bluuebunny/crossref_metadata_2025 huggingface dataset:
A random forest-based framework for genotyping and accuracy assessment of copy number variations
Authors: Zhuang Xuehan , Ye Rui , So Man-Ting , Lam Wai-Yee , Karim Anwarul , Yu Michelle , Ngo Ngoc Diem , Cherny Stacey S , Tam Paul Kwong-Hang , Garcia-Barcelo Maria-Mercè , Tang Clara Sze-man , Sham Pak Chung
Published: September 2020

Detection of copy number variations (CNVs) is essential for uncovering genetic factors underlying human diseases. However, CNV detection by current methods is prone to error, and precisely identifying CNVs from paired-end whole genome sequencing (WGS) data is still challenging. Here, we present a framework, CNV-JACG, for Judging the Accuracy of CNVs and Genotyping using paired-end WGS data. CNV-JACG is based on a random forest model trained on 21 distinctive features characterizing the CNV region and its breakpoints. Using the data from the 1000 Genomes Project, Genome in a Bottle Consortium, the Human Genome Structural Variation Consortium and in-house technical replicates, we show that CNV-JACG has superior sensitivity over the latest genotyping method, SV2, particularly for the small CNVs (≤1 kb). We also demonstrate that CNV-JACG outperforms SV2 in terms of Mendelian inconsistency in trios and concordance between technical replicates. Our study suggests that CNV-JACG would be a useful tool in assessing the accuracy of CNVs to meet the ever-growing needs for uncovering the missing heritability linked to CNVs.
Invasive Haemophilus influenzae Infections in Germany After the Introduction of Routine Childhood Immunization, 2001–2016
Authors: Takla Anja , Schönfeld Viktoria , Claus Heike , Krone Manuel , an der Heiden Matthias , Koch Judith , Vogel Ulrich , Wichmann Ole , Lâm Thiên-Trí
Published: September 2020

Background

Haemophilus influenzae (Hi) serotype b (Hib) vaccination was introduced in Germany in 1990. This study presents a comprehensive overview on the burden of invasive Hi infections for 2001–2016, including serotype distribution and ampicillin resistance.

Methods

Nationwide data from statutory disease surveillance (2001–2016) were linked with laboratory surveillance data (2009–2016). Besides descriptive epidemiology, statistical analyses included multiple imputation to estimate secular trends.

Results

In 2001–2016, 4044 invasive Hi infections were reported. The mean incidence was 3.0 per million inhabitants, higher in males (3.2 vs 2.9 in females) and in the age groups <1 year (15.2) and ≥80 years (15.5). Nontypeable Hi (NTHi) caused 81% (n = 1545) of cases in 2009–2016. Of capsulated cases, 69% were serotype f and 17% serotype b. Of Hib cases eligible for vaccination, 10% (3/29) were fully vaccinated. For 2009–2016, significant increasing trends were observed for NTHi and Hif infections in the age groups <5 years and ≥60 years and for ampicillin resistance in NTHi.

Conclusions

This is one of the most comprehensive Hi data analyses since the introduction of Hib vaccines. NTHi and Hif cause an increasing disease burden among elderly patients and infants. Ampicillin resistance in NTHi must be considered in the treatment of invasive Hi infections.
Acute Cervical Radiculopathy Outcomes: Soft Disc Herniations vs Osteophytes
Authors: Beckworth William Jeremy , Abramoff Benjamin A , Bailey Iain M , Yoon Sook , Umpierrez Monica , Kakarala Aparna , Lee Jacob Y , Ward Laura A , Dows-Martinez Marly N , Yoon S Tim
Published: September 2020

Objective

Prospectively evaluate the clinical outcomes of acute cervical radiculopathy with respect to soft disc herniations vs osteophytes.

Methods

Sixty consecutive patients who had had cervical radiculopathy for ≤1 month were enrolled in the study. Inclusion criteria were radicular pain greater than axial pain and a pain score ≥4 out of 10 on a numerical rating scale. Patients had at least one positive clinical finding: motor, sensory, or reflex changes. Plain films and magnetic resonance imaging were ordered. Follow-up was at 6 weeks and 3, 6, and 12 months. Outcomes included pain scores (neck and upper limb), neck disability index, medication use, opioid use, and need for surgery. Two attending musculoskeletal radiologists reviewed imaging findings for osteophytes vs soft disc herniations at the symptomatic level.

Results

More than 75% reduction in pain was seen in 77% of patients with soft disc herniations and 66% of patients with osteophytes (P > 0.05) at 12 months. A pain score ≤2 out of 10 within 6 to 12 months was seen in 86% of patients with soft disc herniations and 81% of patients with osteophytes (P > 0.05). Moderate or marked improvement at 12 months was seen in 85% of patients with soft discs and 77% of patients with osteophytes (P > 0.05). Baseline–to–12-month numerical rating scale pain scores of patients with soft discs vs osteophytes had overlapping confidence intervals at each follow-up. At 12 months, very few had undergone surgery (7% of patients with soft discs, 11% of patients with osteophytes; P > 0.05) or were on opioids (7% of patients with soft discs, 9% of patients with osteophytes; P > 0.05).

