bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug‐resistant tuberculosis
Authors: Mugabo Pierre , Mulubwa Mwila 
Published: February 2021

IntroductionEthionamide is part of the drug‐resistant tuberculosis regimen whose pharmacokinetic (PK) and pharmacodynamic (PD) information is limited. The aim of the study was to describe the PK and simulate doses to assess PD attainment.MethodsThis was an observational population PK study of patients admitted for drug‐resistant tuberculosis at a hospital in South Africa. Nonlinear mixed‐effects modelling implemented in Monolix 2019R2 was used to estimate population pharmacokinetic parameters. We performed Monte Carlo simulations to assess and optimise the dose regimen. The target Cmax range was 2.5‐5 μg/mL, which is within the minimum inhibitory concentration (MIC) range. The target AUC0‐24h was 140.5 μg*h/mL, which corresponds to the PK/PD target ratio AUC0‐24h/MIC of 56.2.ResultsA one‐compartment pharmacokinetic model with a lag‐time, first‐order absorption and elimination best described the PK of ethionamide. The lag‐time, absorption rate constant (ka), volume of distribution (V/F) and clearance (Cl/F) were 0.66 hours, 0.434 h−1, 180 L and 99.5 L/h, respectively, for a typical individual weighing 52.6 kg. Between‐subject variability in lag‐time, ka, V/F and Cl/F were 38%, 92%, 168% and 120%, respectively. Simulation of the recommended doses of 15‐20 mg/kg, 500 mg, 750 mg and 1000 mg for patients in the weight bands <33, 33‐50, 51‐70 and >70 kg resulted in <17% and 3% of the patients achieving the target Cmax and AUC0‐24h, respectively.ConclusionThere is high variability in ethionamide PK and very few patients attain the desired target exposure at standard or optimised doses. We propose individualised dose regimen optimisation.
Exploring mechanisms of change in a dyadic relationship intervention for siblings in foster care
Authors: Waid Jeffrey , Kothari Brianne H. , Dahlgren Jessica A. , McBeath Bowen , Bank Lew 
Published: February 2021

AbstractThere is increasing recognition of the potential for sibling relationships to promote the well‐being of youth in out‐of‐home care. Efficacious interventions now exist to strengthen the sibling relationships for youth in out‐of‐home care, yet the processes through which these interventions work to enhance sibling relationships remains largely speculative. The current study therefore aimed to identify the critical components of an efficacious dyadic relationship enhancement intervention for siblings in foster care through a secondary analysis of fidelity of implementation and trial outcome data. Data for 168 youth from the treatment condition of the Supporting Siblings in Foster Care study were analysed. Fidelity of implementation was assessed across seven intervention domains: Sibs 4 Life, Positive/Sib Thinking, Activity Planning, Problem Solving, Cooperation, Managing Feelings and Adult Allies. Trial outcome data were drawn from efficacy test results and included a multi‐agent construct of sibling relationship quality. Descriptive statistics detailed intervention implementation, and hierarchical linear models examined associations between intervention coverage, comprehension, and engagement, and 18‐month improvements to the sibling relationship. Results indicate high fidelity to implementation, and Positive/Sib Thinking was the primary intervention domain associated with sibling relationship improvements. Considerations for future mechanisms‐based intervention research with siblings in out‐of‐home care are provided.
De novo variants in neurodevelopmental disorders—experiences from a tertiary care center
Authors: Brunet Theresa , Jech Robert , Brugger Melanie , Kovacs Reka , Alhaddad Bader , Leszinski Gloria , Riedhammer Korbinian M. , Westphal Dominik S. , Mahle Isabella , Mayerhanser Katharina , Skorvanek Matej , Weber Sandrina , Graf Elisabeth , Berutti Riccardo , Necpál Ján , Havránková Petra , Pavelekova Petra , Hempel Maja , Kotzaeridou Urania , Hoffmann Georg F. , Leiz Steffen , Makowski Christine , Roser Timo , Schroeder Sebastian A. , Steinfeld Robert , Strobl‐Wildemann Gertrud , Hoefele Julia , Borggraefe Ingo , Distelmaier Felix , Strom Tim M. , Winkelmann Juliane , Meitinger Thomas , Zech Michael , Wagner Matias 
Published: February 2021

AbstractUp to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent‐offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different—mostly constrained—genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio‐approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.
Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19
Authors: Delaunois Annie , Abernathy Matthew , Anderson Warren D. , Beattie Kylie A. , Chaudhary Khuram W. , Coulot Julie , Gryshkova Vitalina , Hebeisen Simon , Holbrook Mark , Kramer James , Kuryshev Yuri , Leishman Derek , Lushbough Isabel , Passini Elisa , Redfern Will S. , Rodriguez Blanca , Rossman Eric I. , Trovato Cristian , Wu Caiyun , Valentin Jean‐Pierre 
Published: February 2021

AbstractWe applied a set of in silico and in vitro assays, compliant with the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm, to assess the risk of chloroquine (CLQ) or hydroxychloroquine (OH‐CLQ)‐mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin (ERT) and azithromycin (AZI), drugs repurposed during the first wave of coronavirus disease 2019 (COVID‐19). Each drug or drug combination was tested in patch clamp assays on seven cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual Assay) using control (healthy) or high‐risk cell populations, and in human‐induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes. In each assay, concentration‐response curves encompassing and exceeding therapeutic free plasma levels were generated. Both CLQ and OH‐CLQ showed blocking activity against some potassium, sodium, and calcium currents. CLQ and OH‐CLQ inhibited IKr (half‐maximal inhibitory concentration [IC50]: 1 µM and 3–7 µM, respectively) and IK1 currents (IC50: 5 and 44 µM, respectively). When combining OH‐CLQ with AZI, no synergistic effects were observed. The two macrolides had no or very weak effects on the ion currents (IC50 > 300–1000 µM). Using Virtual Assay, both antimalarials affected several TdP indicators, CLQ being more potent than OH‐CLQ. Effects were more pronounced in the high‐risk cell population. In hiPSC‐derived cardiomyocytes, all drugs showed early after‐depolarizations, except AZI. Combining CLQ or OH‐CLQ with a macrolide did not aggravate their effects. In conclusion, our integrated nonclinical CiPA dataset confirmed that, at therapeutic plasma concentrations relevant for malaria or off‐label use in COVID‐19, CLQ and OH‐CLQ use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination.
How to provide a structured clinical assessment of a patient with overweight or obesity
Authors: Bessell Erica , Markovic Tania P. , Fuller Nicholas R. 
Published: February 2021

AbstractWith the increasing prevalence of overweight and obesity worldwide, there is a reciprocal increase in the global economic burden and ill‐health from obesity‐related chronic diseases. Primary healthcare services have a role to play in ensuring early detection of weight issues and in directing patients towards evidence‐based care to slow this progression. Research shows that many people with obesity are motivated to lose weight and want their clinician to initiate a conversation about weight management and treatment options. However, this conversation rarely occurs and there is a significant delay in treatment, resulting in an increased burden on the individual, healthcare system and society. In this paper, the components and rationale for the clinical assessment of adult patients with overweight or obesity, including anthropometric measurements and pathology tests, are described. Recommendations to ascertain the potential factors influencing the development of obesity in the patient, such as lifestyle factors (diet and physical activity) and mental health, are also provided. The potential sequelae of obesity that may be present and the necessary assessments for diagnosis are also addressed. These assessments are vital to ensure the patient is referred to the appropriate allied health services and/or specialists.
Diabetes duration and glycaemic control as predictors of cardiovascular disease and mortality
Authors: Li Fu‐Rong , Yang Hai‐Lian , Zhou Rui , Zheng Jia‐Zhen , Chen Guo‐Chong , Zou Meng‐Chen , Wu Xiao‐Xiang , Wu Xian‐Bo 
Published: February 2021

AbstractAimsTo assess the associations of diabetes duration and glycaemic control (defined by plasma glycated haemoglobin [HbA1c] level) with the risks of cardiovascular disease (CVD) and all‐cause mortality and to determine whether the addition of either or both to the established CVD risk factors can improve predictions.Materials and MethodsA total of 435 679 participants from the UK Biobank without CVD at baseline were included. Cox models adjusting for classic risk factors (sociodemographic and anthropometric characteristics, lipid profiles and medication use) were used, and predictive utility was determined by the C‐index and net reclassification improvement (NRI).ResultsCompared with participants without diabetes, participants with longer diabetes durations and poorer glycaemic control had a higher risk of fatal/nonfatal CVD. Among participants with diabetes, the fully‐adjusted hazard ratios (HRs) for diabetes durations of 5 to <10 years, 10 to <15 years and ≥15 years were 1.15 (95% confidence interval [CI] 0.99, 1.34), 1.50 (95% CI 1.26, 1.79) and 2.22 (95% CI 1.90, 2.58; P‐trend <0.01), respectively, compared with participants with diabetes durations <5 years. In addition, those with the longest disease duration (≥15 years) and poorer glycaemic control (HbA1c ≥64 mmol/mol [8%]) had the highest risk of fatal/nonfatal CVD (HR 3.12, 95% CI 2.52, 3.86). Among participants with diabetes, the addition of both diabetes duration and glycaemic control levels significantly improved both the C‐index (change in C‐index +0.0254; 95% CI 0.0111, 0.0398) and the overall NRI for fatal/nonfatal CVD (0.0992; 95% CI 0.0085, 0.1755) beyond the use of the classic risk factors.ConclusionsBoth longer diabetes duration and poorer glycaemic control were associated with elevated risks of CVD and mortality. Clinicians should consider not only glycaemic control but also diabetes duration in CVD risk assessments for participants with diabetes.
Obesity as a driver of international differences in COVID‐19 death rates
Authors: Gardiner Julian , Oben Jude , Sutcliffe Alastair 
Published: February 2021

AbstractAimTo determine what proportion of the inter‐country variation in death rates can be explained in terms of obesity rates and other known risk factors for coronavirus disease 2019 (COVID‐19).Materials and MethodsCOVID‐19 death rates from 30 industrialized countries were analysed using linear regression models. Covariates modelled population density, the age structure of the population, obesity, population health, per capita gross domestic product (GDP), ethnic diversity, national temperature and the delay in the government imposing virus control measures.ResultsThe multivariable regression model explained 63% of the inter‐country variation in COVID‐19 death rates. The initial model was optimized using stepwise selection. In descending order of absolute size of model coefficient, the covariates in the optimized model were the obesity rate, the hypertension rate, population density, life expectancy, the percentage of the population aged older than 65 years, the percentage of the population aged younger than 15 years, the diabetes rate, the delay in imposing national COVID‐19 control measures, per capita GDP and mean temperature (with a negative coefficient indicating an association between higher national temperatures and lower death rates).ConclusionsA large proportion of the inter‐country variation in COVID‐19 death rates can be explained by differences in obesity rates, population health, population densities, age demographics, delays in imposing national virus control measures, per capita GDP and climate. Some of the unexplained variation is probably attributable to inter‐country differences in the definition of a COVID‐19 death and in the completeness of the recording of COVID‐19 deaths.
Prenatal diagnosis of partial absence of the tricuspid valve with perimembranous ventricular septal defect—The utility of prenatal 4‐dimensional spatiotemporal image correlation rendering
Authors: Karmegaraj Balaganesh , Manickavasagam Madhubala , Ibrahim Syed , Razeen Mohamed , Srimurugan Balaji 
Published: February 2021

AbstractFirst described in 1965 by Johnson and Wilcox, partial absence of the tricuspid valve (TV) associated with a ventricular septal defect (VSD) is a very rare malformation (Ann Surg. 1966;164:334‐336). Heart failure secondary to severe TV regurgitation results in utero fetal compromise (J Am Coll Cardiol. 1991;17:167). We present here a fetus with partial absence of the tricuspid valve with perimembranous VSD.
What factors increase the vulnerability of native birds to the impacts of alien birds?
Authors: Evans Thomas , Jeschke Jonathan M. , Liu Chunlong , Redding David W. , Şekercioğlu Çağan H. , Blackburn Tim M. 
Published: February 2021

Biodiversity impacts caused by alien species can be severe, including those caused by alien birds. In order to protect native birds, we aimed to identify factors that influence their vulnerability to the impacts of alien birds. We first reviewed the literature to identify native bird species sustaining such impacts. We then assigned impact severity scores to each native bird species, depending on the severity of the impacts sustained, and performed two types of analyses. First, we used contingency table tests to examine the distribution of impacts across their severity, type and location, and across native bird orders. Second, we used mixed‐effects models to test factors hypothesised to influence the vulnerability of native birds to the impacts of alien birds.Ground‐nesting shorebirds and seabirds were more prone to impacts through predation, while cavity‐nesting woodpeckers and parrots were more prone to impacts through competition. Native bird species were more vulnerable when they occupied islands, warm regions, regions with climatic conditions similar to those in the native range of the invading alien species, and when they were physically smaller than the invading alien species. To a lesser extent, they were also vulnerable when they shared habitat preferences with the invading alien species.By considering the number and type of native bird species affected by alien birds, we demonstrate predation impacts to be more widespread than previously indicated, but also that damaging predation impacts may be underreported. We identify vulnerable orders of native birds, which may require conservation interventions; characteristics of native birds that increase their vulnerability, which may be used to inform risk assessments; and regions where native birds are most vulnerable, which may direct management interventions. The impacts sustained by native birds may be going unnoticed in many regions of the world: there is a clear need to identify and manage them.
The geography of metapopulation synchrony in dendritic river networks
Authors: Larsen Stefano , Comte Lise , Filipa Filipe Ana , Fortin Marie‐Josée , Jacquet Claire , Ryser Remo , Tedesco Pablo A. , Brose Ulrich , Erős Tibor , Giam Xingli , Irving Katie , Ruhi Albert , Sharma Sapna , Olden Julian D. 
Published: February 2021

AbstractDendritic habitats, such as river ecosystems, promote the persistence of species by favouring spatial asynchronous dynamics among branches. Yet, our understanding of how network topology influences metapopulation synchrony in these ecosystems remains limited. Here, we introduce the concept of fluvial synchrogram to formulate and test expectations regarding the geography of metapopulation synchrony across watersheds. By combining theoretical simulations and an extensive fish population time‐series dataset across Europe, we provide evidence that fish metapopulations can be buffered against synchronous dynamics as a direct consequence of network connectivity and branching complexity. Synchrony was higher between populations connected by direct water flow and decayed faster with distance over the Euclidean than the watercourse dimension. Likewise, synchrony decayed faster with distance in headwater than mainstem populations of the same basin. As network topology and flow directionality generate fundamental spatial patterns of synchrony in fish metapopulations, empirical synchrograms can aid knowledge advancement and inform conservation strategies in complex habitats.
Insomnia disorder: clinical and research challenges for the 21st century
Authors: Ferini‐Strambi Luigi , Auer Reto , Bjorvatn Bjørn , Castronovo Vincenza , Franco Oscar , Gabutti Luca , Galbiati Andrea , Hajak Goeran , Khatami Ramin , Kitajima Tsuyoshi , McEvoy Doug , Nissen Christoph , Perlis Michael , Pevernagie Dirk A. , Randerath Winfried , Riemann Dieter , Rizzo Giovanni , Van Someren Eus , Vgontzas Alexandros , Barazzoni Fabrizio , Bassetti Claudio ,   the European Sleep Foundation
Published: February 2021

AbstractBackground and purposeInsomnia is a common and debilitating disorder that is frequently associated with important consequences for physical health and well‐being.MethodsAn international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field of insomnia and identified future priorities.ResultsThe association of trajectories of insomnia with subsequent quality of life, health and mortality should be investigated in large populations. Prospective health economics studies by separating the costs driven specifically by insomnia and costs attributable to its long‐term effects are needed. Ignoring the heterogeneity of insomnia patients leads to inadequate diagnosis and inefficient treatment. Individualized interventions should be promoted. More data are needed on both the impact of sleep on overnight effects, such as emotion regulation, and the potential compensatory effort to counteract diurnal impairments. Another gap is the definition of neurocognitive deficits in insomnia patients compared to normal subjects after chronic sleep loss. There are also a number of key gaps related to insomnia treatment. Expert guidelines indicate cognitive–behavioural therapy for insomnia as first‐line treatment. They neglect, however, the reality of major healthcare providers. The role of combined therapy, cognitive–behavioural therapy for insomnia plus pharmacological treatment, should be evaluated more extensively.ConclusionWhilst insomnia disorder might affect large proportions of the population, there are a number of significant gaps in the epidemiological/clinical/research studies carried out to date. In particular, the identification of different insomnia phenotypes could allow more cost‐effective and efficient therapies.
Early apathetic, but not depressive, symptoms are associated with poor outcome after stroke
Authors: Lopatkiewicz Anna Maria , Pera Joanna , Slowik Agnieszka , Dziedzic Tomasz 
Published: February 2021

