Prevalence and causes of musculoskeletal impairment in Mahabubnagar District, Telangana State, India: results of a population-based survey.

Background: Musculoskeletal impairments (MSI) are the leading contributor to global years lived with disability. Comparable epidemiological data on MSI is lacking, and are needed to inform health and rehabilitative services. This study aimed to estimate the prevalence and causes of MSI in Telangana State, India. Method: A population-based survey used probability proportionate to size and compact-segment sampling to select 51 clusters of 80 individuals (all ages). Participants were screened using seven questions and any participant who screened positive underwent standardized examination by a physiotherapist for MSI presence, severity and diagnosis. Data were also collected on vision and hearing impairment, depression and self-reported difficulties with physical functioning. Results: The prevalence of MSI was 19.6% (95% CI: 16.7-22.8%) and this increased with age. The majority (82%; 574/699) of MSI was classified as mild, 11% as moderate and 7% as severe. Over half (57%) of MSI diagnoses were acquired non-traumatic causes, with degenerative joint disease being the most common. There was a high unmet need for physiotherapy services (3% attended vs. 40% recommended). One-fifth (21%) of MSI cases also had at least one of vision (10%) or hearing (11%) impairment or depression (3%). Conclusions: MSI is common among persons living in Mahabubnagar District, particularly older adults. These estimates can inform public health initiatives for the planning of health and rehabilitation services

Challenges of assessing community mortality due to respiratory viruses in children aged less than 5 years

Background: Estimating the real impact of respiratory syncytial virus (RSV) disease is key for the development of vaccines and treatments. Ascertaining the burden of community mortality due to RSV is challenging due to the lack of primary data. Therefore, conducting observational studies to determine the factors associated with community mortality due to the virus in developing countries is important.Objective: Our aim in this study was to describe the obstacles, gaps, and challenges that investigators face in low-income, vulnerable regions in 4 developing countries on 3 continents.Results: The main obstacles and challenges of ascertaining community mortality due to RSV were defining strategies to consent families for testing before burial, sampling individuals at the household level, supporting bereaved parents with different cultural and religious backgrounds, establishing tailored strategies for studies in challenging settings, and integrating RSV mortality data from nasopharyngeal samples.Conclusion: Detailed logistical planning based on population sociodemographic information, grief counseling, staff training, and a multidisciplinary approach with adequate laboratory infrastructure is critical to successful observational community-based RSV studies

A Role for Immune Complexes in Enhanced Respiratory Syncytial Virus Disease

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral pneumonia in infants and young children. Administration of a formalin inactivated vaccine against RSV to children in the 1960s resulted in increased morbidity and mortality in vaccine recipients who subsequently contracted RSV. This incident precluded development of subunit RSV vaccines for infants for over 30 years, because the mechanism of illness was never clarified. An RSV vaccine for infants is still not available

A theory of how active behavior stabilises neural activity: neural gain modulation by closed-loop environmental feedback

During active behaviours like running, swimming, whisking or sniffing, motor actions shape sensory input and sensory percepts guide future motor commands. Ongoing cycles of sensory and motor processing constitute a closed-loop feedback system which is central to motor control and, it has been argued, for perceptual processes. This closed-loop feedback is mediated by brainwide neural circuits but how the presence of feedback signals impacts on the dynamics and function of neurons is not well understood. Here we present a simple theory suggesting that closed-loop feedback between the brain/body/environment can modulate neural gain and, consequently, change endogenous neural fluctuations and responses to sensory input. We support this theory with modeling and data analysis in two vertebrate systems. First, in a model of rodent whisking we show that negative feedback mediated by whisking vibrissa can suppress coherent neural fluctuations and neural responses to sensory input in the barrel cortex. We argue this suppression provides an appealing account of a brain state transition (a marked change in global brain activity) coincident with the onset of whisking in rodents. Moreover, this mechanism suggests a novel signal detection mechanism that selectively accentuates active, rather than passive, whisker touch signals. This mechanism is consistent with a predictive coding strategy that is sensitive to the consequences of motor actions rather than the difference between the predicted and actual sensory input. We further support the theory by re-analysing previously published two-photon data recorded in zebrafish larvae performing closed-loop optomotor behaviour in a virtual swim simulator. We show, as predicted by this theory, that the degree to which each cell contributes in linking sensory and motor signals well explains how much its neural fluctuations are suppressed by closed-loop optomotor behaviour. More generally we argue that our results demonstrate the dependence of neural fluctuations, across the brain, on closed-loop brain/body/environment interactions strongly supporting the idea that brain function cannot be fully understood through open-loop approaches alone

Global respiratory syncytial virus–related infant community deaths

BACKGROUND : Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. METHODS : The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital. RESULTS : We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8−3.3) was lower than in-hospital (2.4 months; IQR: 1.5−4.0; P < .0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, P < 0.0001). CONCLUSIONS : We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines.The Bill & Melinda Gates Foundation.am2023Medical Virolog

Global Respiratory Syncytial Virus-Related Infant Community Deaths.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. METHODS: The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital. RESULTS: We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8-3.3) was lower than in-hospital (2.4 months; IQR: 1.5-4.0; P < .0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, P < 0.0001). CONCLUSIONS: We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines

Global respiratory syncytial virus–related infant community deaths

Background Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. Methods The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital. Results We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8−3.3) was lower than in-hospital (2.4 months; IQR: 1.5−4.0; P < .0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, P < 0.0001). Conclusions We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines

Titins Funktion in der gesunden und erkrankten gestreiften Muskulatur

Table of contents I 1 Abstract 1 2 Zusammenfassung 2 3 Introduction 3 3.1 Structure and function of striated muscles 3 3.1.1 Myofibrillogenesis 3 3.1.2 Structure and function of the sarcomere 5 3.2 Titin 6 3.2.1 Titin isoforms 7 3.2.2 Titin binding proteins 9 3.3 Clinical relevance 15 3.3.1 Titin mutations in cardiomyopathies 15 3.3.2 Titin mutations in muscular dystrophies 17 3.4 Aims of the study 18 4 Material and methods 20 4.1 Material 20 4.1.1 Chemicals and kits 20 4.1.2 Enzymes 20 4.1.3 Oligonucleotides 21 4.1.4 Antibodies 23 4.1.5 Equipment 24 4.1.6 Software 25 4.2 Methods 25 4.2.1 Animal procedures and experiments 25 4.2.2 Molecular methods 27 4.2.3 Biochemical methods 33 4.2.4 Histological methods 37 4.2.5 Bioinformatics 39 4.2.6 Statistical analysis 39 5 Results 40 5.1 Generation and validation of the titin Ex2 knockout (TiEx2MCK) 40 5.1.1 Generation of the titin exon 2 knockout 40 5.1.2 Validation of Ex2 knockout 42 5.2 Generation and validation of the titin M band knockout (TiMexMCK) 45 5.2.1 Generation of the M band knockout 45 5.2.2 Validation of the M band knockout 46 5.3 Comparative phenotyping of the Ex2 and the M band knockout 49 5.3.1 Skeletal muscle phenotypes 49 5.3.2 Cardiac phenotypes 57 5.3.3 Analysis of the Ex2 and M band knockout transcriptome 63 5.4 Analysis of the Ex2 and M band knockout proteome 66 6 Discussion 75 6.1 Genetic approaches towards understanding titin biology 75 6.2 Titin deletions lead to skeletal and cardiac abnormalities 77 6.2.1 Sarcomeric disassembly results in skeletal muscular atrophy 79 6.2.2 Disruption of the sarcomere structure affects cardiac development 87 6.3 Conclusions and perspectives 103 7 Bibliography 109 8 Abbreviations 129 9 List of figures 135 10 List of tables 137 Acknowledgement 138 Curriculum vitae 140Titin forms a continuous filament along the myofibril and is essential for the development, the maintenance and the passive stiffness of the sarcomere. It contains the cardiac specific elastic N2B, and differentially spliced elastic PEVK region, as well as a titin kinase domain. Mutations of titin have been associated with severe cardiac and skeletal myopathies such as dilated cardiomyopathy (DCM) or hereditary myopathy with early respiratory failure (HMERF). To understand the role of titin’s functional domains in striated muscle health and disease, we created diverse knockout mice (KO). They demonstrated the importance of M band titin for the structural integrity of the sarcomere and the relation of the N2B and PEVK domains to cardiac trophic signaling and ventricular filling. To eliminate the holoprotein, we have generated a complete Titin knockout (TiEx2MCK) flanking the exon containing the ATG with lox sites and expressing the CRE recombinase in striated muscle. The comparison of the Z-disc to the M band KO mouse included phenotypic, morphologic, ultrastructural, transcriptomic and proteomic analyses. Both KO models developed a severe skeletal muscle atrophy caused by the disassembly of the sarcomere which led to a decreased body weight, strength endurance, and survival. The same sarcomere disassembly was present in cardiomyocytes of both models but led to the development of DCM in the TiEx2MCK KO whereas M band titin deficiency led to cardiac atrophy. These cardiac abnormalities can contribute to the decreased survival of the Z-disc KO animals. The proteomic analysis of both KO models revealed the differential expression of atrophy and hypertrophy associated proteins such as FHL2. We concluded that in both animal models, the skeletal muscle atrophy was caused by sarcomere disassembly, which also contributed to the cardiac phenotype. Additionally, titin’s N-terminus affects trophic signaling in the heart. This study validated titin’s role as an essential sarcomeric protein that does not only serve as an elastic scaffold, but also contributes to the regulation of striated muscle size.Titin bildet ein kontinuierliches Filament entlang der Myofibrille und ist wichtig für den Aufbau, den Erhalt und die passive Steifheit des Sarkomeres. Das Protein enthält die herzspezifische elastische N2B Domäne und die differenziell gespleiβte PEVK-Region, sowie eine Kinase-Domäne. Titin- Mutationen können zu schweren Herz- und Skeletmuskel-Erkrankungen wie dilatative Kardiomyopahtie oder der hereditären Myopathie mit frühem respiratorischem Fehler (HMERF) führen. Um die Rolle der unterschiedlichen Titindomänen in Funktion und Erkrankung der gestreiften Muskulatur zu untersuchen, haben wir unterschiedliche Knockout Mausmodelle generiert. Diese demonstrierten die Relevanz der M Bande für die strukturelle Integrität des Sarkomeres und die Rolle der N2B- and PEVK Domänen in der kardialen trophischen Reizweiterleitung und der Füllung des Ventrikels. Um das Gesamtprotein zu entfernen, haben wir das ATG-Exon mit lox Rekombinationssequenzen flankiert und die Cre Rekombinase in gestreiftem Muskel exprimiert (TiEx2MCK). Der Vergleich der Z Scheiben- und M-Banden- Knockout- Maus umfasste phänotypische, morphologische, ultrastrukturelle, transkriptomische und proteomische Analysen. Beide KO-Modelle entwickelten eine schwere Skeletmuskelatrophie die durch eine Auflösung der Sarkomerstruktur verursacht wurde und zu Gewichtsverlust, reduzierter Kraftausdauer und hoher Mortalität führte. Die Auflösung der Sarkomerstruktur betraf gleichermassen Kardiomyozyten beider KO Modelle, führte jedoch zur Ausbildung einer DCM im TiEx2MCK KO und einer kardialen Atrophie bei titin M Banden Defizienz. Diese kardialen Veränderungen können zur erhöhten Mortalität der Z Scheiben KO Tiere beitragen. Die Analyse des Proteoms beider KO Modelle zeigte die differenzielle Expression von Atrophie- und Hypertrophy assoziierten Proteinen wie FHL2. Entsprechend scheint die Skeletmuskelatrophie vorwiegend durch den Zusammenbruch der Sarkomerstruktur ausgelöst zu werden, die ebenfalls zum kardialen Phänotyp beiträgt. Zusätzlich führt der Verlust des Titin N Terminus zu veränderter trophischer Signaltransduktion im Herzen. Diese Studie validierte Titins Rolle als essentielles Sarkomerprotein, welches nicht nur als elastisches Gerüst fungiert, sondern auch an der Regulation des Wachstums der gestreiften Muskulatur beteiligt ist

Selfie-Presentation in Everyday Life: A Large-scale Characterization of Selfie Contexts on Instagram

Copyright © 2017, Association for the Advancement of Artificial Intelligence (www.aaai.org). All rights reserved.Presented at the International AAAI Conference on Web and Social Media (ICWSM), May 15 – 18, 2017, in Montreal, Canada.Carefully managing the presentation of self via technology is a core practice on all modern social media platforms. Recently, selfies have emerged as a new, pervasive genre of identity performance. In many ways unique, selfies bring us full-circle to Goffman—blending the online and offline selves together. In this paper, we take an empirical, Goffman-inspired look at the phenomenon of selfies. We report a large-scale, mixed-method analysis of the categories in which selfies appear on Instagram—an online community comprising over 400M people. Applying computer vision and network analysis techniques to 2.5M selfies, we present a typology of emergent selfie categories which represent emphasized identity statements. To the best of our knowledge, this is the first large-scale, empirical research on selfies. We conclude, contrary to common portrayals in the press, that selfies are really quite ordinary: they project identity signals such as wealth, health and physical attractiveness common to many online media, and to offline life

Selfie-Presentation in Everyday Life: A Large-Scale Characterization of Selfie Contexts on Instagram

Carefully managing the presentation of self via technology is a core practice on all modern social media platforms. Recently, selfies have emerged as a new, pervasive genre of identity performance. In many ways unique, selfies bring us full-circle to Goffman — blending the online and offline selves together. In this paper, we take an empirical, Goffman-inspired look at the phenomenon of selfies. We report a large-scale, mixed-method analysis of the categories in which selfies appear on Instagram — an online community comprising over 400M people. Applying computer vision and network analysis techniques to 2.5M selfies, we present a typology of emergent selfie categories which represent emphasized identity statements. To the best of our knowledge, this is the first large-scale, empirical research on selfies. We conclude, contrary to common portrayals in the press, that selfies are really quite ordinary: they project identity signals such as wealth, health and physical attractiveness common to many online media, and to offline life