Conclusions

The majority of patients, but not all patients, with acute radiculopathies improved with time. This was seen with both soft disc herniations and osteophytes.
Victims and suspects of modern slavery: Identifying subgroups using latent class analysis
Authors: Lightowlers Carly , Broad Rose , Gadd David
Published: September 2020

We explored heterogeneity (subgroups) amongst victims and suspects of modern slavery offences using a cross-sectional extract of police data from a large metropolitan area in the UK with details of 540 victims and 380 suspects (reported to the police between April 2015 and June 2018). Latent class analysis was used to identify subgroups of victims and suspects based on the manifest demographic (age, sex, and place of birth) and exploitation type variables. Amongst suspects, classes distinguished between ‘Male sex traffickers’ (82%) and ‘Labour and domestic traffickers’ (18%). Amongst victims, four classes were identified as: ‘Sexually and domestically exploited women’ (30%) and ‘Sexually exploited girls’ (35%), ‘Men exploited in licit and illicit markets’ (26%), and ‘Criminally exploited boys’ (9%). These findings reveal trafficking as structured by gender, generation, and migration, but caution against defining the problem as one of exclusively male offenders exploiting women and children victims, even while this is commonplace.
SHORT-TERM ANNUAL VARIATIONS OF RADON CONCENTRATION IN WORKPLACES: SOME RESULTS IN A RESEARCH INSTITUTE
Authors: Venoso G , Ampollini M , Antignani S , Caprio M , Carpentieri C , Di Carlo C , Bochicchio F
Published: September 2020

Many international and national regulations on radon in workplaces, including the 2013/59/Euratom Council Directive, are based on the annual average of indoor radon concentration, assuming it is representative of the long-term average. However, a single annual radon concentration measurement does not reflect annual variations (i.e. year-to-year variations) of radon concentration in the same location. These variations, if not negligible, should be considered for an optimized implementation of regulations. Unfortunately, studies on annual variations in workplaces can be difficult and time-consuming and no data have been published on scientific journals on this issue. Therefore, we carried out a study to obtain a first evaluation of short-term annual variations in workplaces of a research institute in Rome (Italy). The radon concentration was measured in 120 rooms (mainly offices and laboratories) located in 23 buildings. In each room, two 1-year long measurements were performed, with an interval between the two measurements of up to 3 years. The results show variability between the two 1-year long measurements higher than the variability observed in a sample of dwellings in the same area. Further studies are required to confirm the results and to extend the study to other types of workplaces.
Dioxin Disrupts Dynamic DNA Methylation Patterns in Genes That Govern Cardiomyocyte Maturation
Authors: de Gannes Matthew , Ko Chia-I , Zhang Xiang , Biesiada Jacek , Niu Liang , Koch Sheryl E , Medvedovic Mario , Rubinstein Jack , Puga Alvaro
Published: September 2020

Congenital heart disease (CHD), the leading birth defect worldwide, has a largely unknown etiology, likely to result from complex interactions between genetic and environmental factors during heart development, at a time when the heart adapts to diverse physiological and pathophysiological conditions. Crucial among these is the regulation of cardiomyocyte development and postnatal maturation, governed by dynamic changes in DNA methylation. Previous work from our laboratory has shown that exposure to the environmental toxicant tetrachlorodibenzo-p-dioxin (TCDD) disrupts several molecular networks responsible for heart development and function. To test the hypothesis that the disruption caused by TCDD in the heart results from changes in DNA methylation and gene expression patterns of cardiomyocytes, we established a stable mouse embryonic stem cell line expressing a puromycin resistance selectable marker under control of the cardiomyocyte-specific Nkx2-5 promoter. Differentiation of these cells in the presence of puromycin induces the expression of a large suite of cardiomyocyte-specific markers. To assess the consequences of TCDD treatment on gene expression and DNA methylation in these cardiomyocytes, we subjected them to transcriptome and methylome analyses in the presence of TCDD. Unlike control cardiomyocytes maintained in vehicle, the TCDD-treated cardiomyocytes showed extensive gene expression changes, with a significant correlation between differential RNA expression and DNA methylation in 111 genes, many of which are key elements of pathways that regulate cardiovascular development and function. Our findings provide an important clue toward the elucidation of the complex interactions between genetic and epigenetic mechanisms after developmental TCDD exposure that may contribute to CHD.
Treatment of COVID-19 with Chloroquine: Implication for Malaria Chemotherapy Using ACTs in Disease Endemic Countries
Authors: Quashie Neils Ben , Duah-Quashie Nancy Odurowah
Published: September 2020

Based on reports of parasite resistance and on World Health Organization recommendation, chloroquine was replaced with the artemisinin-based combination therapies (ACTs) as the first choice of drugs for the treatment of uncomplicated malaria. Disuse of chloroquine led to restoration of drug-sensitive parasite to some extent in certain countries. Ever since chloroquine and hydroxychloroquine were touted as potential treatment for coronavirus disease 2019 (COVID-19), there has been a dramatic surge in demand for the drugs. Even in areas where chloroquine is proscribed, there has been an unexpected increase in demand and supply of the drug. This situation is quite worrying as the indiscriminate use of chloroquine may produce drug-resistant parasites which may impact negatively on the efficacy of amodiaquine due to cross-resistance. Amodiaquine is a partner drug in one of the ACTs and in some of the drugs used for intermittent preventive treatment. We herein discuss the consequences of the escalated use of chloroquine in the management of COVID-19 on chemotherapy or chemoprevention of malaria and offer an advice. We speculate that parasite strains resistant to chloroquine will escalate due to the increased and indiscriminate use of the drug and consequently lead to cross-resistance with amodiaquine which is present in some drug schemes aforementioned. Under the circumstance, the anticipated hope of reverting to the use of the ‘resurrected chloroquine’ to manage malaria in future is likely to diminish. The use of chloroquine and its derivatives for the management of COVID-19 should be controlled.
Eating Behaviors of Late and Moderately Preterm Infants at Two Years of Age and Their Associations With Mothers’ Mental Health
Authors: Duran Sedef , Duran Rıdvan , Acunaş Betül , Cesur Gülay , Çiftdemir Nükhet Aladağ
Published: September 2020

