling study, we combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic and pharmacodynamic models. We modelled SMC drug attributes for several possible modes of action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum parasite killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions. Model predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When children younger than 5 years receive four SMC cycles with high levels of coverage (ie, 69% of children receiving all cycles), drug candidates require a duration of protection half-life higher than 23 days (elimination half-life >10 days) to achieve reductions higher than 75% in clinical incidence and severe disease (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is crucial to achieve these targets, requiring more than 60% of children to receive all SMC cycles and more than 90% of children to receive at least one cycle regardless of the protection duration of the drug. Although efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determining cycle timing. Explicitly designing or selecting drug properties to increase community uptake is paramount. Bill & Melinda Gates Foundation and the Swiss National Science Foundation.

Strongly Convergent Homogeneous Approximations to Inhomogeneous Markov Jump Processes and Applications

The study of time-inhomogeneous Markov jump processes is a traditional topic within probability theory that has recently attracted substantial attention in various applications. However, their flexibility also incurs a substantial mathematical burden which is usually circumvented by using well-known generic distributional approximations or simulations. This article provides a novel approximation method that tailors the dynamics of a time-homogeneous Markov jump process to meet those of its time-inhomogeneous counterpart on an increasingly fine Poisson grid. Strong convergence of the processes in terms of the Skorokhod J1 metric is established, and convergence rates are provided. Under traditional regularity assumptions, distributional convergence is established for unconditional proxies, to the same limit. Special attention is devoted to the case where the target process has one absorbing state and the remaining ones transient, for which the absorption times also converge. Some applications are outlined, such as univariate hazard-rate density estimation, ruin probabilities, and multivariate phase-type density evaluation. Funding: M. Bladt and O. Peralta would like to acknowledge financial support from the Swiss National Science Foundation Project 200021_191984. O. Peralta acknowledges financial support from NSF Award #1653354 and AXA Research Fund Award on “Mitigating risk in the wake of the pandemic”.

Electronic Nicotine-Delivery Systems for Smoking Cessation

BackgroundElectronic nicotine-delivery systems — also called e-cigarettes — are used by some tobacco smokers to assist with quitting. Evidence regarding the efficacy and safety of these systems is needed.MethodsIn this open-label, controlled trial, we randomly assigned adults who were smoking at least five tobacco cigarettes per day and who wanted to set a quit date to an intervention group, which received free e-cigarettes and e-liquids, standard-of-care smoking-cessation counseling, and optional (not free) nicotine-replacement therapy, or to a control group, which received standard counseling and a voucher, which they could use for any purpose, including nicotine-replacement therapy. The primary outcome was biochemically validated, continuous abstinence from smoking at 6 months. Secondary outcomes included participant-reported abstinence from tobacco and from any nicotine (including smoking, e-cigarettes, and nicotine-replacement therapy) at 6 months, respiratory symptoms, and serious adverse events.ResultsA total of 1246 participants underwent randomization; 622 participants were assigned to the intervention group, and 624 to the control group. The percentage of participants with validated continuous abstinence from tobacco smoking was 28.9% in the intervention group and 16.3% in the control group (relative risk, 1.77; 95% confidence interval, 1.43 to 2.20). The percentage of participants who abstained from smoking in the 7 days before the 6-month visit was 59.6% in the intervention group and 38.5% in the control group, but the percentage who abstained from any nicotine use was 20.1% in the intervention group and 33.7% in the control group. Serious adverse events occurred in 25 participants (4.0%) in the intervention group and in 31 (5.0%) in the control group; adverse events occurred in 272 participants (43.7%) and 229 participants (36.7%), respectively.ConclusionsThe addition of e-cigarettes to standard smoking-cessation counseling resulted in greater abstinence from tobacco use among smokers than smoking-cessation counseling alone. (Funded by the Swiss National Science Foundation and others; ESTxENDS ClinicalTrials.gov number, NCT03589989.)

