bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual methylation and hydroxymethylation study of alcohol use disorder
Authors: Clark Shaunna L. , Chan Robin F. , Zhao Min , Xie Lin Y. , Copeland William E. , Penninx Brenda W.J.H. , Aberg Karolina A. , van den Oord Edwin J.C.G.
Published: September 2020

Using an integrative, multi-tissue design we sought to characterize methylation and hydroxymethylation changes in blood and brain associated with alcohol use disorder (AUD). First, we used epigenomic deconvolution to perform cell-type specific methylome-wide association studies within subpopulations of granulocytes/T-cells/B-cells/monocytes in 1,132 blood samples. Blood findings were then examined for overlap with AUD-related associations in methylation and hydroxymethylation in 50 human post-mortem brain samples. Follow-up analyses investigated if overlapping findings mediated AUD-associated transcription changes in the same brain samples. Lastly, we replicated our blood findings in an independent sample of 412 individuals and aimed to replicate published alcohol methylation findings using our results.

Cell-type specific analyses in blood identified methylome-wide significant associations in monocytes and T-cells. The monocyte findings were significantly enriched for AUD-related methylation and hydroxymethylation in brain. Hydroxymethylation in specific sites mediated AUD-associated transcription in the same brain samples. As part of the most comprehensive methylation study of AUD to date, this work involved the first cell-type specific methylation study of AUD conducted in blood, identifying and replicating a finding in DLGAP1 that may be involved in AUD-related brain impairment. In this first study to consider the role of hydroxymethylation in AUD, we found evidence for a novel mechanism for cognitive deficits associated with AUD. Our results suggest promising new avenues for AUD research.
How the clinical research community responded to the COVID-19 pandemic: An analysis of the COVID-19 clinical studies in ClinicalTrials.gov
Authors: He Zhe , Erdengasileng Fnu , Luo Xiao , Xing Aiwen , Charness Neil , Bian Jiang
Published: September 2020

Objective

The novel coronavirus disease (COVID-19), broke out in December 2019, is a global pandemic. Rapidly in the past few months, a large number of clinical studies have been initiated worldwide to find effective therapeutics, vaccines, and preventive strategies. In this study, we aim to understand the landscape of COVID-19 clinical research and identify the gaps and issues that may cause difficulty in recruitment and the lack of population representativeness.

Materials and Methods

We analyzed 2,034 COVID-19 studies registered in the largest public registry - ClinicalTrials.gov. Leveraging natural language processing, descriptive analysis, association analysis, and clustering analysis, we characterized COVID-19 clinical studies by phase and design features. Particularly, we analyzed their eligibility criteria to understand: (1) whether they considered the reported underlying health conditions that may lead to severe illnesses, and (2) if these studies excluded older adults, either explicitly or implicitly, which may reduce the generalizability of these studies in older adults.

Results

The 5 most frequently tested drugs are Hydroxychloroquine (N=148), Azithromycin (N=46), Tocilizumab (N=29), Lopinavir (N=20), and Ritonavir (N=20). Most trials did not have an upper age limit and did not exclude patients with common chronic conditions such as hypertension and diabetes that are prevalent in older adults. However, known risk factors that may lead to severe illnesses have not been adequately considered by existing studies.

Conclusions

A careful examination of the registered COVID-19 clinical studies can identify the research gaps and inform future COVID-19 trial design towards balanced internal validity and generalizability.
Childhood Vitiligo: A Retrospective Clinico-Epidemiological Study
Authors: Ahmed Ahmed Abdul-Aziz , Ahmed Hayder Saad , Mohammed Mustafa Hameed , Shanshal Mohammed
Published: September 2020

Background

Vitiligo is an acquired depigmentary disorder of the skin, mucous membrane and hair follicle resulting from selective destruction of melanocytes.

Aims of Study

Identify the clinico-epidemiological characteristics of childhood vitiligo.