Objectives:

Preterm infants are at high risk for nutritional difficulties during the neonatal period and early childhood. Long‐term nutritional difficulties contribute to unbalanced food intake and growth disorders and are the source of major emotional stress for the family. The aim of this study is to investigate the eating problems of late and moderately preterm (LMPT) infants at the age of 2 years, and to examine the association of these problems with the mental status of their mothers.

Methods:

In this cross‐sectional study, group 1 included LMPT infants born between 32 and 36 + 6 weeks of gestation and Group 2 included term infants born between 37 and 41 + 6 weeks of gestation. Children's Nutrition Difficulties Questionnaire and 21‐item Depression Anxiety and Stress Scales (DASS 21) were used for the detection of nutritional difficulties of infants and mothers’ mental health status.

Results:

Groups 1 and 2 were consisted of 79 LMPT and 38 term infants, respectively. Late and moderately preterm infants were found to have a lower drive‐to‐eat and food repertoire scores as well as lower appetite and food enjoyment than term infants. Pickiness and food neophobia were found to be higher in LMPT infants than term infants. The DASS‐21 scores of the mothers of the LMPT infants were higher than those of the term ones.

Conclusions:

These findings suggest that LMPT infants have more nutritional difficulties at the age of 2 years than term infants and their mothers exhibit more emotional distress than term infant's mothers.
Associations Between Maternal Thyroid Function in Pregnancy and Obstetric and Perinatal Outcomes
Authors: Lee Sun Y. , Cabral Howard J. , Aschengrau Ann , Pearce Elizabeth N.
Published: September 2020

(Abstracted from J Clin Endocrinol Metab 2020;105(5):e2015–e2023)

The fetus depends on maternal thyroid hormone crossing via a placental route in a critical period of development during the first trimester. Untreated maternal hypothyroidism increases risk of adverse pregnancy outcomes including fetal loss, preeclampsia, abruption placenta, and postpartum hemorrhage, as well as adverse perinatal outcomes including premature birth, low birth weight (LBW), and neonatal respiratory distress syndrome (RDS).
Alzheimer Disease Worries, Fears, and Stigma and Their Relationship to Genetic and Interventional Research Engagement
Authors: Bardach Shoshana H. , Kent Saida , Jicha Gregory A.
Published: September 2020

Background:

Alzheimer disease (AD) research increasingly requires healthy individuals willing to undergo genetic testing.

Objective:

This study seeks to: (1) describe older adults’ beliefs about AD genetic testing, worry about AD, and fear of AD stigma, and (2) explore how these constructs relate to research participation.

Methods:

Surveys were sent to participants active in AD-observational research and those that were not. Three measures of research participation were explored: (1) being a current research participant, (2) self-report of clinical trial participation, and (3) expressing genetic registry interest.

Results:

The majority of the 502 respondents perceived greater benefit than the risk associated with AD genetic testing. AD worry and perceptions of AD stigma were low. Higher levels of AD worry and lower perceptions of AD stigma were associated with being a current AD research volunteer. AD worry and stigma were unrelated to clinical trial participation or genetic registry interest; these research participation measures were associated with AD genetic testing benefit.

Conclusions:

Beliefs about AD genetic testing, AD worry, and AD stigma are related to research participation, but relationships vary based on the research participation investigated. Future work should identify how these findings can inform outreach and recruitment efforts.
A Mathieu function boundary spectral method for scattering by multiple variable poro-elastic plates, with applications to metamaterials and acoustics
Authors: Colbrook Matthew J. , Kisil Anastasia V.
Published: September 2020

Many problems in fluid mechanics and acoustics can be modelled by Helmholtz scattering off poro-elastic plates. We develop a boundary spectral method, based on collocation of local Mathieu function expansions, for Helmholtz scattering off multiple variable poro-elastic plates in two dimensions. Such boundary conditions, namely the varying physical parameters and coupled thin-plate equation, present a considerable challenge to current methods. The new method is fast, accurate and flexible, with the ability to compute expansions in thousands (and even tens of thousands) of Mathieu functions, thus making it a favourable method for the considered geometries. Comparisons are made with elastic boundary element methods, where the new method is found to be faster and more accurate. Our solution representation directly provides a sine series approximation of the far-field directivity and can be evaluated near or on the scatterers, meaning that the near field can be computed stably and efficiently. The new method also allows us to examine the effects of varying stiffness along a plate, which is poorly studied due to limitations of other available techniques. We show that a power-law decrease to zero in stiffness parameters gives rise to unexpected scattering and aeroacoustic effects similar to an acoustic black hole metamaterial.
Exponential stability in Mindlin’s Form II gradient thermoelasticity with microtemperatures of type III
Authors: Aouadi M. , Passarella F. , Tibullo V.
Published: September 2020