AbstractBackground and purposeDepression and apathy are frequent neuropsychiatric disturbances after stroke and may appear together. Despite the overlap in symptoms between poststroke depression and apathy, these two syndromes might be associated with different prognoses and benefit from different treatments. We aimed to disentangle the relationship between early depressive and apathetic symptoms and outcome after stroke.MethodsOf 698 enrolled patients with ischemic stroke, we included 443 participants (median age = 69 years, 51% female) who underwent depressive and apathetic symptom assessment on Day 8 after stroke. We divided patients into four groups: without greater depressive and apathetic symptoms (Group 1), with only apathetic symptoms (Group 2), with only depressive symptoms (Group 3), and with both depressive and apathetic symptoms (Group 4).ResultsAfter adjusting for age and stroke severity, Group 2 and Group 4 had an increased risk of poor 3‐month outcome (odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.16–3.38, p = 0.01 and OR = 1.58, 95% CI = 1.24–2.01, p < 0.01, respectively). Group 2 and Group 4 also had an increased risk of poor 12‐month outcome (OR = 3.85, 95% CI = 2.19–6.78, p < 0.01 and OR = 1.54, 95% CI = 1.22–1.96, p < 0.01, respectively) and mortality (hazard ratio [HR] = 2.76, 95% CI = 1.19–6.41, p = 0.02 and HR = 1.77, 95% CI = 1.32–2.38, p < 0.01, respectively). Compared with Group 1, Group 3 did not have an increased risk of unfavorable outcomes.ConclusionsEarly apathetic, but not depressive, symptoms are related to worse outcomes after stroke. Our study underscores the importance of recognizing apathetic symptoms independently from depressive symptoms.
Association between neuropathy and B‐vitamins: A systematic review and meta‐analysis
Authors: Stein Johannes , Geisel Juergen , Obeid Rima 
Published: February 2021

AbstractBackgroundPeripheral neuropathy (PN) is common in patients with diseases that are in turn associated with deficiency of the B‐vitamins, and vitamin treatment has shown mixed results.MethodsThis systematic review and meta‐analysis studied the association between PN/pain and B‐vitamin biomarkers and investigated whether vitamin treatment can ameliorate the symptoms. PubMed and Web of Science were searched according to the study protocol.ResultsA total of 46 observational and seven interventional studies were identified and included in the data synthesis. The presence of PN was associated with lowered B12 levels (pooled estimate [95% CIs] = 1.51 [1.23–1.84], n = 34, Cochran Q Test I2 = 43.3%, p = 0.003) and elevated methylmalonic acid (2.53 [1.39–4.60], n = 9, I2 = 63.8%, p = 0.005) and homocysteine (3.48 [2.01–6.04], n = 15, I2 = 70.6%, p < 0.001). B12 treatment (vs. the comparators) showed a non‐significant association with symptom improvement (1.36 (0.66–2.79), n = 4, I2 = 28.9%). Treatment with B1 was associated with a significant improvement in symptoms (5.34 [1.87–15.19], n = 3, I2 = 64.6%, p = 0.059). Analysis of seven trials combined showed a non‐significant higher odds ratio for improvement under treatment with the B‐vitamins (2.58 [0.98–6.79], I2 = 80.0%, p < 0.001).ConclusionsPN is associated with lowered plasma vitamin B12 and elevated methylmalonic acid and homocysteine. Overall, interventional studies have suggested that B‐vitamins could improve symptoms of PN. Available trials have limitations and generally did not investigate vitamin status prior to treatment. Well‐designed studies, especially in non‐diabetes PN, are needed. This meta‐analysis is registered at PROSPERO (ID: CRD42020144917).