Development of basic motor competencies and connections with sport participation

Introduction During childhood, children develop their motor competencies. Basic motor competencies (BMC) are a central prerequisite for participation in sport activities (Herrmann et al., 2016) and form the basis for sport-specific skills (Hulteen et al., 2018). In school, children have a choice of formal (e.g. sports club) and informal (free play) settings in which they can engage in sports activities (Neuber &amp; Golenia, 2018). Children who are active in sports clubs have a higher level of BMC (Herrmann et al., 2017). Methods As part of the longitudinal study “Development of basic motor competencies in childhood (EMOKK-study)”, funded by the Swiss National Science Foundation (SNSF), the BMC of N = 659 preschool children (51% boys) and N = 393 1st and 2nd grade children (49.4% boys) were assessed at two measurement points. In addition, parent questionnaires were used to assess the children’s sport participation. In initial analyses, the development of BMC was calculated using ANCOVA, with age as a covariate. Results Differences between girls and boys could be observed in preschool as well as in 1st and 2nd grade. Boys showed better performance in “object-movement” whereas girls were better in “self-movement”. From first to second grade, sports club participation increased (F(1, 467) = 28.546, p &lt; .001, η2 = .058). In both measurement points, boys were more often active in sport clubs than girls. First and second graders who were active in a sports club performed significantly better in both competence areas (“object-movement”: t1: p &lt; .001, d = .42; t2: p &lt; .001, d = .68; “self-movement”: t1: p = .002, d = .38; t2: p = .001, d = .40) than children who were not. Discussion Children who were active in club sports show a higher level of BMC, which seems to persist in the longitudinal section. This indicates an early selection effect and the importance of BMC for club sport. In further analyses, variables on informal sport activities will also be considered.

Exploring Medical Career Choice to Better Inform Swiss Physician Workforce Planning: Protocol for a National Cohort Study.

A medical student's career choice directly influences the physician workforce shortage and the misdistribution of resources. First, individual and contextual factors related to career choice have been evaluated separately, but their interaction over time is unclear. Second, actual career choice, reasons for this choice, and the influence of national political strategies are currently unknown in Switzerland. The overall objective of this study is to better understand the process of Swiss medical students' career choice and to predict this choice. Our specific aims will be to examine the predominately static (ie, sociodemographic and personality traits) and predominately dynamic (ie, learning context perceptions, anxiety state, motivation, and motives for career choice) variables that predict the career choice of Swiss medical school students, as well as their interaction, and to examine the evolution of Swiss medical students' career choice and their ultimate career path, including an international comparison with French medical students. The Swiss Medical Career Choice study is a national, multi-institution, and longitudinal study in which all medical students at all medical schools in Switzerland are eligible to participate. Data will be collected over 4 years for 4 cohorts of medical students using questionnaires in years 4 and 6. We will perform a follow-up during postgraduate training year 2 for medical graduates between 2018 and 2022. We will compare the different Swiss medical schools and a French medical school (the University of Strasbourg Faculty of Medicine). We will also examine the effect of new medical master's programs in terms of career choice and location of practice. For aim 2, in collaboration with the Swiss Institute for Medical Education, we will implement a national career choice tracking system and identify the final career choice of 2 cohorts of medical students who graduated from 4 Swiss medical schools from 2010 to 2012. We will also develop a model to predict their final career choice. Data analysis will be conducted using inferential statistics, and machine learning approaches will be used to refine the predictive model. This study was funded by the Swiss National Science Foundation in January 2023. Recruitment began in May 2023. Data analysis will begin after the completion of the first cohort data collection. Our research will inform national stakeholders and medical schools on the prediction of students' future career choice and on key aspects of physician workforce planning. We will identify targeted actions that may be implemented during medical school and may ultimately influence career choice and encourage the correct number of physicians in the right specialties to fulfill the needs of currently underserved regions. DERR1-10.2196/53138.

Un esempio di mappatura dell’italiano antico: la carta «‑GN‑» del progetto MIRA

Abstract This paper intends to present the first results of the project Mappatura dell’Italo-Romanzo Antico (MIRA) funded by the Swiss National Science Foundation (SNSF) for the period 2022–2026. The project’s main goal is the mapping of the linguistic situation of Italy before the year 1400. We illustrate one type of linguistic map, the one concerned with single linguistic features (such as the reflexes of Latin vowels, consonants, consonant clusters, etc.), using the outcomes of Latin ‑gn‑. We show how the geographic distribution of the various reflexes can be displayed graphically and how the data from our principal source, the Atlante Grammaticale della Lingua Italiana delle Origini (AGLIO) can be integrated with the scrutiny of other texts and with secondary bibliography. Furthermore, we discuss critical points regarding the balance of our corpus – in a diachronic, diatopic and diastratic/diaphasic perspective – and the expediency of different solutions for the visualization of our findings.