In this paper, we derive a nonlinear strain gradient theory of thermoelastic materials with microtemperatures taking into account micro-inertia effects as well. The elastic behaviour is assumed to be consistent with Mindlin’s Form II gradient elasticity theory, while the thermal behaviour is based on the entropy balance of type III postulated by Green and Naghdi for both temperature and microtemperatures. The work is motivated by increasing use of materials having microstructure at both mechanical and thermal levels. The equations of the linear theory are also obtained. Then, we use the semigroup theory to prove the well-posedness of the obtained problem. Because of the coupling between high-order derivatives and microtemperatures, the obtained equations do not have exponential decay. A frictional damping for the elastic component, whose form depends on the micro-inertia, is shown to lead to exponential stability for the type III model.
Sensorimotor upper limb therapy does not improve somatosensory function and may negatively interfere with motor recovery: a randomized controlled trial in the early rehabilitation phase after stroke
Authors: Nele De Bruyn , Leen Saenen , Liselot Thijs , Annick Van Gils , Eva Ceulemans , Bea Essers , Christophe Lafosse , Marc Michielsen , Hilde Beyens , Fabienne Schillebeeckx , Kaat Alaerts , Geert Verheyden
Published: September 2020

Question

Is sensorimotor upper limb (UL) therapy of more benefit for motor and somatosensory outcome than motor therapy?

Design

Randomised assessor-blinded multi-centre controlled trial with block randomization stratified for neglect, severity of motor impairment, and type of stroke.

Participants

40 first-ever stroke patients with UL sensorimotor impairments admitted to the rehabilitation centre

Intervention

Both groups received 16 hours of additional therapy over four weeks consisting of sensorimotor (N=22) or motor (N=18) UL therapy.

Outcome measures

Action Research Arm test (ARAT) as primary outcome, and other motor and somatosensory measures were assessed at baseline, post-intervention and after four weeks follow-up.

Results

No significant between-group differences were found for change scores in ARAT or any somatosensory measure between the three time points. For UL impairment (Fugl-Meyer assessment), a significant greater improvement was found for the motor group compared to the sensorimotor group from baseline to post-intervention (mean (SD) improvement 14.65 (2.19) versus 5.99 (2.06); p=0.01) and from baseline to follow-up (17.38 (2.37) versus 6.75 (2.29); p=0.003).

Conclusion

UL motor therapy may improve motor impairment more than UL sensorimotor therapy in patients with sensorimotor impairments in the early rehabilitation phase post stroke. For these patients, integrated sensorimotor therapy may not improve somatosensory function and may negatively influence motor recovery.

Trial registration

The trial is registered at clinicaltrials.govNCT03236376.
Gut permeability and cognitive decline: A pilot investigation in the Northern Manhattan Study
Authors: Rundek Tatjana , Roy Sabita , Hornig Mady , Cheung Ying Kuen , Gardener Hannah , DeRosa Janet , Levin Bonnie , Wright Clinton B. , Brutto Victor A. Del , Elkind Mitchell SV , Sacco Ralph L.
Published: September 2020

Background

Gut microbiota may impact cognitive function and decline, though data is limited. This pilot study examines the associations between gut dysbiosis products, plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14), with cognitive decline and immune molecule activation among 40 participants in the longitudinal population-based Northern Manhattan Study.

Methods

We selected stroke- and dementia-free participants at baseline with high activation levels of core components of the immune signaling pathways underlying microbiota metabolite-cognitive associations (IL-1, IL-17, TNF). Participants were followed with up to three complete neuropsychological assessments.

Results

Elevated sCD14 was associated with high levels of IL-1 (p<0.05), whereas in samples where only IL-17 and TNF were increased, LPS and sCD14 levels were not elevated. LPS was associated with decline in global cognitive performance over 2-3 assessments (adjusted β=-0.023 per SD per year, 95%CI:-0.036, −0.010). The association between sCD14 and cognitive decline was marginal (adjusted β=-0.018 per SD per year, 95%CI:-0.040, 0.004).

Conclusions

These preliminary data support the hypothesis that gut dysbiosis leads to systemic and neuro-inflammation, and subsequently cognitive decline. Further large targeted and untargeted gut microbiota-derived metabolomic studies are needed.
Improvement and Multi-Population Generalizability of a Deep Learning-Based Chest Radiograph Severity Score for COVID-19
Authors: Li Matthew D. , Arun Nishanth T. , Aggarwal Mehak , Gupta Sharut , Singh Praveer , Little Brent P. , Mendoza Dexter P. , Corradi Gustavo C.A. , Takahashi Marcelo S. , Ferraciolli Suely F. , Succi Marc D. , Lang Min , Bizzo Bernardo C. , Dayan Ittai , Kitamura Felipe C. , Kalpathy-Cramer Jayashree
Published: September 2020

Purpose

To improve and test the generalizability of a deep learning-based model for assessment of COVID-19 lung disease severity on chest radiographs (CXRs) from different patient populations.

Materials and Methods

A published convolutional Siamese neural network-based model previously trained on hospitalized patients with COVID-19 was tuned using 250 outpatient CXRs. This model produces a quantitative measure of COVID-19 lung disease severity (pulmonary x-ray severity (PXS) score). The model was evaluated on CXRs from four test sets, including 3 from the United States (patients hospitalized at an academic medical center (N=154), patients hospitalized at a community hospital (N=113), and outpatients (N=108)) and 1 from Brazil (patients at an academic medical center emergency department (N=303)). Radiologists from both countries independently assigned reference standard CXR severity scores, which were correlated with the PXS scores as a measure of model performance (Pearson r). The Uniform Manifold Approximation and Projection (UMAP) technique was used to visualize the neural network results.