Patients and Methods

A retrospective study carried out at the dermato-venereology clinic of Salah Al-Din Hospital. A total of 120 vitiligo patients, all younger than 17 years old, were enrolled.

Results

Among included patients, (40%) were male and (60%) were female (M:F=2:3). The mean age of onset was (11.5±6.4 years) with (60.8%) of patients were (11-17) years old, (25%) were (6-11) years and (14.2%) were (0-5) years old. Majority of patients were from urban area (87.5%). Generalized types of vitiligo account for (56.7%) besides (22.5%), (17.5%) and (3.3%) represented focal, acrafacial and segmental vitiligo, respectively. Only (8.3%) have nail changes, presented as longitudinal ridging followed by leukonychia. Family history was positive in (37.5%) of vitiligo patients. Treatment used for vitiligo were topical corticosteroids (92.5%), topical calcineurin inhibitors (55%), NB-UVB (84.2%), and systemic steroids (30.8%).

Conclusions

Majority of childhood vitiligo develops after puberty and predominantly affects female. Generalized vitiligo is the most frequent type. Atopic dermatitis is the most common associated disease.
Seroprevalence of SARS-CoV-2 among adults in three regions of France following the lockdown and associated risk factors: a multicohort study
Authors: Carrat Fabrice , de Lamballerie Xavier , Rahib Delphine , Blanché Hélène , Lapidus Nathanael , Artaud Fanny , Kab Sofiane , Renuy Adeline , de Edelenyi Fabien Szabo , Meyer Laurence , Lydié Nathalie , Charles Marie-Aline , Ancel Pierre-Yves , Jusot Florence , Rouquette Alexandra , Priet Stéphane , Saba Villarroel Paola Mariela , Fourié Toscane , Lusivika-Nzinga Clovis , Nicol Jerome , Legot Stephane , Druesne-Pecollo Nathalie , Esseddik Younes , Lai Cindy , Gagliolo Jean-Marie , Deleuze Jean-François , Bajos Nathalie , Severi Gianluca , Touvier Mathilde , Zins Marie ,   for the SAPRIS and SAPRIS-SERO study groups
Published: September 2020

Background

To estimate the seroprevalence of SARS-CoV-2 infection in May-June 2020 after the lockdown in adults living in three regions in France and to identify the associated risk factors.

Methods

Participants in a survey on COVID-19 from an existing consortium of three general adult population cohorts living in the Ile-de-France (IDF) or Grand Est (GE) - two regions with high rate of COVID-19, or in the Nouvelle-Aquitaine (NA) – with a low rate, were asked to take a dried-blood spot (DBS) for anti-SARS-CoV-2 antibodies assessment.

The primary outcome was a positive anti-SARS-CoV-2 ELISA IgG result against the spike protein of the virus (ELISA-S). The secondary outcomes were a positive ELISA IgG against the nucleocapsid protein (ELISA-NP), anti-SARS-CoV-2 neutralizing antibodies titers ≥40 (SN), and predicted positivity obtained from a multiple imputation model (MI). Prevalence estimates were adjusted using sampling weights and post-stratification methods.

Findings

Between May 4, 2020 and June 23, 2020, 16,000 participants were asked to provide DBS, and 14,628 were included in the analysis, 983 with a positive ELISA-S, 511 with a positive ELISA-NP, 424 with SN≥40 and 941±31 with a positive MI. Adjusted estimates of seroprevalence (positive ELISA-S) were 10.0% (95%CI 9.1%;10.9%) in IDF, 9.0% (95%CI 7.7%; 10.2%) in GE and 3.1% (95%CI 2.4%; 3.7%), in NA. The adjusted prevalence of positive ELISA-NP, SN and MI were 5.7%, 5.0% and 10.0% in IDF, 6.0%, 4.3% and 8.6% in GE, and 0.6%, 1.3% and 2.5% in NA, respectively. A higher seroprevalence was observed in younger participants and when at least one child or adolescent lived in the same household. A lower seroprevalence was observed in smokers compared to non-smokers.