Real-world trough concentrations and effectiveness of long-acting cabotegravir and rilpivirine: a multicenter prospective observational study in Switzerland

The efficacy and tolerability of long-acting cabotegravir and rilpivirine were demonstrated in Phase III trials. However, low concentrations combined with other risk factors have been associated with an increased risk of virologic failure. This study aims to verify whether drug concentrations measured in a real-world setting are consistent with those previously reported. SHCS-879 is a nationwide observational study within the Swiss HIV Cohort Study for the monitoring of people with HIV (PWH) on long-acting cabotegravir plus rilpivirine. Samples were collected from March 2022 to March2023. Overall, 725 samples were obtained from 186 PWH. Our data show a large inter-individual variability in cabotegravir and rilpivirine concentrations, with some individuals exhibiting repeatedly low concentrations. Rilpivirine trough concentrations were consistent with those from Phase III trials, while cabotegravir concentrations were lower. The first concentrations quartile was only slightly above the target of 664ng/mL. Exploratory statistical analyses found 35% (p<0·01) lower cabotegravir trough in males compared to females. Overall, 172 PWH (92%) remained suppressed and three experienced virologic failures (1·6%), of those, two had sub-optimal drug exposure. No association was found between low trough levels and detectable viral load. Real-world cabotegravir concentrations are substantially lower than previously reported. However, these concentrations appear sufficient to ensure sustained virological suppression in almost every PWH. These reassuring data challenge the rather conservative thresholds adopted to date, which may raise unnecessary concerns. Yet, our study reveals that some PWH have repeatedly very low drug levels, for reasons that remain to be elucidated. This work was funded by the Swiss National Science Foundation, grant number N◦ 324730_192449. This study received no support from pharmaceutical industries. This study was performed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project #879, and by the SHCS research foundation. The SHCS data were gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers).

Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development

Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors. Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland.

Electrochemical, Microstructural and Mechanical Investigations of H2O2-Driven Degradation of Ti6Al4V

Titanium and its alloys consitute one of the main classes of materials utilized as non-biodegradable implants in the human body. The corrosion resistance of titanium is mainly due to the presence of a thin, compact and passive layer on its surface. However, this layer degrades in the presence of reactive oxygen species, such as oxygen peroxide (H2O2) [1,2]. This leads to the device degradation and the release of its constituents in the surrounding tissues, which may bring about serious health issues (peri-implantitis, osteolysis, neurotoxicity...) [3]. H2O2 is produced by the immune system during inflammatory episodes by specific enzymes, such as NADPH oxidase and superoxide dismutase [4]. It is also utilized by surgeons at high concentrations (ca. 1 M) during peri-implant tissue disinfection. Ti6Al4V (titanium grade 5, an α + β alloy) is a popular implant material because of its excellent mechanical properties. However, in recent years, Ti6Al4V with equiaxed α grains (and β phase located at the grain boundaries) was reported to undergo a significant degradation by H2O2 characterized by the growth of a thick oxide layer on the α grains and the development of porosity and cracks in the β phase [1]. Ti6Al4V could be susceptible to stress corrosion cracking (SCC) under mechanical load due to the β phase dissolution in H2O2-containing physiological solutions (Figure 1). However, no clear link has been established yet between the corrosive environment, the mechanical load and the microstructure of the Ti6Al4V alloy.This contribution will report about the influence of H2O2 concentration on the in vitro corrosion of Ti6Al4V simulating inflammation conditions (low concentration) as well as disinfection procedures (high concentrations). Results on the electrochemical behavior (monitored by impedance spectroscopy), the degraded microstructure (obtained with focused ion beam scanning electron microscopy and transmission electron microscopy) and the impact of the H2O2-driven degradation on the mechanical properties of the alloy will be presented and discussed.Acknowledgements:The authors gratefully acknowledge the financial support of the French National Research Agency (grant agreement ANR-22-CE93-0007-02) and that of the Swiss National Science Foundation (grant agreement 200021L_213161).

SARS-CoV-2 convalescence and hybrid immunity elicits mucosal immune responses

Mucosal antibodies play a key role in the protection against SARS-CoV-2 infection in the upper respiratory tract, and potentially in limiting virus replication and therefore onward transmission. While systemic immunity to SARS-CoV-2 is well understood, we have a limited understanding about the antibodies present on the nasal mucosal surfaces. In this study, we evaluated SARS-CoV-2 mucosal antibodies following previous infection, vaccination, or a combination of both. Paired nasal fluid and serum samples were collected from 143 individuals, which include convalescent, vaccinated, or breakthrough infections. We detected a high correlation between IgG responses in serum and nasal fluids, which were higher in both compartments in vaccinated compared to convalescent participants. Contrary, nasal and systemic SARS-CoV-2 IgA responses were weakly correlated, indicating a compartmentalization between the local and systemic IgA responses. SARS-CoV-2 secretory component IgA (s-IgA) antibodies, present exclusively on mucosal surfaces, were detected in the nasal fluid only in a minority of vaccinated subjects and were significantly higher in previously infected individuals. Depletion of IgA antibodies in nasal fluids resulted in a tremendous reduction of neutralization activity against SARS-CoV-2, indicating that IgA is the crucial contributor to neutralization in the nasal mucosa. Neutralization against SARS-CoV-2 was higher in the mucosa of subjects with previous SARS-CoV-2 infections compared to vaccinated participants. In summary, we demonstrate that currently available vaccines elicit strong systemic antibody responses, but SARS-CoV-2 infection generates higher titers of binding and neutralizing mucosal antibodies. Our results support the importance to develop SARS-CoV-2 vaccines that elicit mucosal antibodies. The work was funded by the COVID-19 National Research Program 78 (grant number 198412) of the Swiss National Science Foundation.

Efficacy and moderators of efficacy of cognitive behavioural therapies with a trauma focus in children and adolescents: an individual participant data meta-analysis of randomised trials

Existing clinical trials of cognitive behavioural therapies with a trauma focus (CBTs-TF) are underpowered to examine key variables that might moderate treatment effects. We aimed to determine the efficacy of CBTs-TF for young people, relative to passive and active control conditions, and elucidate putative individual-level and treatment-level moderators. This was an individual participant data meta-analysis of published and unpublished randomised studies in young people aged 6-18 years exposed to trauma. We included studies identified by the latest UK National Institute of Health and Care Excellence guidelines (completed on Jan 29, 2018) and updated their search. The search strategy included database searches restricted to publications between Jan 1, 2018, and Nov 12, 2019; grey literature search of trial registries ClinicalTrials.gov and ISRCTN; preprint archives PsyArXiv and bioRxiv; and use of social media and emails to key authors to identify any unpublished datasets. The primary outcome was post-traumatic stress symptoms after treatment (<1 month after the final session). Predominantly, one-stage random-effects models were fitted. This study is registered with PROSPERO, CRD42019151954. We identified 38 studies; 25 studies provided individual participant data, comprising 1686 young people (mean age 13·65 years [SD 3·01]), with 802 receiving CBTs-TF and 884 a control condition. The risk-of-bias assessment indicated five studies as low risk and 20 studies with some concerns. Participants who received CBTs-TF had lower mean post-traumatic stress symptoms after treatment than those who received the control conditions, after adjusting for post-traumatic stress symptoms before treatment (b=-13·17, 95% CI -17·84 to -8·50, p<0·001, τ2=103·72). Moderation analysis indicated that this effect of CBTs-TF on post-traumatic stress symptoms post-treatment increased by 0·15 units (b=-0·15, 95% CI -0·29 to -0·01, p=0·041, τ2=0·03) for each unit increase in pre-treatment post-traumatic stress symptoms. This is the first individual participant data meta-analysis of young people exposed to trauma. Our findings support CBTs-TF as the first-line treatment, irrespective of age, gender, trauma characteristics, or carer involvement in treatment, with particular benefits for those with higher initial distress. Swiss National Science Foundation.