Results

Tuning the deep learning model with outpatient data improved model performance in two United States hospitalized patient datasets (r=0.88 and r=0.90, compared to baseline r=0.86). Model performance was similar, though slightly lower, when tested on the United States outpatient and Brazil emergency department datasets (r=0.86 and r=0.85, respectively). UMAP showed that the model learned disease severity information that generalized across test sets.

Conclusions

Performance of a deep learning-based model that extracts a COVID-19 severity score on CXRs improved using training data from a different patient cohort (outpatient versus hospitalized) and generalized across multiple populations.
COVID19 epidemic modelling and the effect of public health interventions in India-SEIQHRF model
Authors: Sengupta Pooja , Ganguli Bhaswati , Chatterjee Aditya , Roy Sugata Sen , Chatterjee Moumita
Published: September 2020

A dynamic epidemic modeling, based on real time data, of COVID19 has been attempted for India and few selected Indian states. Various scenarios of intervention strategies to contain the spread of the disease are explored.
Model-based and model-free characterization of epidemic outbreaks
Authors: Dehning Jonas , Spitzner F. Paul , Linden Matthias C. , Mohr Sebastian B. , Neto Joao Pinheiro , Zierenberg Johannes , Wibral Michael , Wilczek Michael , Priesemann Viola
Published: September 2020

Here, we provide detailed background information for our work on Bayesian inference of change-points in the spread of SARS-CoV-2 and the effectiveness of non-pharmaceutical interventions (Dehning et al., Science, 2020). We outline the general background of Bayesian inference and of SIR-like models. We explain the assumptions that underlie model-based estimates of the reproduction number and compare them to the assumptions that underlie model-free estimates, such as used in the Robert-Koch Institute situation reports. We highlight effects that originate from the two estimation approaches, and how they may cause differences in the inferred reproduction number. Furthermore, we explore the challenges that originate from data availability — such as publication delays and inconsistent testing — and explain their impact on the time-course of inferred case numbers. Along with alternative data sources, this allowed us to cross-check and verify our previous results.
KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney
Authors: Mori Yutaro , Fink Corby , Ichimura Takaharu , Sako Keisuke , Mori Makiko , Lee Nathan N. , Aschauer Philipp , Padmanabha Das Krishna M. , Hong SoonGweon , Song Minsun , Padera Robert F. , Weins Astrid , Lee Luke P. , Nasr Mahmoud L. , Dekaban Gregory A. , Dikeakos Jimmy D. , Bonventre Joseph V.
Published: September 2020

SARS-CoV-2 precipitates respiratory distress by infection of airway epithelial cells and is often accompanied by acute kidney injury. We report that Kidney Injury Molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1) is expressed in lung and kidney epithelial cells in COVID-19 patients and is a receptor for SARS-CoV-2. Human and mouse lung and kidney epithelial cells express KIM-1 and endocytose nanoparticles displaying the SARS-CoV-2 spike protein (virosomes). Uptake was inhibited by anti-KIM-1 antibodies and TW-37, a newly discovered inhibitor of KIM-1-mediated endocytosis. Enhanced KIM-1 expression by human kidney tubuloids increased uptake of virosomes. KIM-1 binds to the SARS-CoV-2 Spike protein in vitro. KIM-1 expressing cells, not expressing angiotensin-converting enzyme 2 (ACE2), are permissive to SARS-CoV-2 infection. Thus, KIM-1 is an alternative receptor to ACE2 for SARS-CoV-2. KIM-1 targeted therapeutics may prevent and/or treat COVID-19.
Involvement of mutant and wild-type CYSLTR2 in the development and progression of uveal nevi and melanoma
Authors: Nell Rogier J. , Menger Nino V. , Versluis Mieke , Luyten Gregorius P.M. , Verdijk Robert M. , Madigan Michele C. , Jager Martine J. , van der Velden Pieter A.
Published: September 2020

Background

Activating Gαq signalling mutations are considered an early event in the development of uveal melanoma. Whereas most tumours harbour a mutation in GNAQ or GNA11, CYSLTR2 (encoding G-protein coupled receptor CysLT2R) forms a rare alternative. The role of wild-type CysLT2R in uveal melanoma remains unknown.

Methods

We performed a digital PCR-based molecular analysis of benign choroidal nevi and primary uveal melanomas. Publicly available bulk and single cell sequencing data were mined to further study wild-type and mutant CYSLTR2.

Results

1/16 nevi and 2/120 melanomas carried the CYSLTR2 mutation. The mutation was subclonal in the nevus, while being clonal in both melanomas. In the melanomas, secondary, subclonal CYSLTR2 alterations shifted the allelic balance towards the mutant. The resulting genetic heterogeneity was confirmed in distinct areas of both tumours. At the RNA level, further silencing of wild-type and preferential expression of mutant CYSLTR2 was identified, which was also observed in 2/3 CYSLTR2 mutant melanomas from the TCGA cohort. In CYSLTR2 wild-type melanomas, high expression of CYSLTR2 originated from melanoma cells and correlated to tumour inflammation.

Conclusions

Our findings suggest that CYSLTR2 is involved in both early and late development of uveal melanoma. Whereas the CYSLTR2 p.L129Q mutation is likely to be the initiating oncogenic event, various mechanisms further increase the mutant allele abundance during tumour progression. This makes mutant CysLT2R an attractive therapeutic target in uveal melanoma. In GNAQ, GNA11 and PLCB4 mutant melanomas, expression of wild-type CYSLTR2 possibly facilitates an interaction with immune cells in the microenvironment and may also have therapeutic potential.
The enactment of compassionate leadership by nursing and midwifery managers: Results from an international online survey
Authors: Papadopoulos Irena , Wright Steve , Lazzarino Runa , Koulouglioti Christina , Aagard Magdeline , Akman Özlem , Alpers Lise-Merete , Apostolara Paraskevi , Araneda B. Julieta , Biglete-Pangilinan Sylvia , Regev Orit Eldar , González-Gil Maria Teresa , Kouta Christiana , Krepinska Radka , Lesińska-Sawicka Małgorzata , Liskova Miroslava , Lopez-Diaz Lucero , Malliarou Maria , Martín-García Ángel , Muñoz S. Mara , Nagórska Małgorzata , Ngunyulu Roinah Nkhensani , Nissim Sara , Nortvedt Line , Oconer-Rubiano Florinda , Oter-Quintana Cristina , öztürk Candan , Papp Katalin , Piratoba-Hernandez Blanca , Rousou Elena , Tolentino-Diaz Maria Ymelda , Tothova Valerie , Zorba Akile
Published: September 2020

Aim

To explore the views of an international sample of nursing and midwifery managers concerning attributes that they associate with compassionate management.

Method

A cross-sectional online survey. Using a snowballing sampling method, 1,217 responses were collected from nursing and midwifery managers in 17 countries. A total of complete 933 responses to a question related to which actions and behaviours indicated that a manager was exercising compassionate leadership were analysed for this paper. Firstly, content analysis of the responses was conducted, and secondly a relative distribution of the identified themes for the overall sample and for each participating country was calculated.

Results

Six main themes were identified describing the attributes of a compassionate leader: 1) Virtuous Support, 2) Communication, 3) Personal Virtues of the Manager, 4) Participatory Communication, 5) Growth/Flourishing/ Nurturing, and 6) Team Cohesion. The first three themes mentioned above collectively accounted for 63% of the responses, and can therefore be considered to be the most important characteristics of compassionate management behaviour.

Conclusion

The key indicators of compassionate management in nursing and midwifery which were identified emphasise approachability, active and sensitive listening, sympathetic responses to staff members’ difficulties (especially concerning child- and other caring responsibilities), active support of and advocacy for the staff team, and active problem solving and conflict resolution. While there were differences between the countries’ views on compassionate healthcare management, some themes were widely represented among different countries’ responses, which suggest key indicators of compassionate management that apply across cultures.
Integrative Genomics Analysis Reveals a Novel 21q22.11 Locus Contributing to Susceptibility of COVID-19
Authors: Ma Yunlong , Huang Yukuan , Zhao Sen , Yao Yinghao , Zhang Yaru , Qu Jia , Wu Nan , Su Jianzhong
Published: September 2020

The systematic identification of host genetic risk factors is essential for the understanding and treatment of COVID-19. By performing a meta-analysis of two independent genome-wide association (GWAS) summary datasets (N = 680,128), a novel locus at 21q22.11 was identified to be associated with COVID-19 infection (rs9976829 in IFNAR2 and upstream of IL10RB, OR = 1.16, 95% CI = 1.09 - 1.23, P = 2.57×10−6). The rs9976829 represents a strong splicing quantitative trait locus (sQTL) for both IFNAR2 and IL10RB genes, especially in lung tissue (P 1.8×10−24). Gene-based association analysis also found IFNAR2 was significantly associated with COVID-19 infection (P = 2.58×10−7). Integrative genomics analysis of combining GWAS with eQTL data showed the expression variations of IFNAR2 and IL10RB have prominent effects on COVID-19 in various types of tissues, especially in lung tissue. The majority of IFNAR2-expressing cells were dendritic cells (40%) and plasmacytoid dendritic cells (38.5%), and IL10RB-expressing cells were mainly nonclassical monocytes (29.6%). IFNAR2 and IL10RB are targeted by several interferons-related drugs. Together, our results uncover 21q22.11 as a novel susceptibility locus for COVID-19, in which individuals with G alleles of rs9976829 have a higher probability of COVID-19 susceptibility than those with non-G alleles.
Clinical conditions and their impact on utility of genetic scores for prediction of acute coronary syndrome
Authors: Lee Jiwoo , Kiiskinen Tuomo , Mars Nina , Jukarainen Sakari ,   FinnGen Project, Ingelsson Erik , Neale Benjamin , Ripatti Samuli , Natarajan Pradeep , Ganna Andrea
Published: September 2020

Aims

Early prediction of acute coronary syndrome (ACS) is a major goal for prevention of coronary heart disease (CHD). Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual’s genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS.