Interpretation

At the end of the lockdown the prevalence of anti-SARS-CoV-2 IgG or neutralizing antibodies remained low in the French adult population, even in regions with high reported rates of COVID-19.
“Social distancing: barriers to its implementation and how they can be overcome – a rapid systematic review and synthesis of qualitative studies”
Authors: Sadjadi Mahan , Mörschel Katharina Selda , Petticrew Mark
Published: September 2020

Aim

To systematically review qualitative literature on social distancing in order to identify and describe factors that enable or prevent its implementation.

Methods

A rapid systematic qualitative review was conducted in accordance with PRISMA and ENTREQ guidelines. A comprehensive systematic search was carried out in MEDLINE, EMBASE, PsychINFO, Global Health, CINAHL and Web of Science. Included papers (i) report on primary qualitative studies (ii) of the barriers and facilitators to the implementation of social distancing measures (iii) in potentially epidemic infectious diseases. After critical appraisal and standardised data extraction, a meta-ethnographical approach was used for synthesis. Review findings were assessed for strength and reliability using CerQUAL.

Results

28 papers were included from the systematic search that yielded 5620 results. One additional paper was found by searching references. The review identifies two broad categories of barriers to social distancing measures: individual- or community-level psychological or sociological phenomena, and perceived shortcomings in governmental action. Based on this, 25 themes are identified that can be addressed to improve the implementation of social distancing.

Conclusion

There are many barriers, on different levels, to the implementation of social distancing measures. Among other findings, the review identifies the need for good communication as well as the need for authorities to provide comprehensive support as two key opportunities to increase acceptability and adherence. High-quality research is needed during the COVID-19 pandemic to better describe mechanisms by which implementation of social distancing can be improved, and, more importantly, what is already known has to be put into practice.
LDL/Apo B ratio and Lp (a) Each Predict Coronary Artery Disease in Type2 Diabetes Independent of ASCVD Risk Score: A Case-Cohort Study
Authors: Rabizadeh Soghra , Rajab Armin , Mechanick Jeffrey I. , Moosaie Fatemeh , Rahimi Yekta , Nakhjavani Manouchehr , Esteghamati Alireza
Published: September 2020

Aim

To evaluate the predictive value of the LDL-C/ApoB ratio for coronary heart disease (CHD) in patients with type2 diabetes (T2D).

Methods

In this case-cohort study, (apo)lipoproteins and glycemic indices were measured in 1058 individuals with T2D from February 2002 to March 2019, with a median duration of follow up of 10 years.

Results

Of 1058 patients with T2D, coronary heart disease occurred in 242 patients. Increased waist circumference, waist-to-hip ratio, and hemoglobin A1c, low-density lipoprotein cholesterol (LDL-C)/Apolipoprotein B (ApoB) ratio, presence of hypertension and metabolic syndrome, and insulin and statin use were more prevalent among patients with CHD (P<0.001). Logistic regression analysis showed that an LDL-C/ApoB ratio equal or lower than 1.2, as well as a Lp(a) cutoff level more than 25.45 mg/dl could each predict CHD independent of ASCVD risk score [adjusted OR:1.841, CI:1.257 – 2.698, P<0.001 and adjusted OR: 1.433, CI:1.014 – 2.026, P=0.041) respectively] when adjusted for multiple confounders.The atherogenic index of plasma (AIP) did not predict CHD.

