Swiss National Research Articles

Which experimental factors govern successful animal-to-human translation in multiple sclerosis drug development? A systematic review and meta-analysis

Despite successes in multiple sclerosis (MS) drug development, the effectiveness of animal studies in predicting successful bench-to-bedside translation is uncertain. Our goal was to identify predictors of successful animal-to-human translation for MS by systematically comparing animal studies of approved disease-modifying therapies (DMTs) with those that failed in clinical trials due to efficacy or safety concerns. Systematic review of animal studies testing MS DMTs, identified from searches in PubMed and EMBASE. A random effect meta-analysis was fitted to the data to compare outcome effect sizes for approved versus failed DMTs. Effect sizes and testing under diverse experimental conditions were assessed as potential predictors for successful translation. We included 497 animal studies, covering 15 approved and 11 failed DMTs, tested in approximately 30'000 animals. DMTs were tested in a small repertoire of experimental parameters: about 86% of studies used experimental autoimmune encephalomyelitis (EAE), 80% used mice, and 76% used female animals. There was no association between animal study outcomes or testing DMTs under varied conditions (e.g., different laboratories or models) and successful approval. Surprisingly, 91% of animal studies were published after first-in-MS trial and 91% after official regulatory approval. Our findings emphasize the complexity in carrying drugs from animals to clinical practice. Specific challenges include limited experimental methods in animal research and a disconnect between preclinical and clinical research. We advocate for efforts to streamline drug development for MS to improve animal research's relevance for patients. NIH, Swiss National Science Foundation, Universities Federation for Animal Welfare.

Profiles of Primary School Children’s Sports Participation and Their Motor Competencies

Background/Objectives: Children participate in various organized and informal physical activities (PAs) in their leisure time, presenting diverse objectives and environments for motor and social development. However, current research often focuses on specific, mostly organized activities, overlooking the complexity of participation across different settings. This study aimed to (1) identify groups of children with similar characteristics based on their participation in five organized and informal sports activities and (2) examine how the groups differ regarding gender, age, BMI, motor competencies (MCs), and attendance in institutionalized care at school. Methods: The study included n = 1717 1st and 2nd graders (M = 7.60 years, SD = 0.59, 50.7% girls) and n = 1319 3rd and 4th graders (M = 9.46 years, SD = 0.57, 49.4% girls) from the “EMOKK” study, funded by the Swiss National Science Foundation. Data were collected via parent questionnaires on leisure sports participation, and MCs were assessed using MOBAK-1-2 and 3-4 tests. Latent profile analyses (LPAs) and univariate ANOVAs were used to identify group differences. Results: A three-profile LPA model best fits the data, revealing differences in participation across individual and team sports, optional school sports, free play on the school playground, and informal activities during leisure time. Children involved more in team sports (profiles: allrounder and very active sportsperson) participate more in informal play and present better MCs than children participating mainly in individual sports (profile: individual sportsperson). Girls were predominantly in the individual sports profile, while boys were more evenly spread across all groups. These findings highlight the importance of designing targeted interventions that promote participation in both organized and informal sports, particularly for children with lower levels of PA. Conclusions: Children show different patterns of engagement in different interrelated organized and informal leisure PA contexts. These specific patterns and the children’s MCs should be taken into account for the targeted promotion of PAs during leisure time.

Body ownership alterations in stroke emerge from reduced proprioceptive precision and damage to the frontoparietal network.

Stroke patients often experience alterations in their subjective feeling of ownership for the affected limb, which can hinder motor function and interfere with rehabilitation. In this study, we aimed at disentangling the complex relationship between sensory impairment, body ownership (BO), and motor control in stroke patients. We recruited 20 stroke patients with unilateral upper limb sensory deficits and 35 age-matched controls. Participants performed a virtual reality reaching task with a varying displacement between their real unseen hand and a visible virtual hand. We measured reaching errors and subjective ownership ratings as indicators of hand ownership. Reaching errors were modeled using a probabilistic causal inference model, in which ownership for the virtual hand is inferred from the level of congruency between visual and proprioceptive inputs and used to weigh the amount of visual adjustment to reaching movements. Stroke patients were more likely to experience ownership over an incongruent virtual hand and integrate it into their motor plans. The model explained this tendency in terms of a decreased capability of detecting visuo-proprioceptive incongruences, proportionally to the amount of proprioceptive deficit. Lesion analysis further revealed that BO alterations, not fully explained by the proprioceptive deficit, are linked to frontoparietal network damage, suggesting a disruption in higher-level multisensory integration functions. Collectively, our results show that BO alterations in stroke patients can be quantitatively predicted and explained in a computational framework as the result of sensory loss and higher-level multisensory integration deficits. Swiss National Science Foundation (163951).