Methods and Results

We explored the association between 405 clinical conditions diagnosed before baseline and 9,080 incident cases of ACS in 387,832 individuals from the UK Biobank. We identified 80 conventional (e.g., stable angina pectoris (SAP), type 2 diabetes mellitus) and unconventional (e.g., diaphragmatic hernia, inguinal hernia) associations with ACS. Results were replicated in 6,430 incident cases of ACS in 177,876 individuals from FinnGen. The association between PS and ACS was consistent in individuals with and without most clinical conditions. However, a diagnosis of SAP yielded a differential association between PS and ACS. PS was associated with a significantly reduced (interaction p-value=2.87×10−8) risk for ACS in individuals with SAP (HR=1.163 [95% CI: 1.082–1.251]) compared to individuals without SAP (HR=1.531 [95% CI: 1.497–1.565]). These findings were replicated in FinnGen (interaction p-value=1.38×10−6).

Conclusion

In summary, while most clinical conditions did not impact utility of PS for prediction of ACS, we found that PS was substantially less predictive of ACS in individuals with prevalent stable CHD. PS for ACS may be more appropriate for asymptomatic individuals than symptomatic individuals with clinical suspicion for CHD.
Accuracy of self-reported HIV testing history and awareness of HIV-positive status among people living with HIV in four Sub-Saharan African countries
Authors: Xia Yiqing , Milwid Rachael M , Godin Arnaud , Boily Marie-Claude , Johnson Leigh F , Marsh Kimberly , Eaton Jeffrey W , Maheu-Giroux Mathieu
Published: September 2020

Background

In many countries in Sub-Saharan Africa, self-reported HIV testing history and awareness of HIV-positive status from household surveys are used to estimate the percentage of people living with HIV (PLHIV) who know their HIV status. Despite widespread use, there is limited empirical information on the sensitivity of those self-reports, which can be affected by non-disclosure.

Methods

Bayesian latent class models were used to estimate the sensitivity of self-reported HIV testing history and awareness of HIV-positive status in four Population-based HIV Impact Assessment surveys in Eswatini, Malawi, Tanzania, and Zambia. Antiretroviral (ARV) metabolites biomarkers were used to identify persons on treatment who did not accurately report their status. For those without ARV biomarkers, the pooled estimate of non-disclosure among untreated persons was 1.48 higher than those on treatment.

Results

Among PLHIV, the sensitivity of self-reported HIV testing history ranged 96% to 99% across surveys. Sensitivity of self-reported awareness of HIV status varied from 91% to 97%. Non-disclosure was generally higher among men and those aged 15-24 years. Adjustments for imperfect sensitivity did not substantially influence estimates of of PLHIV ever tested (difference <4%) but the proportion of PLHIV aware of their HIV-positive status was higher than the unadjusted proportion (difference <8%).

Conclusions

Self-reported HIV testing histories in four Eastern and Southern African countries are generally robust although adjustment for non-disclosure increases estimated awareness of status. These findings can contribute to further refinements in methods for monitoring progress along the HIV testing and treatment cascade.
Environmental and climatic impact on the infection and mortality of SARS-CoV-2 in Peru
Authors: Samillan Victor J. , Flores Diana , Rojas Eduardo , Zutta Brian R.
Published: September 2020

The role of the environment and climate in the transmission and case-fatality rates of SARS-CoV-2 is still being investigated. Elevation and air quality are believed to be significant factors in the current development of the pandemic, but the influence of additional environmental factors remain unclear.

In this study, we explored the relationship between the cumulative number of infections and mortality cases with climate (temperature, precipitation, solar radiation, water vapor pressure, wind), environmental data (elevation, NDVI, PM2.5 and NO2 concentration), and population density in Peru. Using the data from confirmed cases of infection from 1287 districts and confirmed cases of mortality in 479 districts, we used Spearman’s correlations to assess the correlation between environmental and climatic factors with cumulative infection cases, cumulative mortality and case-fatality rate. We also explored district cases by the ecozones of coast, sierra, high montane forest and lowland rainforest.

Multiple linear regression models indicate elevation, mean solar radiation, air quality, population density and green cover are influential factors in the distribution of infection and mortality of SARS-CoV-2 in Peru. Case-fatality rate was weakly associated with elevation. Our results also strongly suggest that exposure to poor air quality is a significant factor in the mortality of individuals with SARS-CoV-2 below the age of 30.

We conclude that environmental and climatic factors do play a significant role in the transmission and case-fatality rates in Peru, however further study is required to see if these relationships are maintained over time.
Whole-genome analysis of Malawian Plasmodium falciparum isolates identifies potential targets of allele-specific immunity to clinical malaria
Authors: Shah Zalak , Naung Myo T. , Moser Kara A. , Adams Matthew , Buchwald Andrea G. , Dwivedi Ankit , Ouattara Amed , Seydel Karl B , Mathanga Don P. , Barry Alyssa E. , Serre David , Laufer Miriam K. , Silva Joana C. , Takala-Harrison Shannon
Published: September 2020

Individuals acquire immunity to clinical malaria after repeated Plasmodium falciparum infections. This immunity to disease is thought to reflect the acquisition of a repertoire of responses to multiple alleles in diverse parasite antigens. In previous studies, we identified polymorphic sites within individual antigens that are associated with parasite immune evasion by examining antigen allele dynamics in individuals followed longitudinally. Here we expand this approach by analyzing genome-wide polymorphisms using whole genome sequence data from 140 parasite isolates representing malaria cases from a longitudinal study in Malawi and identify 25 genes that encode likely targets of naturally acquired immunity and that should be further characterized for their potential as vaccine candidates.
Emergence of Canonical Functional Networks from the Structural Connectome
Authors: Xie Xihe , Damasceno Pablo F. , Cai Chang , Nagarajan Srikantan , Raj Ashish
Published: September 2020

