573 research outputs found

    Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

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    Background: Approximately 450‚ÄČ000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2¬∑1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13¬∑0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63‚ÄČ093 individuals in the FHSC registry, 11‚ÄČ848 (18¬∑8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50¬∑2%) of 11‚ÄČ476 included individuals were female and 5720 (49¬∑8%) were male. Sex data were missing for 372 (3¬∑1%) of 11‚ÄČ848 individuals. Median age at registry entry was 9¬∑6 years (IQR 5¬∑8-13¬∑2). 10‚ÄČ099 (89¬∑9%) of 11‚ÄČ235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10¬∑1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5¬∑2%) of 11‚ÄČ848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92¬∑4%] of 10‚ÄČ202) than in children and adolescents from non-high-income countries (199 [48¬∑0%] of 415). 3414 (31¬∑6%) of 10‚ÄČ804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72¬∑4%) of 10‚ÄČ428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5¬∑00 mmol/L (IQR 4¬∑05-6¬∑08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

    Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

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    Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p‚ÄČ=‚ÄČ0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p‚ÄȂȧ‚ÄČ0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p‚ÄČ=‚ÄČ0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p‚ÄČ=‚ÄČ0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p‚ÄČ=‚ÄČ0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI ‚ąí 0.47, 1.37, p‚ÄČ=‚ÄČ0.34) and hospital (adj. difference 1.4 days; 95% CI ‚ąí 0.62, 2.35, p‚ÄČ=‚ÄČ0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p‚ÄČ=‚ÄČ0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson‚Äôs disease (PD) and Alzheimer‚Äôs disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aő≤42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

    Sleep quality and quantity in caregivers of children with type 1 diabetes using closed-loop insulin delivery or a sensor-augmented pump

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    Introduction. Parents of children living with type 1 diabetes (T1D) often report short and/or poor quality sleep. The development of closed-loop systems promises to transform the management of T1D. This study compared sleep quality and quantity in caregivers of children using a closed-loop system (CL) or sensor-augmented pump (SAP) therapy. Method. Data from sleep diaries, accelerometers, and questionnaires were provided by forty parents (classified as caregiver 1 (main analyses) or 2 (supplementary analyses) based on their contribution towards treatment management) of 21 very young children aged 1 to 7‚ÄČyears living with T1D (mean age: 4.7 (SD‚ÄČ=‚ÄČ1.7)). Assessments were made at a single post-randomisation time point when the child was completing either the 16-week CL arm (n‚ÄČ=‚ÄČ10) or the 16-week SAP arm (n‚ÄČ=‚ÄČ11) of the main study. Results. Overall, there was a mixed pattern of results and group differences were not statistically significant at the level. However, when we consider the direction of results and results from caregiver 1, sleep diary data showed that parents of the CL (as compared to the SAP) group reported a shorter sleep duration but better sleep quality, fewer awakenings, and less wake after sleep onset (WASO). Actiwatch data showed that caregiver 1 of the CL (as compared to the SAP) group had a shorter sleep latency; greater sleep efficiency; and less wake after sleep onset. Results from the Pittsburgh Sleep Quality Index also showed better sleep quality for caregiver 1 of the CL group as compared to the SAP group. Conclusions. Results from this study suggest that sleep quality and quantity in parents of children using CL were not significantly different to those using SAP. Considering effect sizes and the direction of the non-significant results, CL treatment could be associated with better sleep quality in the primary caregiver. However, further research is needed to confirm these findings. This trial is registered with NCT05158816

    Optimized De Novo Eriodictyol Biosynthesis in Streptomyces albidoflavus Using an Expansion of the Golden Standard Toolkit for Its Use in Actinomycetes

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    Eriodictyol is a hydroxylated flavonoid displaying multiple pharmaceutical activities, such as antitumoral, antiviral or neuroprotective. However, its industrial production is limited to extraction from plants due to its inherent limitations. Here, we present the generation of a Streptomyces albidoflavus bacterial factory edited at the genome level for an optimized de novo heterologous production of eriodictyol. For this purpose, an expansion of the Golden Standard toolkit (a Type IIS assembly method based on the Standard European Vector Architecture (SEVA)) has been created, encompassing a collection of synthetic biology modular vectors (adapted for their use in actinomycetes). These vectors have been designed for the assembly of transcriptional units and gene circuits in a plug-and-play manner, as well as for genome editing using CRISPR-Cas9-mediated genetic engineering. These vectors have been used for the optimization of the eriodictyol heterologous production levels in S. albidoflavus by enhancing the flavonoid-3′-hydroxylase (F3’H) activity (by means of a chimera design) and by replacing three native biosynthetic gene clusters in the bacterial chromosome with the plant genes matBC (involved in extracellular malonate uptake and its intracellular activation into malonyl-CoA), therefore allowing more malonyl-CoA to be devoted to the heterologous production of plant flavonoids in this bacterial factory. These experiments have allowed an increase in production of 1.8 times in the edited strain (where the three native biosynthetic gene clusters have been deleted) in comparison with the wild-type strain and a 13 times increase in eriodictyol overproduction in comparison with the non-chimaera version of the F3′H enzyme

    A search for an unexpected asymmetry in the production of e(+)mu(-) and e(-)mu(+) pairs in proton-proton collisions recorded by the ATLAS detector at root s=13 TeV

