The Cretaceous of the Swiss Jura Mountains: an improved lithostratigraphic scheme

In the course of the HARMOS project of the Swiss Geological Survey, the lithostratigraphic subdivisions of the Cretaceous sedimentary rocks outcropping in the Swiss Jura Mountains were revisited. New formation names are proposed where only inadequate facies terms existed so far. As in some cases outcrop conditions in the Swiss Jura do not allow for logging complete sections to characterise the formations, type localities in neighbouring France have been chosen. The following formations (Fm.) are defined to describe the Cretaceous lithological units (from bottom to top): Goldberg Fm., Pierre-Châtel Fm., Vions Fm., Chambotte Fm., Vuache Fm., Grand Essert Fm., Gorges de l’Orbe Fm., Vallorbe Fm., Perte du Rhône Fm., Narlay Fm. Dating of the formations is based on biostratigraphy (ammonites, echinids, dasycladalean algae, foraminifera, calpionellids, dinocysts, nannofossils). The fossils indicate Berriasian through to Coniacian ages. The lithostratigraphic units describe the general evolution from a shallow, peritidal platform to deeper-water shelf environments, then the installation of a carbonate platform, and finally the drowning of this platform followed by the predominance of pelagic conditions. The common lateral and vertical changes in facies and sedimentation rates as well as numerous hiatuses within the formations testify to a complex interplay of tectonics, climate, and sea level that controlled the Swiss Jura realm during the Cretaceous

La Formation du Grand Essert (Jura franco-suisse; Valanginien supérieur p.p. à Hauterivien supérieur basal)

Le terme de Formation du Grand Essert a été proposé en 2016 pour remplacer ceux de « Marnes d’Hauterive » auct. et « Pierre jaune de Neuchâtel » auct. attribués à l’« Hauterivien » auct. dans le Jura franco-suisse. L’objet de cette note est, dans un premier temps, de décrire et d’interpréter la lithologie de la coupe-type représentative de cette nouvelle formation, d’une épaisseur de 112,5 m, relevée dans la localité-type du Grand Essert le long de la route D991, entre Confort et Chésery, sur la rive gauche de la vallée de la Valserine (Jura méridional, Ain, France). La Formation du Grand Essert comprend, à la base, le Membre d’Hauterive composé de 52 m de marnes dans lesquelles apparaissent des bancs et des nodules calcaires contenant souvent des grains de quartz et de glauconie. Les faciès indiquent un milieu calme en dessous de la limite de l’action des vagues de beau temps, avec l’apport périodique de matériel bioclastique allochtone. Au-dessus, le Membre de Neuchâtel d’une épaisseur de 60,5 m se compose de calcaires bioclastiques localement quartzo-glauconieux. Au sein de ce membre s’intercale un horizon marneux d’origine marine, les Marnes des Uttins. Les bancs calcaires montrent des structures sédimentaires entrecroisées qui suggèrent la présence de courants tidaux. Dans un deuxième temps, les auteurs proposent des corrélations basées sur la biostratigraphie (ammonites et dinokystes) et l’analyse séquentielle, entre la coupe-type et d’autres coupes et forages publiés dans le Jura franco-suisse. La corrélation avec une coupe du Bassin vocontien (Haut Vergons) permet de discuter jusqu’à quel point l’enregistrement sédimentaire de la Formation du Grand Essert était contrôlé par des fluctuations du niveau marin. Finalement, les ammonites et dinokystes permettent de bien dater la Formation du Grand Essert qui s’étend du Valanginien supérieur pro parte jusqu’à la base de l’Hauterivien supérieur. Le Membre d’Hauterive commence dans la zone à Peregrinus. L’intervalle Peregrinus-Furcillata est partout fortement condensé (comme la partie sommitale de la Formation du Vuache sous-jacente dans le Jura neuchâtelois) tandis que les sédiments de la zone à Radiatus sont bien représentés. La limite entre le Membre d’Hauterive et le Membre de Neuchâtel se situe dans la zone à Loryi. Le Membre de Neuchâtel occupe la partie supérieure de la zone à Loryi et toute la zone à Nodosoplicatum. La limite Nodosoplicatum / Sayni se trouve au sein de la partie sommitale du Membre de Neuchâtel. La base de la Formation des Gorges de l’Orbe sus-jacente est datée de la zone à Sayni

Training for impact : the socio-economic impact of a fit for purpose health workforce on communities

Across the globe, a "fit for purpose" health professional workforce is needed to meet health needs and challenges while capitalizing on existing resources and strengths of communities. However, the socio-economic impact of educating and deploying a fit for purpose health workforce can be challenging to evaluate. In this paper, we provide a brief overview of six promising strategies and interventions that provide context-relevant health professional education within the health system. The strategies focused on in the paper are:1. Distributed community-engaged learning: Education occurs in or near underserved communities using a variety of educational modalities including distance learning. Communities served provide input into and actively participate in the education process.2. Curriculum aligned with health needs: The health and social needs of targeted communities guide education, research and service programmes.3. Fit for purpose workers: Education and career tracks are designed to meet the needs of the communities served. This includes cadres such as community health workers, accelerated medically trained clinicians and extended generalists.4. Gender and social empowerment: Ensuring a diverse workforce that includes women having equal opportunity in education and are supported in their delivery of health services.5. Interprofessional training: Teaching the knowledge, skills and attitudes for working in effective teams across professions.6. South-south and north-south partnerships: Sharing of best practices and resources within and between countries.In sum, the sharing of resources, the development of a diverse and interprofessional workforce, the advancement of primary care and a strong community focus all contribute to a world where transformational education improves community health and maximizes the social and economic return on investment

Science in the Swiss public: the state of science communication and public engagement with science in Switzerland

Science communication and public engagement with science have repeatedly been called for in recent years, particularly during the COVID-19 pandemic. Therefore, die Swiss Academies of the Arts and Sciences have set up an expert group to assess the state of science communication in Switzerland, and to provide recommendations for how to improve it. The expert group report is based on a comprehensive review of the available interdisciplinary scholarship analyzing science communication and public engagement with science in Switzerland. Selectively, it also incorporates original data, international findings, and secondary analyses where little or no published scholarly work was available. The report covers a wide range of facets of science communication and public engagement in Switzerland, from public attitudes towards science over individuals and organizations engaging in science communication and engagement formats to news and social media representations of science. On this basis, it formulates 20 recommendations for improving science communication in Switzerland

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701