Relationship between MRI brain-age heterogeneity, cognition, genetics and Alzheimer’s disease neuropathology

Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer's disease (AD). Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42-85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n=291), resilient in both (n=260) or advanced in one/resilient in the other (n=163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task). Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits. The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life. The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute.

Exploring and Controlling Chemistry Using Quantum Logic.

Over the past years, the development of experimental techniques for the coherent manipulation and control of isolated quantum systems has made impressive progress. Such 'quantum-logic' methods are also highly attractive in a chemical context in view of unravelling and controlling the quantum dynamics of molecular collisions and chemical reactions. Quantum technologies have the potential to transform the way chemical dynamics are investigated - by providing highly sensitive methods for state readout and spectroscopy, by opening up new pathways for the quantum-state preparation of molecules and by enabling an improved control of their microscopic behavior on the single-particle level. However, for complex quantum systems like molecules, these techniques are still in their infancy and their considerable potential remains to be unlocked. The aim of the present research program supported by an Advanced Grant of the Swiss National Science Foundation is to merge the fields of quantum science and chemical dynamics by advancing quantum technologies to polyatomic molecular ions and by applying them to the study of ion-molecule collisions and chemical reactions. In this article, we review the salient experimental methods as well as prospects and challenges in the development of molecular quantum technologies and their applications to chemistry.

Significant pre-post effects on a patient-reported outcome measure in inpatient rehabilitation

Abstract Background We conducted a pilot study for the Swiss National Association for Quality Development in Hospitals and Clinics (ANQ) in the inpatient rehabilitation setting. The aim was to assess the suitability of a generic health-related quality of life patient-reported outcome measure (PROM) as an outcome quality indicator for public reporting across all rehabilitation domains on a national level. Methods In a multi-stage expert-based selection process, the PROMIS Global Health 10 was selected for piloting. We collected data from 29 rehabilitation clinics from April to December 2023. Mean T-scores and effect sizes were analysed across different rehabilitation domains. Patients’ need for assistance in completing the questionnaire was also assessed. Results A dataset of 2261 cases yielded a cleaned sample of 2083, with 1217 complete cases. Mean T-scores for physical health (PHS) and mental health (MHS) significantly differed (p < 0.001) at admission and discharge across all rehabilitation domains. The largest effects were observed in PHS for pulmonary (38.9(7.3); 46.0(7.6); dz = 0.95) and cardiologic rehabilitation (41.7(7.4); 47.9(7.2); dz = 0.85), and in MHS for internal medicine (44.1(6.9); 49.1(5.6); dz = 0.80) and psychosomatic rehabilitation (36.0(7.2); 45.2(8.2); dz = 1.19), while the smallest effects were noted in PHS for paraplegia (36.3(7.2); 39.8(7.2); dz = 0.50) and in MHS for the musculoskeletal rehabilitation domain (46.2(7.9); 48.7(7.4); dz = 0.33). Of all complete cases, 40.5% needed assistance in filling in the PROM and support needs were distributed unequally across rehabilitation domains, ranging from 10.0% in psychosomatic to 70.3% in geriatric rehabilitation. Conclusions The study presents a nuanced understanding of HRQOL across various rehabilitation domains, with notable effects observed across all domains, alongside significant assistance needs. Key messages • PROMIS-GH10 shows significant pre-post effects on physical and mental health in Swiss inpatient rehabilitation, with notable effects observed across all domains. • Observable barriers in implementation are evident due to substantial assistance requirements.