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    This search, a type not previously performed at ATLAS, uses a comparison of the production cross sections for e(+)mu(-) and e(-)mu(+) pairs to constrain physics processes beyond the Standard Model. It uses 139 fb(-1) of proton-proton collision data recorded at root s = 13 TeV at the LHC. Targeting sources of new physics which prefer final states containing e(+)mu(-) and e(-)mu(+), the search contains two broad signal regions which are used to provide model-independent constraints on the ratio of cross sections at the 2% level. The search also has two special selections targeting supersymmetric models and leptoquark signatures. Observations using one of these selections are able to exclude, at 95% confidence level, singly produced smuons with masses up to 640 GeV in a model in which the only other light sparticle is a neutralino when the R-parity-violating coupling lambda(23)(1)' is close to unity. Observations using the other selection exclude scalar leptoquarks with masses below 1880 GeV when g(1R)(eu) = g(1R)(mu c) = 1, at 95% confidence level. The limit on the coupling reduces to g(1R)(eu) = g(1R)(mu c) = 0.46 for a mass of 1420 GeV

    Adaptaci√≥n y validaci√≥n al espa√Īol del cuestionario UGEQ para la evaluaci√≥n de la cohesi√≥n grupal en estudiantes universitarios

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    Introduction: the assessment of group cohesion is a fundamental aspect in the context of higher education. However, there is a need for appropriate and specific instruments to assess this construct in the university context. Objective: to adapt and validate the University Group Environment Questionnaire (UGEQ) group cohesion measure to the Spanish population. Method: the sample used for this study consisted of 309 Spanish university students, with a mean age of 22.61 (SD=5.5). For data analysis, a confirmatory factorial analysis was performed, following the structure of the original instrument (UGEQ). Results: the results suggest optimal adjustment indices (CFI= 0.92; TLI=0.90; SRMR=0.068 and RMSEA= 0.081 [90% CI: 0.071-0.092]) and appropriate internal consistency (0.88 [95% CI: 0.86-0.90]) and temporal stability. Discussion: these findings support the use of the UGEQ as a valid and reliable instrument to assess group cohesion in the Spanish university context.Introducci√≥n: la evaluaci√≥n de la cohesi√≥n grupal es un aspecto fundamental en el contexto de la educaci√≥n superior. Sin embargo, existe la necesidad de instrumentos apropiados y espec√≠ficos para evaluar este constructo en el contexto universitario. Objetivo: adaptar y validar el University Group Environment Questionnaire (UGEQ) para evaluar la cohesi√≥n grupal en poblaci√≥n espa√Īola. M√©todo: la muestra utilizada para este estudio estuvo formada por 309 estudiantes universitarios, con una edad media de 22,61 a√Īos (DE=5,5). Para el an√°lisis de los datos, se realiz√≥ un an√°lisis factorial confirmatorio, siguiendo la estructura del instrumento original (UGEQ). Resultados: los resultados sugieren √≠ndices de ajuste √≥ptimos (CFI= 0,92; TLI=0,90; SRMR=0,068 y RMSEA= 0,081 [IC 90%: 0,071-0,092]) y consistencia interna adecuada (0,88 [IC 95%: 0,86-0,90]) y estabilidad temporal. Discusi√≥n: estos hallazgos apoyan el uso del UGEQ como un instrumento v√°lido y fiable para evaluar la cohesi√≥n grupal en el contexto universitario espa√Īol

    Sub-types of insomnia in adolescents: Insights from a quantitative/molecular twin study

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    Background: Insomnia with short sleep duration has been postulated as more severe than that accompanied by normal/long sleep length. While the short duration subtype is considered to have greater genetic influence than the other subtype, no studies have addressed this question. This study aimed to compare these subtypes in terms of: (1) the heritability of insomnia symptoms; (2) polygenic scores (PGS) for insomnia symptoms and sleep duration; (3) the associations between insomnia symptoms and a wide variety of traits/disorders. Methods: The sample comprised 4000 pairs of twins aged 16 from the Twins Early Development Study. Twin models were fitted to estimate the heritability of insomnia in both groups. PGS were calculated for self-reported insomnia and sleep duration and compared among participants with short and normal/long sleep duration. Results: Heritability was not significantly different in the short sleep duration group (A = 0.13 [95%CI = 0.01, 0.32]) and the normal/long sleep duration group (A = 0.35 [95%CI = 0.29, 0.40]). Shared environmental factors accounted for a substantial proportion of the variance in the short sleep duration group (C = 0.19 [95%CI = 0.05, 0.32]) but not in the normal/long sleep duration group (C = 0.00 [95%CI = 0.00, 0.04]). PGS did not differ significantly between groups although results were in the direction expected by the theory. Our results also showed that insomnia with short (as compared to normal/long) sleep duration had a stronger association with anxiety and depression (p < .05)‚ÄĒalthough not once adjusting for multiple testing. Conclusions: We found mixed results in relation to the expected differences between the insomnia subtypes in adolescents. Future research needs to further establish cut-offs for ‚Äėshort‚Äô sleep at different developmental stages and employ objective measures of sleep.TEDS is supported by a programme grant to Professor Robert Plomin from the UK Medical Research Council (MR/V012878/1 and previously MR/M021475/1) as well as Medical Research Council grant to AR (grant number G1100559) with additional support from the US National Institutes of Health (AG046938)

    Falls Predict Acute Hospitalization in Parkinson's Disease

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    [Background] There is a need for identifying risk factors for hospitalization in Parkinson‚Äôs disease (PD) and also interventions to reduce acute hospital admission.[Objective] To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort.[Methods] PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson‚Äôs DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit.[Results] Thirty-five out of 605 (5.8%) PD patients (62.5¬Ī8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065‚Äď5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319‚Äď6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757‚Äď8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124‚Äď4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080‚Äď8.322; p = 0.035) was an independent predictor of AH.[Conclusion] Falls is an independent predictor of AH in PD patients.Peer reviewe
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