Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Additional file 1 of Enhanced survival of hypoimmunogenic otic progenitors following intracochlear xenotransplantation: repercussions for stem cell therapy in hearing loss models

Additional file 1. Supplemental information. Section 1: Supplementary methods. 1.1. Differentiation of hi-iPSCs toward otic neural progenitors. 1.2. Quantitative RT-qPCR. 1.3. Immunocytochemistry. 1.4. Flow cytometry analysis. 1.5. Generation of ONP spheroids for transplantation. 1.6. Intracochlear transplantation of ONPs through round window. 1.7. Immunohistochemistry and donor cell quantification; Section 2: Supplementary figures. Figure S1. Overexpression of HLA-G and PD-L1 genes in hypoimmunogenic iPSCs. Figure S2. G-banded karyotyping of hypoimmunogenic iPSCs. Figure S3. Surface expression of HLA-G and PD-L1 transgenes diminishes in hypoimmunogenic cells during differentiation from iPSC to ONP stage. Figure S4. Intratympanic transplantation of ONP spheroids. Figure S5. Representation of the mid-modiolar cryosections used for quantification of donor cells. Figure S6. Intracochlear transplantation of wild-type iPSC–derived ONP spheroids (wt-ONP). Figure S7. Intracochlear transplantation of hypoimmunogenic iPSC–derived ONP spheroids (hi-ONP). Figure S8. Distribution of ONP count/mm² values

Uniform data set language measures for bvFTD and PPA diagnosis and monitoring.

IntroductionThe Frontotemporal Lobar Degeneration Module (FTLD-MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD-MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring.MethodsLinear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 168), non-fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data.ResultsAmong PPAs, the FTLD-MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change.DiscussionThe FTLD-MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring

40 Jahre Lehrkräftebildung an der Universität Passau: Ein- und Ausblicke

Inhalt Vorwort |1 Matthias Brandl Didaktik der Deutschen Sprache und Literatur |6 Walter Seifert, Karla Müller & Markus Pissarek „Deutsch als Zweitsprache“ als Bestandteil der Lehrer*innen-Bildung in Deutschland, Bayern und Passau: Ein Rückblick auf die Entwicklung des Faches anhand von Expert*innen-Interviews |13 Julia Ricart Brede & Sibylle Draber Didaktik der Mathematik |23 Matthias Brandl, Birgit Brandl & Stefanie Winkler Musikpädagogik im Didaktikfach – Einblicke in die Besonderheiten des Musikunterrichts |34 Gabriele Schellberg & Christina Fehrenbach Psychologie für den Lehrberuf an der Universität Passau |48 Detlef Urhahne, Judith Schweppe und Susanne Mayr Von der Katechese zur Religionspädagogik - Die Entwicklung von Theologie und Religions-lehrer*innen-Bildung an der Universität Passau |55 Hans Mendl Algorithmisches Denken und Programmieren im Grundschullehramtsstudium |68 Luisa Greifenstein, Ute Heuer & Gordon Fraser Fit für die Zukunft – Transformation gestalten mit Bildung für nachhaltige Entwicklung (BNE) in der Lehrkräftebildung |78 Michaela Würdinger-Gaidas & Florian Stelzer Didaktische Innovation in der Lehrkräftebildung: Theorie und Praxis der Lehre in den Passauer Innovationslaboren |86 Jutta Mägdefrau, Hannes Birnkammerer, Sabrina Kufner, Verena Köstler, Christian Müller Historisches Lernen im digitalisierten Geschichtsunterricht: Flipped Classroom und historische Spurensuche vor Ort |95 Norbert Lehning Mediensemiotik und Medienkunde als Basis von Information and Media Literacy (IML). Fachwissenschaftliche Einblicke am Beispiel des Videospiels Wolfenstein II: The New Colossus |101 Jan-Oliver Decker & Jakob Kelsch InVerS: Motive und Begründungslinien für die Wahl des Berufs Lehrkraft im internationalen Vergleich. Ein Forschungsprojekt des Lehrstuhls für Erziehungswissenschaft mit dem Schwerpunkt Diversitätsforschung und Bildungsräume der Mittleren Kindheit |113 Susanne Fesl, Eva Rutter und Simone Maria Springer Der Klassenrat als Ort politischen Lernens? |127 Michael Freund Das Studium des Erweiterungsfachs Ethik an der Universität Passau – maximale Relevanz und minimale Ausbildung? | 134 Florian Wobse