Abstract

How do functional brain networks emerge from the underlying wiring of the brain? We examine how resting-state functional activation patterns emerge from the underlying connectivity and length of white matter fibers that constitute its “structural connectome”. By introducing realistic signal transmission delays along fiber projections, we obtain a complex-valued graph Laplacian matrix that depends on two parameters: coupling strength and oscillation frequency. This complex Laplacian admits a complex-valued eigen-basis in the frequency domain that is highly tunable and capable of reproducing the spatial patterns of canonical functional networks without requiring any detailed neural activity modeling. Specific canonical functional networks can be predicted using linear superposition of small subsets of complex eigenmodes. Using a novel parameter inference procedure we show that the complex Laplacian outperforms the real-valued Laplacian in predicting functional networks. The complex Laplacian eigenmodes therefore constitute a tunable yet parsimonious substrate on which a rich repertoire of realistic functional patterns can emerge. Although brain activity is governed by highly complex nonlinear processes and dense connections, our work suggests that simple extensions of linear models to the complex domain effectively approximate rich macroscopic spatial patterns observable on BOLD fMRI.
Stoichiometric modeling of artificial string chemistries
Authors: Moyer Devlin , Pacheco Alan R. , Bernstein David B. , Segrè Daniel
Published: September 2020

Uncovering the general principles that govern the architecture of metabolic networks is key to understanding the emergence and evolution of living systems. Artificial chemistries,in silicorepresentations of chemical reaction networks arising from a defined set of mathematical rules, can help address this challenge by enabling the exploration of alternative chemical universes and the possible metabolic networks that could emerge within them. Here we focus on artificial chemistries in which strings of characters represent simplified molecules, and string concatenation and splitting represent possible chemical reactions. We study string chemistries using tools borrowed from the field of stoichiometric constraint-based modeling of organismal metabolic networks, through a novel Python package, ARtificial CHemistry NEtwork Toolbox (ARCHNET). In addition to exploring the complexity and connectivity properties of different string chemistries, we developed a network-pruning algorithm that can generate minimal metabolic networks capable of producing a specified set of biomass precursors from a given assortment of environmental molecules within the string chemistry framework. We found that the identities of the metabolites in the biomass reaction wield much more influence over the structure of the minimal metabolic networks than the identities of the nutrient metabolites — a notion that could help us better understand the rise and evolution of biochemical organization. Our work provides a bridge between artificial chemistries and stoichiometric modeling, which can help address a broad range of open questions, from the spontaneous emergence of an organized metabolism to the structure of microbial communities.
Early Anti-SARS-CoV-2 Convalescent Plasma in Patients Admitted for COVID-19: A Randomized Phase II Clinical Trial
Authors: Balcells María Elvira , Rojas Luis , Le Corre Nicole , Martínez-Valdebenito Constanza , Ceballos María Elena , Ferrés Marcela , Chang Mayling , Vizcaya Cecilia , Mondaca Sebastián , Huete Álvaro , Castro Ricardo , Sarmiento Mauricio , Villarroel Luis , Pizarro Alejandra , Ross Patricio , Santander Jaime , Lara Barbara , Ferrada Marcela , Vargas-Salas Sergio , Beltrán-Pavez Carolina , Soto-Rifo Ricardo , Valiente-Echeverría Fernando , Caglevic Christian , Mahave Mauricio , Selman Carolina , Gazitúa Raimundo , Briones José Luis , Villarroel-Espindola Franz , Balmaceda Carlos , Espinoza Manuel A. , Pereira Jaime , Nervi Bruno
Published: September 2020

Background

Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.

Methods

Open-label, single-center, randomized clinical trial performed in an academic center in Santiago, Chile from May 10, 2020, to July 18, 2020, with final follow-up August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptoms onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted in immediate CP (early plasma group) versus no CP unless developing pre-specified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days or death. Key secondary outcomes included: time to respiratory failure, days of mechanical ventilation, hospital length-of-stay, mortality at 30 days, and SARS-CoV-2 RT-PCR clearance rate.

Results

Of 58 randomized patients (mean age, 65.8 years, 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We found no benefit in the primary outcome (32.1% vs 33.3%, OR 0.95, 95% CI 0.32-2.84, p>0.99) in the early versus deferred CP group. In-hospital mortality rate was 17.9% vs 6.7% (OR 3.04, 95% CI 0.54-17.2, p=0.25), mechanical ventilation 17.9% vs 6.7% (OR 3.04, 95% CI 0.54-17.2, p=0.25), and prolonged hospitalization 21.4% vs 30% (OR 0.64, 95%CI, 0.19-2.1, p=0.55) in early versus deferred CP group, respectively. Viral clearance rate on day 3 (26% vs 8%, p=0.20) and day 7 (38% vs 19%, p=0.37) did not differ between groups. Two patients experienced serious adverse events within 6 or less hours after plasma transfusion.

Conclusion

Immediate addition of CP therapy in early stages of COVID-19 -compared to its use only in case of patient deterioration-did not confer benefits in mortality, length of hospitalization or mechanical ventilation requirement.

Clinical Trials Registration

NCT04375098