Arginine or Hypertonic Saline–Stimulated Copeptin to Diagnose AVP Deficiency

BackgroundDistinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline–stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline–stimulated copeptin in the diagnosis of AVP deficiency.MethodsIn this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline.ResultsOf the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline–stimulated copeptin (estimated difference, −21.2 percentage points; 95% CI, −28.7 to −14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6).ConclusionsAmong adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline–stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.)

“Collaboration with parents isn’t a burden. It’s just a natural part of my work.” - Parental Involvement in Switzerland – An Analysis of Attitudes and Practices of Swiss Primary School Teachers

The subject of home-school relationship is normatively charged and has increasingly become the focal point of pedagogical discourse in the past years. The article reports results of the project “Home-School Cooperation”, which was supported by the Swiss National Science Foundation. This qualitative study examines, how teachers shape their interaction with parents. The main research question is, which habitualised background convictions guide the interaction of teachers with parents. The data was collected in 10 Swiss primary schools. 39 interviews with teachers and headmasters were transcribed for case reconstructions. They were analysed using sequence analysis according to the method of objective hermeneutics (Oevermann, 2000, 2002a) and interpreted in the tradition of the “Deutungsmusteranalyse” (analyses of patterns of interpretation) (Dewe, 1984). We refer to Oevermann’s theory of professionalisation (Oevermann, 1996, 2002b). Main results are: Teacher–parent cooperation differs as follows: active vs. passive focus on action; dominant client focus; the way the school’s interests is enforced on parents. Teachers show three different interpretations on school–family relationship. “Schools and families as unconnected agents of socialization”; “schools and families as disparate actors of socialization” and “cooperation as a partnership in a professionalised work alliance”. Moreover, seven super-individually interaction patterns can be reconstructed.

Efficacy and safety of moxidectin compared with ivermectin against Strongyloides stercoralis infection in adults in Laos and Cambodia: a randomised, double-blind, non-inferiority, phase 2b/3 trial

Infection with the soil-transmitted helminth Strongyloides stercoralis affects up to 600 million people globally, most of whom live in rural areas with poor sanitation. If untreated, infection leads to long-lasting morbidity and might even be life-threatening. Moxidectin might be a promising alternative to ivermectin, the only currently recommended single-dose treatment. We aimed to assess whether moxidectin is non-inferior in terms of efficacy and safety compared with ivermectin. In this randomised, double-blind, parallel-group, non-inferiority, phase 2b/3 trial in communities in Laos and Cambodia, adults aged 18-65 years were screened for the presence of S stercoralis larvae in their stool via sextuplicate quantitative Baermann assays. Using computer-generated group allocation (block randomisation stratified by infection intensity), parasitologically (two or more positive Baermann assays) and clinically eligible participants were randomly assigned (1:1) to receive single oral doses of either moxidectin (8 mg) and ivermectin-matched placebo, or ivermectin (200 μg/kg bodyweight) and moxidectin-matched placebo. The primary endpoint was cure rate assessed at 14-21 days after treatment, using the available-case population analysed according to intention-to-treat principles. Moxidectin was considered non-inferior to ivermectin if the lower limit of the two-sided 95% CI of the difference was greater than the non-inferiority margin of -10 percentage points. Safety endpoints were assessed before treatment, and at 2-3 h, 24 h, and 14-21 days after treatment. This trial is registered at ClinicalTrials.gov, NCT04056325 and NCT04848688. Between Dec 6, 2020, and May 21, 2022, 4291 participants were screened, 726 of whom were enrolled and randomly assigned to moxidectin (n=363) or ivermectin (n=363). For the participants with primary outcome data, we observed a cure rate of 93·6% (95% CI 90·5 to 96·0; 324 of 346 participants) in the moxidectin group and 95·7% (93·0 to 97·6; 335 of 350 participants) in the ivermectin group, resulting in a between-group difference of -2·1 percentage points (95% CI -5·5 to 1·3). The most common adverse events were abdominal pain (32 [9%] of 363 with moxidectin vs 34 [9%] of 363 with ivermectin) and headache (25 [7%] vs 30 [8%]), which were predominantly mild and transient. Moxidectin was non-inferior to ivermectin in terms of efficacy in the treatment of strongyloidiasis. Additionally, both drugs had a similar safety profile. The fixed dose and lower cost of moxidectin compared with ivermectin make it a valuable alternative for people with strongyloidiasis. Swiss National Science Foundation.