Diagnostic Accuracy of Magnetic Resonance Imaging Measures of Brain Atrophy Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Degeneration

Altres ajuts: Global Brain Health Institute (GBHI), Alzheimer's Association, and Alzheimer's Society (GBHI ALZ UK-21-720973, AACSF-21-850193); NIH grants (AG019724, AG032306, AG045390, NS092089, AG045333, AG056749, AG062422, K24AG053435, K08AG052648, R01AG059794, R01AG056850-01A1, R21AG056974, R01AG061566, K23AG059888); Fondo de Investigaciones Sanitario; Centro de Investigación en Red-Enfermedades Neurodegenerativas program (Program 1, Alzheimer Disease); Fondo Europeo de Desarrollo Regional, Unión Europea, una manera de hacer Europa; La Marató de TV3 (20141210); Generalitat de Catalunya; Banco Bilbao Vizcaya Argentaria foundation.Importance: The accurate diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is hampered by imperfect clinical-pathological correlations. Objective: To assess and compare the diagnostic value of the magnetic resonance parkinsonism index (MRPI) and other magnetic resonance imaging-based measures of cerebral atrophy to differentiate between PSP, CBD, and other neurodegenerative diseases. Design, Setting, and Participants: This prospective diagnostic study included participants with 4-repeat tauopathies (4RT), PSP, CBD, other neurodegenerative diseases and available MRI who appeared in the University of California, San Francisco, Memory and Aging Center database. Data were collected from October 27, 1994, to September 29, 2019. Data were analyzed from March 1 to September 14, 2021. Main Outcomes and Measures: The main outcome of this study was the neuropathological diagnosis of PSP or CBD. The clinical diagnosis at the time of the MRI acquisition was noted. The imaging measures included the MRPI, cortical thickness, subcortical volumes, including the midbrain, pons, and superior cerebellar peduncle volumes. Multinomial logistic regression models (MLRM) combining different cortical and subcortical regions were defined to discriminate between PSP, CBD, and other pathologies. The areas under the receiver operating characteristic curves (AUROC) and cutoffs were calculated to differentiate between PSP, CBD, and other diseases. Results: Of the 326 included participants, 176 (54%) were male, and the mean (SD) age at MRI was 64.1 (8.0) years. The MRPI showed good diagnostic accuracy for the differentiation between PSP and all other pathologies (accuracy, 87%; AUROC, 0.90; 95% CI, 0.86-0.95) and between 4RT and other pathologies (accuracy, 80%; AUROC, 0.82; 95% CI, 0.76-0.87), but did not allow the discrimination of participants with CBD. Its diagnostic accuracy was lower in the subgroup of patients without the canonical PSP-Richardson syndrome (PSP-RS) or probable corticobasal syndrome (CBS) at MRI. MLRM combining cortical and subcortical measurements showed the highest accuracy for the differentiation between PSP and other pathologies (accuracy, 95%; AUROC, 0.98; 95% CI, 0.97-0.99), CBD and other pathologies (accuracy, 83%; AUROC, 0.86; 95% CI, 0.81-0.91), 4RT and other pathologies (accuracy, 89%; AUROC, 0.94; 95% CI, 0.92-0.97), and PSP and CBD (accuracy, 91%; AUROC, 0.95; 95% CI, 0.91-0.99), even in participants without PSP-RS or CBS at MRI. Conclusions and Relevance: In this study, the combination of widely available cortical and subcortical measures of atrophy on MRI discriminated between PSP, CBD, and other pathologies and could be used to support the diagnosis of 4RT in clinical practice

Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum

ObjectiveMicrotubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers.MethodsWe compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles.ResultsSymptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline.InterpretationNetwork connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023

Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research.

IntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research.HighlightsThe ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses