Cluster Analysis of Symptoms Among Patients with Upper Extremity Musculoskeletal Disorders

Introduction Some musculoskeletal disorders of the upper extremity are not readily classified. The study objective was to determine if there were symptom patterns in self-identified repetitive strain injury (RSI) patients. Methods Members (n = 700) of the Dutch RSI Patients Association filled out a detailed symptom questionnaire. Factor analysis followed by cluster analysis grouped correlated symptoms. Results Eight clusters, based largely on symptom severity and quality were formulated. All but one cluster showed diffuse symptoms; the exception was characterized by bilateral symptoms of stiffness and aching pain in the shoulder/neck. Conclusions Case definitions which localize upper extremity musculoskeletal disorders to a specific anatomical area may be incomplete. Future clustering studies should rely on both signs and symptoms. Data could be collected from health care providers prospectively to determine the possible prognostic value of the identified clusters with respect to natural history, chronicity, and return to work

Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance

Phagocytic removal of apoptotic cells occurs efficiently in vivo such that even in tissues with significant apoptosis, very few apoptotic cells are detectable1. This is thought to be due to the release of find-me signals by apoptotic cells that recruit motile phagocytes such as monocytes, macrophages, and dendritic cells, leading to the prompt clearance of the dying cells2. However, the identity and in vivo relevance of such find-me signals are not well understood. Here, through several lines of evidence, we identify extracellular nucleotides as a critical apoptotic cell find-me signal. We demonstrate the caspase-dependent release of ATP and UTP (in equimolar quantities) during the early stages of apoptosis by primary thymocytes and cell lines. Purified nucleotides at these concentrations were sufficient to induce monocyte recruitment comparable to apoptotic cell supernatants. Enzymatic removal of ATP and UTP (by apyrase or ectopic CD39 expression) abrogated the ability of apoptotic cell supernatants to recruit monocytes in vitro and in vivo. We then identified the ATP/UTP receptor P2Y2 as a critical sensor of nucleotides released by apoptotic cells using RNAi depletion studies in monocytes, and macrophages from P2Y2-null mice3. The in vivo relevance of nucleotides in apoptotic cell clearance was revealed by two approaches. First, in a murine air-pouch model, apoptotic cell supernatants induced a three-fold greater recruitment of monocytes and macrophages compared to supernatants from healthy cells; this recruitment was abolished by depletion of nucleotides and significantly decreased in P2Y2−/− mice. Second, clearance of apoptotic thymocytes was significantly impaired by either depletion of nucleotides or interference with P2Y receptor function (by pharmacological inhibition, or in P2Y2−/− mice). These results identify nucleotides as a critical find-me cue released by apoptotic cells to promote P2Y2-dependent phagocyte recruitment, and provide strong evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, n(effective) = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (vertical bar r(g)vertical bar > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range vertical bar r(g)vertical bar = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.Peer reviewe

Genetic and environmental influences on human height from infancy through adulthood at different levels of parental education

Genetic factors explain a major proportion of human height variation, but differences in mean stature have also been found between socio-economic categories suggesting a possible effect of environment. By utilizing a classical twin design which allows decomposing the variation of height into genetic and environmental components, we tested the hypothesis that environmental variation in height is greater in offspring of lower educated parents. Twin data from 29 cohorts including 65,978 complete twin pairs with information on height at ages 1 to 69 years and on parental education were pooled allowing the analyses at different ages and in three geographic-cultural regions (Europe, North America and Australia, and East Asia). Parental education mostly showed a positive association with offspring height, with significant associations in mid-childhood and from adolescence onwards. In variance decomposition modeling, the genetic and environmental variance components of height did not show a consistent relation to parental education. A random-effects meta-regression analysis of the aggregate-level data showed a trend towards greater shared environmental variation of height in low parental education families. In conclusion, in our very large dataset from twin cohorts around the globe, these results provide only weak evidence for the study hypothesis.Peer reviewe

Parental Education and Genetics of BMI from Infancy to Old Age : A Pooled Analysis of 29 Twin Cohorts

Objective The objective of this study was to analyze how parental education modifies the genetic and environmental variances of BMI from infancy to old age in three geographic-cultural regions. Methods A pooled sample of 29 cohorts including 143,499 twin individuals with information on parental education and BMI from age 1 to 79 years (299,201 BMI measures) was analyzed by genetic twin modeling. Results Until 4 years of age, parental education was not consistently associated with BMI. Thereafter, higher parental education level was associated with lower BMI in males and females. Total and additive genetic variances of BMI were smaller in the offspring of highly educated parents than in those whose parents had low education levels. Especially in North American and Australian children, environmental factors shared by co-twins also contributed to the higher BMI variation in the low education level category. In Europe and East Asia, the associations of parental education with mean BMI and BMI variance were weaker than in North America and Australia. Conclusions Lower parental education level is associated with higher mean BMI and larger genetic variance of BMI after early childhood, especially in the obesogenic macro-environment. The interplay among genetic predisposition, childhood social environment, and macro-social context is important for socioeconomic differences in BMI.Peer reviewe

Spatial heterogeneity and environmental predictors of permafrost region soil organic carbon stocks

Large stocks of soil organic carbon (SOC) have accumulated in the Northern Hemisphere permafrost region, but their current amounts and future fate remain uncertain. By analyzing dataset combining >2700 soil profiles with environmental variables in a geospatial framework, we generated spatially explicit estimates of permafrost-region SOC stocks, quantified spatial heterogeneity, and identified key environmental predictors. We estimated that Pg C are stored in the top 3 m of permafrost region soils. The greatest uncertainties occurred in circumpolar toe-slope positions and in flat areas of the Tibetan region. We found that soil wetness index and elevation are the dominant topographic controllers and surface air temperature (circumpolar region) and precipitation (Tibetan region) are significant climatic controllers of SOC stocks. Our results provide first high-resolution geospatial assessment of permafrost region SOC stocks and their relationships with environmental factors, which are crucial for modeling the response of permafrost affected soils to changing climate

Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The Fate of the pulmonary autograft and left ventricle after Ross-operation in children

Einleitung: Das Ziel dieser Arbeit war die Darstellung der Ergebnisse der Ross- Operation in der Kinderherzchirurgie der Universitätsmedizin Göttingen als Verfahren des AKE durch die eigene Pulmonalklappe (Autograft) bei Kindern und Jugendlichen unter besonderer Berücksichtigung der Haltbarkeit und Funktion des pulmonalen Autografts und der postoperativen Entwicklung des hypertrophierten linken Ventrikels. Zu diesem Zwecke wurden retrospektiv klinische Daten bezüglich der linksventrikulären Funktion und Haltbarkeit des pulmonalen Autografts und der klinischen Belastbarkeit ausgewertet. Patienten und Methoden: Untersucht wurden die Entwicklung der Neo-Aortenklappe (Autograftklappe) und des linken Ventrikels nach Ross-Operation bei 31 Patienten unter 21 Jahren, die zwischen 1994 und 2008 in Göttingen operiert wurden. Das Alter der untersuchten Patienten betrug zum Operationszeitpunkt zwischen 6 Monaten und 20 Jahren (Mittelwert: 133 Monate b= 11,1 Jahre). Der Nachbeobachtungszeitraum variierte zwischen 10 Monaten und 14 Jahren (Mittelwert: 67 Monate b= 5,6 Jahre). Retrospektiv wurden 2 verfügbare postoperative Echokardiographien bezüglich der Durchmesser des Aortenklappenrings, der Aortenwurzel, des sino-tubulären Übergangs, des LVESD, des LVEDD, des IVS und der linksventrikulären HW ausgewertet. Zur Vergleichbarkeit des untersuchten Kollektivs mit gesunden Kindern und Jugendlichen wurden mit Hilfe von Regressionskurven nach Daubeney et al. (1999) und Pettersen et al. (2008) Z-Werte für die gemessenen Durchmesser bestimmt und ihre Entwicklung durch statistische Methoden ausgewertet. Ergebnisse: Im untersuchten Patientenkollektiv konnte kein signifikanter Anstieg der Z-Werte der Durchmesser der Neo-Aortenklappe und des linken Ventrikels beobachtet werden. Die Z-Werte des Neo-Aortenwurzel-Durchmessers und des LVEDD näherten sich im Verlauf signifikant den Normkurven an. Bei keinem Patienten wurde ein Ersatz des Autografts notwendig. 1 Patient benötigte eine operative Revision der Neo-Aortenklappe in Form einer supravalvul¨aren Kürzung und Ummantelung der Autograft-Wurzel bzw. des sino-tubulären Übergangs. Bei 15 Patienten kam es im Verlauf zu einer Autograftinsuffizienz ersten Grades. Diese beobachteten Einschränkungen der Neo-Aortenklappenfunktion im Sinne einer geringen oder trivialen Insuffizienz waren ohne klinische Relevanz. 1 Patientin verstarb unmittelbar postoperativ an einer intrazerebralen Blutung. Zu weiteren schwerwiegenden Komplikationen kam es nicht. Die Haltbarkeit des Pulmonalis-Ersatzes durch einen Homograft oder einen Xenograft war bereits innerhalb der ersten postoperativen Dekade limitiert. Im postoperativen Nachbeobachtungszeitraum benötigten 5 Patienten einen Austausch des Implantats. Bei den ausgetauschten Homografts handelte es sich in 3 Fällen um Pulmonalis-Homografts und in 2 Fällen um Aortenhomografts. Fazit: Die Ross-Operation ist ein Verfahren des AKE, das besonders für Kinder und Jugendliche auf Grund des Wachstumspotentials, der exzellenten Hämodynamik, der Regenerationsfähigkeit, der Infektresistenz, der uneingeschränkten natürlichen Funktion und der Athrombogenität besonders geeignet ist. Auch für Frauen mit Kinderwunsch und junge Männer mit Risikoprofil (durch Sport oder verletzungsträchtige Berufstätigkeit) oder Patienten mit Kontraindikation für eine Phenprocoumon-Therapie ist die Ross- Operation wegen der nicht notwendigen Marcumarisierung eine attraktive Behandlungsoption. Die befürchtete Dilatation des Autografts im Langzeitverlauf konnte nicht beobachtet werden