The role of preoperative immunonutrition on morbidity and immune response after cystectomy: protocol of a multicenter randomized controlled trial (INCyst Trial)

IntroductionCancer, malnutrition, and surgery negatively impact patient’s immune system. Despite standardized surgical technique and the development of new perioperative care protocols, morbidity after cystectomy remains a serious challenge for urologists. Most common postoperative complications, such as infections and ileus, often lead to longer length of stay and worse survival. The immune system and its interaction with the gut microbiota play a pivotal role in cancer immunosurveillance and in patient’s response to surgical stress. Malnutrition has been identified as an independent and modifiable risk factor for both mortality and morbidity. Immunonutrition (IN) may improve the nutritional status, immunological function, and clinical outcome of surgical patients. Aims of the study are (1) to evaluate the impact of IN on morbidity and mortality at 30 and 90 days after cystectomy and (2) to determine immune and microbiota signature that would predict IN effect.MethodsThis is a randomized, multicentric, controlled, pragmatic, parallel-group comparative study, supported by the Swiss National Science Foundation. A total of 232 patients is planned to be enrolled between April 2023 and June 2026. Three participating centers (Lausanne, Bern, and Riviera-Chablais) have been selected. All patients undergoing elective radical and simple cystectomy will be randomly assigned to receive 7 days of preoperative IN (Oral Impact®, Nestlé, Switzerland) versus standard of care (control group) and followed for 90 days after surgery. For the exploratory outcomes, blood, serum, urine, and stool samples will be collected in patients treated at Lausanne. In order to determine the impact of IN on immune fitness, patients enrolled at Lausanne will be vaccinated against influenza and the establishment of the vaccine-specific immune response will be followed. Analysis of the microbiota and expression of argininosuccinate synthetase 1 as potential biomarker will also be performed.Discussion and conclusionStrengths of the INCyst study include the randomized, multicenter, prospective design, the large number of patients studied, and the translational investigation. This study will challenge the added value of preoperative IN in patients undergoing cystectomy, assessing the clinical effect of IN on the onset of postoperative morbidity and mortality after cystectomy. Furthermore, it will provide invaluable data on the host immune response and microbiota composition.Trial registrationClinicalTrials.gov NCT05726786. Registered on March 9, 2023.

Associations between Cooking Methods and Socio-Demographic, Dietary, and Anthropometric Factors: Results from the Cross-Sectional Swiss National Nutrition Survey

Introduction: Appropriate cooking methods can improve food safety, decrease contaminants, and increase nutrient bioavailability. Few studies assessed the sociodemographic characterization of their use in European populations. We aimed to characterize the socio-demographic, lifestyle, and anthropometric predictors of cooking methods in the Swiss population. Methods: Adults aged 18–75 years (n = 2,050) participating in the cross-sectional national nutrition survey in Switzerland (menuCH) (2014–2015), representing the 7 main regions in the country. We used logistic regressions to assess the probability of the presence or absence of boiled, roasted, microwaved, oven-cooked, gratinated, fried, steamed, and grilled foods by sociodemographic variables. Results: Among all participants, the most frequently used cooking methods were boiling (46%), stove-cooking (19%), and steaming (8%). Single participants had a higher probability of consuming grilled or fried foods (68%) than their married counterparts and participants with obesity had a higher probability of consuming grilled or fried foods (67% or 135%) compared to those with normal weight. Divorced or separated participants had a 55% lower probability of consuming roasted foods than married participants. Those following a diet had a 57% lower probability of consuming grilled foods compared to those not on a diet. Conclusion: We found differences in the distribution of cooking methods in the Swiss population by sociodemographic variables. Further studies should examine the link between cooking methods and disease risk.

Residential exposure to solar ultraviolet radiation and risk of childhood hematological malignancies in Switzerland: A census-based cohort study.

Still little is known about possible environmental risk factors of childhood hematological malignancies (CHM). Previous studies suggest that ultraviolet radiation (UVR) exposure is associated with a lower risk of acute lymphoblastic leukemia (ALL) in children. We investigated the association between solar UVR exposure and risk of CHM in Switzerland, a country with greatly varying topography and weather conditions. We included all resident children aged 0-15 years from the Swiss National Cohort during 1990-2016 and identified incident cancer cases through probabilistic record linkage with the Swiss Childhood Cancer Registry. We estimated the overall annual mean UV level and the mean level for the month of July during 2004-2018 at children's homes using a climatological model of the midday (11 am-3 pm) UV-index (UVI) with a spatial resolution of 1.5-2 km. Using risk-set sampling, we obtained a nested case-control data set matched by birth year and fitted conditional logistic regression models (virtually equivalent to analyzing full cohort data using proportional hazards models) adjusting for sex, neighborhood socio-economic position, urbanization, air pollution, and background ionizing radiation. Our analyses included 1446 cases of CHM. Estimated adjusted hazard ratios (HR) per unit increase in UVI in July were 0.76 (95% CI 0.59-0.98) for leukemia and 0.74 (0.55-0.98) for ALL. Results for annual exposure were similar but confidence intervals were wider and included one. We found no evidence for an association for lymphoma overall (HR 1.14, 95% CI 0.59-2.19 for annual exposure) or diagnostic subgroups. Our study provides further support for an inverse association between exposure to ambient solar UVR and childhood ALL.

Exploring Carolingian and Romanesque cycles: a study of the detached wall paintings from the Church of St. Johann in Müstair

Twenty-six fragment of wall paintings detached from the upper register of the Carolingian and Romanesque cycles of the church of St. John in Müstair (Switzerland) have been part of the Swiss National Museum collection since the beginning of the twentieth century. As some of these objects were in a critical state of conservation, a research project was launched to assess and document their conditions, and to gain knowledge about painting materials and execution techniques, in view of planning a conservation project. In a first phase, non-destructive analyses were carried out, using handheld XRF and portable FTIR spectroscopy; followed by the targeted collection of samples for detailed analysis in the laboratory. In parallel, similar investigations were carried out on the imprints left on the walls of the church’s attic. The results allowed the identification of the pigment palette and the execution technique. Besides earth pigments such as ochres, a lime-based white, probably bianco di San Giovanni, and limited amounts of lapis lazuli were used in both painting cycles. For the Carolingian cycle, Egyptian blue and mixtures of several lead-based pigments were also identified. In several instances, the deterioration of lead-based pigments resulted in shades of grey to black severely modifying the original appearance of the wall paintings. Additionally, both cycles have suffered from pigment alteration due to fire. The obtained results, together with iconographic considerations, allowed for an extended interpretation of possible original colour palette.Graphical

Conference Report: Challenging Construction Grammar: New Insights from Morphology (8–12 April 2024; Monte Verità, Switzerland)

As reflected in its title, this workshop, which took place from the eighth to the twelfth of April 2024 at Monte Verità, Ascona, Switzerland, focused on constructional perspectives in their application to morphology (Hoffmann & Trousdale 2013). As Construction Grammar has become an important theoretical framework within linguistics, it has been applied in morphological studies from both synchronic (e.g., Booij 2010; Jackendoff & Audring 2020) and diachronic perspectives (Hartmann 2019; Van Goethem & Norde 2020). Nevertheless, Construction Morphology is a comparatively young branch of Construction Grammar that poses many open questions and challenges. The questions that were asked within this workshop relate to the connection between morphology and Construction Grammar as a framework, the handling of phenomena situated at the interface of morphology and syntax, and how phenomena that are specific for the scope of morphology can be captured from a constructional point of view. To address this issue, young and early career researchers were invited to present their current work. These contributions were complemented by the contributions of the invited plenary speakers Muriel Norde (Humboldt University of Berlin), Francesca Masini (University of Bologna), Livio Gaeta (University of Turin), Kristel Van Goethem (University of Louvain) and Steffen Höder (University of Kiel). The workshop was organised by Elena Smirnova (University of Neuchâtel), Martin Hilpert (University of Neuchâtel) and Jenny Audring (University of Leiden), and made possible with the generous support of SCF (Congressi Stefano Franscini, https://csf.ethz.ch), the SNF (Swiss National Science Foundation, Programm Scientific Exchanges, Grant Nr IZSEZ0_221843) and the FLSH (Faculty of Arts and Humanities) of the University of Neuchâtel.

Symptom trajectories in infancy for the prediction of subsequent wheeze and asthma in the BILD and PASTURE cohorts: a dynamic network analysis

Host and environment early-life risk factors are associated with progression of wheezing symptoms over time; however, their individual contribution is relatively small. We hypothesised that the dynamic interactions of these factors with an infant's developing respiratory system are the dominant factor for subsequent wheeze and asthma. In this dynamic network analysis we used data from term healthy infants from the Basel-Bern Infant Lung Development (BILD) cohort (435 neonates aged 0-4 weeks recruited in Switzerland between Jan 1, 1999, and Dec 31, 2012) and replicated the findings in the Protection Against Allergy Study in Rural Environments (PASTURE) cohort (498 infants aged 0-12 months recruited in Germany, Switzerland, Austria, France, and Finland between Jan 1, 2002, and Oct 31, 2006). BILD exclusion criteria for the current study were prematurity (<37 weeks), major birth defects, perinatal disease of the neonate, and incomplete follow-up period. PASTURE exclusion criteria were women younger than 18 years, a multiple pregnancy, the sibling of a child was already included in the study, the family intended to move away from the area where the study was conducted, and the family had no telephone connection. Outcome groups were subsequent wheeze, asthma, and healthy. The first outcome was defined as ever wheezed between the age of 2 years and 6 years. Week-by-week correlations of the determining factors with cumulative symptom scores (CSS) were calculated from weeks 2 to 52 (BILD) and weeks 8 to 52 (PASTURE). The complex dynamic interaction between the determining factors and the CSS was assessed via dynamic host-environment correlation network, quantified by a simple descriptor: trajectory function G(t). Wheeze outcomes at age 2-6 years were compared in 335 infants from BILD and 437 infants from PASTURE, and asthma outcomes were analysed at age 6 years in a merged cohort of 783 infants. CSS was significantly different for wheeze and asthma outcomes and became increasingly important during infancy in direct comparison with all determining factors. Weekly symptoms were tracked for groups of infants, showing a non-linear increase with time. Using logistic regression classification, G(t) distinguished between the healthy group and wheeze or asthma groups (area under the curve>0·97, p<0·0001; sensitivity analysis confirmed significant CSS association with wheeze [BILD p=0·0002 and PASTURE p=0·068]) and G(t) was also able to distinguish between the farming and non-farming exposure groups (p<0·0001). Similarly to other risk factors, CSS had weak sensitivity and specificity to identify risks at the individual level. At group level however, the dynamic host-environment correlation network properties (G(t)) showed excellent discriminative ability for identifying groups of infants with subsequent wheeze and asthma. Results from this study are consistent with the 2018 Lancet Commission on asthma, which emphasised the importance of dynamic interactions between risk factors during development and not the risk factors per se. The Swiss National Science Foundation, the Kühne Foundation, the EFRAIM study EU research grant, the FORALLVENT study EU research grant, and the Leibniz Prize.

Vulnerability to heat-related mortality and the effect of prevention measures: a time-stratified case-crossover study in Switzerland.

Swiss climate scenarios predict increases in the frequency and intensity of extreme heat episodes in the future. For the effective prevention of heat-related mortality, several aspects of the population's vulnerability to heat must be understood on a local level. A nationwide analysis of individual death records was conducted, enabling a more comprehensive understanding than typical heat studies based on aggregated data. A total of 320,306 individual death records from the Swiss National Cohort with precise address information during the warm season (May to September) from 2003-2016 were linked to indoor and outdoor high-resolution daily temperature estimates. A time-stratified case-crossover study combined with distributed lag non-linear models was then performed to assess the temperature-mortality associations for various causes of death and to estimate the potential effect modification of individual characteristics. Additionally, it was explored whether the effect of extreme heat changed over time in regions with and without cantonal heat-health action plans (HHAPs). Using the temperature with the lowest cause-specific mortality risk (minimum mortality temperature) as the reference temperature, extreme heat (defined as ambient daily maximum temperature reaching 33 °C) was associated with a strong increase in all-cause mortality (odds ratio (OR): 1.21, 95% CI: 1.17-1.25) and disease-specific mortality from Alzheimer's disease and dementia (OR: 1.67, 95% CI: 1.48-1.88), COPD (OR: 1.37, 95% CI: 1.12-1.67), diabetes (OR: 1.34, 95% CI: 1.06-1.70), and myocardial infarction (OR: 1.26, 95% CI: 1.10-1.44). Indoor temperatures above 24 °C were found to be critical for mortality. The population most vulnerable to heat included older adults (≥75 years), unmarried individuals, people with a low education level, older women with low neighbourhood socioeconomic position, and men under 75 years old with low socioeconomic position. Overall, the risk of heat-related all-cause mortality in 2009-2016 was lower than that in 2003-2008. The decrease was significantly stronger in the region where cantonal HHAPs were implemented. This study provides important information for planning targeted and effective measures to reduce heat-related health risks in Switzerland. It demonstrates that HHAPs contribute to reducing heat-related mortality, although they may not reach the high-risk population of individuals with low socioeconomic position. Future prevention efforts should also target the less privileged population, including people younger than 75 years.

Who watches the watchdogs? Central bank board members and banking supervisors in Switzerland (1907–2008)

ABSTRACT The Swiss financial center developed spectacularly during the 20th century, becoming one of the main hubs for cross-border financial transactions. The regulatory environment that enabled this growth is still poorly understood. This contribution examines the government appointees who controlled the banking supervisory institutions (Swiss National Bank and Federal Banking Commission). The focus is on the individuals who supervised those two institutions and analyzes the evolution of their board members from their creation, in 1907 and 1935 respectively, to 2008. This prosopographical study – using indicators such as gender, age, education, career paths and political affiliation – seeks to determine: a) their typical socio-professional profile, b) their closeness to the banking industry and c) their representativeness of society, politics, and business. My findings highlight both significant changes in the last decade of the century, with an increase in the level of education and a drop in political affiliation, and a long-term stability of the socio-professional profile of the board members: middle-aged to elderly men, with a PhD in law or economics, considerable experience in the banking or business world, and often an affiliation with the governing political parties. Both institutions were supervised by individuals with close connections to the financial industry. They became arenas for elite networking, simultaneously failing to represent large segments of society.

How to (Mass-)Digitize Newspapers in Switzerland &amp;#x2013; The Swiss National Library Approach - Renewed

How to (Mass-)Digitize Newspapers in Switzerland &amp;#x2013; The Swiss National Library Approach - Renewed

Testing for a causal role of thyroid hormone measurements within the normal range on human metabolism and diseases: a systematic Mendelian randomization

Variation in thyroid function parameters within the normal range has been observationally associated with adverse health outcomes. Whether those associations reflect causal effects is largely unknown. We systematically tested associations between genetic differences in thyrotropin (TSH) and free thyroxine (FT4) within the normal range and more than 1100 diseases and more than 6000 molecular traits (metabolites and proteins) in three large population-based cohorts. This was performed by combining individual and summary level genetic data and using polygenic scores and Mendelian randomization (MR) methods. We performed a phenome-wide MR study in the OpenGWAS database covering thousands of complex phenotypes and diseases. Genetically predicted TSH or FT4 levels within the normal range were predominately associated with thyroid-related outcomes, like goitre. The few extra-thyroidal outcomes that were found to be associated with genetic liability towards high but normal TSH levels included atrial fibrillation (odds ratio=0.92, p-value=2.13×10-3), thyroid cancer (odds ratio=0.57, p-value=2.97×10-4), and specific biomarkers, such as sex hormone binding globulin (β=-0.046, p-value=1.33×10-6) and total cholesterol (β=0.027, p-value=5.80×10-3). In contrast to previous studies that have described the association with thyroid hormone levels and disease outcomes, our genetic approach finds little evidence of an association between genetic differences in thyroid function within the normal range and non-thyroidal phenotypes. The association described in previous studies may be explained by reverse causation and confounding. This research was funded by the Swiss National Science Foundation (P1BEP3_200041). The Fenland study (DOI 10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1, MC_PC_13046 and MC_UU_00006/1). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-UU_12015/1, MC_PC_13048 and MC_UU_00006/1).

The Glass Mosaic of S. Agnese fuori le mura: New Tesserae in the Puzzle of Early Medieval Rome

The present study, which is part of a wider inter-disciplinary research project on Medieval Rome funded by the Swiss National Science Foundation, focuses on the archaeometric characterisation of glass tesserae from the apse mosaic of the church of S. Agnese fuori le mura, dated to the 7th century AD and never analysed until now. The main aims of the study are the identification of chemical compositions of glassy matrices and colouring/opacifying techniques by means of the combination of micro-textural, chemical, and mineralogical data. In S. Agnese tesserae, the results show the presence of glassy matrices and opacifiers/pigments, typical of both Roman and Late Antique/Early Medieval periods. The technological features identified (in particular, glassy matrices and opacifiers/pigments) allow us to discriminate not only new-production tesserae, i.e., those probably produced in the 7th century for the realisation of the S. Agnese mosaic, but also those obtained from recycling or re-using previous glass. This testifies to a quite complex “puzzle”, unusual in other glass mosaics from the same city and coeval with S. Agnese, supporting further the potentiality of archaeometric studies on glass to uncover the technical and socio-cultural knowledge that underpins its manufacturing, use, re-use, and recycling in the Early Medieval Rome.

Clearance of erythrocytes from the subarachnoid space through cribriform plate lymphatics in female mice

Atraumatic subarachnoid haemorrhage (SAH) is associated with high morbidity and mortality. Proposed mechanisms for red blood cell (RBC) clearance from the subarachnoid space (SAS) are erythrolysis, erythrophagocytosis or through efflux along cerebrospinal fluid (CSF) drainage routes. We aimed to elucidate the mechanisms of RBC clearance from the SAS to identify targetable efflux pathways. Autologous fluorescently-labelled RBCs along with PEGylated 40kDa near-infrared tracer (P40D800) were infused via the cisterna magna (i.c.m.) in female reporter mice for lymphatics or for resident phagocytes. Drainage pathways for RBCs to extracranial lymphatics were evaluated by in vivo and in situ near-infrared imaging and by immunofluorescent staining on decalcified cranial tissue or dural whole-mounts. RBCs drained to the deep cervical lymph nodes 15min post i.c.m. infusion, showing similar dynamics as P40D800 tracer. Postmortem in situ imaging and histology showed perineural accumulations of RBCs around the optic and olfactory nerves. Numerous RBCs cleared through the lymphatics of the cribriform plate, whilst histology showed no relevant fast RBC clearance through dorsal dural lymphatics or by tissue-resident macrophage-mediated phagocytosis. This study provides evidence for rapid RBC drainage through the cribriform plate lymphatic vessels, whilst neither fast RBC clearance through dorsal dural lymphatics nor through spinal CSF efflux or phagocytosis was observed. Similar dynamics of P40D800 and RBCs imply open pathways for clearance that do not impose a barrier for RBCs. This finding suggests further evaluation of the cribriform plate lymphatic function and potential pharmacological targeting in models of SAH. Swiss National Science Foundation (310030_189226), SwissHeart (FF191155).

Sparse Integer Programming Is Fixed-Parameter Tractable

We study the general integer programming problem where the number of variables n is a variable part of the input. We consider two natural parameters of the constraint matrix A: its numeric measure a and its sparsity measure d. We present an algorithm for solving integer programming in time [Formula: see text], where g is some computable function of the parameters a and d, and L is the binary encoding length of the input. In particular, integer programming is fixed-parameter tractable parameterized by a and d, and is solvable in polynomial time for every fixed a and d. Our results also extend to nonlinear separable convex objective functions. Funding: F. Eisenbrand, C. Hunkenschröder, and K.-M. Klein were supported by the Swiss National Science Foundation (SNSF) within the project “Convexity, geometry of numbers, and the complexity of integer programming” [Grant 163071]. A. Levin and S. Onn are partially supported by the Israel Science Foundation [Grant 308/18]. A. Levin is also partially supported by the Israel Science Foundation [Grant 1467/22]. S. Onn is also partially supported by the Dresner Chair at the Technion. M. Koutecký is partially supported by Charles University project UNCE 24/SCI/008, and by the project 22-22997S of the Grantová Agentura České Republiky (GA ČR).

Made in Frankfurt? The Monetary Policy of the Swiss National Bank Since 1973

The paper investigates the monetary policy of the Swiss National Bank (SNB) in the post-Bretton Woods era, shedding light on the dynamics between the SNB and the Bundesbank and its successor, the European Central Bank, respectively. Our econometric analysis shows a high degree of synchronisation between the SNB’s interest rate changes and the decisions made in Frankfurt. The results also suggest a strong tendency toward direct exchange rate targeting before 1999, which coincides with a period of lower demand shock synchronization. This finding is supported by our analysis of the minutes of the Governing Board of the SNB for the period between 1982 and 1993. The discussions and decisions of the board show that Swiss monetary policy was largely guided by policy rate changes of the Bundesbank. The SNB routinely set the policy rate below the policy rate of the Bundesbank to enforce an implicit exchange rate target.