Conclusion

This study showed that LDL-C/ApoB ratio and Lp(a) each, but not the atherogenic index of plasma, may be considered as an indicator of CHD independent of ASCVD risk score in patients with T2D. This finding merits further clarification to optimize preventive strategies for CHD.
Contrasting recruitment of skin-associated adipose depots during cold challenge of mouse and human
Authors: Kasza Ildiko , Kühn Jens-Peter , Völzke Henry , Hernando Diego , Xu Yaohui G. , Siebert John W. , Gibson Angela LF , Yen C.-L. Eric , Nelson David W. , MacDougald Ormond A. , Richardson Nicole E. , Lamming Dudley W. , Kern Philip A. , Alexander CM
Published: September 2020

Mammalian skin impacts metabolic efficiency system-wide, controlling the rate of heat loss and consequent heat production. Here we compare the unique fat depots associated with mouse and human skin, to determine whether they have corresponding function and regulation. For human, we assay a skin-associated fat (SAF) body-wide depot to distinguish it from the subcutaneous fat pads characteristic of abdomen and upper limbs. We show that the thickness of SAF is not related to general adiposity; it is much thicker (1.6-fold) in women than men, and highly subject-specific. We used molecular and cellular assays of β-adrenergic induced lipolysis and found that dermal white adipose tissue (dWAT) in mice is resistant to lipolysis; in contrast, the body-wide human SAF depot becomes lipolytic, generating heat in response to β-adrenergic stimulation. In mice challenged to make more heat to maintain body temperature (either environmentally or genetically), there is a compensatory increase in thickness of dWAT: A corresponding β-adrenergic stimulation of human skin adipose (in vivoor in explant) depletes adipocyte lipid content. We summarize the regulation of skin-associated adipocytes by age, sex, and adiposity, for both species. We conclude that the body-wide dWAT depot of mice shows unique regulation that enables it to be deployed for heat preservation; combined with the actively lipolytic subcutaneous mammary fat pads they enable thermal defense. The adipose tissue that covers human subjects produces heat directly, providing an alternative to the brown adipose tissues.

KEY POINTS SUMMARY

Several distinct strategies produce and conserve heat to maintain body temperature of mammals, each associated with unique physiologies, with consequence for wellness and disease susceptibility

Highly regulated properties of skin offset the total requirement for heat production

We hypothesize that the adipose component of skin is primarily responsible for modulating heat flux; here we evaluate the relative regulation of adipose depots in mouse and human, to test their recruitment to heat production and conservation

We found that insulating mouse dermal white adipose tissue accumulates in response to environmentally- and genetically-induced cool stress; this layer is one of two adipose depots closely apposed to mouse skin, where the subcutaneous mammary gland fat pads are actively recruited to heat production

In contrast, the body-wide adipose depot associated with human skin produces heat directly, potentially creating an alternative to the centrally regulated brown adipose tissue
HieRFIT: Hierarchical Random Forest for Information Transfer
Authors: Kaymaz Yasin , Ganglberger Florian , Tang Ming , Fernandez-Albert Francesc , Lawless Nathan , Sackton Timothy
Published: September 2020

The emergence of single-cell RNA sequencing (scRNA-seq) has led to an explosion in novel methods to study biological variation among individual cells, and to classify cells into functional and biologically meaningful categories. Here, we present a new cell type projection tool, HieRFIT (HierarchicalRandomForest forInformationTransfer), based on hierarchical random forests. HieRFIT usesa prioriinformation about cell type relationships to improve classification accuracy, taking as input a hierarchical tree structure representing the class relationships, along with the reference data. We use an ensemble approach combining multiple random forest models, organized in a hierarchical decision tree structure. We show that our hierarchical classification approach improves accuracy and reduces incorrect predictions especially for inter-dataset tasks which reflect real life applications. We use a scoring scheme that adjusts probability distributions for candidate class labels and resolves uncertainties while avoiding the assignment of cells to incorrect types by labeling cells at internal nodes of the hierarchy when necessary. Using HieRFIT, we re-analyzed publicly available scRNA-seq datasets showing its effectiveness in cell type cross-projections with inter/intra-species examples. HieRFIT is implemented as an R package and it is available at (https://github.com/yasinkaymaz/HieRFIT/releases/tag/v1.0.0)
Selecting pharmacies for COVID-19 testing to ensure access
Authors: Risanger Simon , Singh Bismark , Morton David , Meyers Lauren Ancel
Published: September 2020

Rapid diagnostic testing for COVID-19 is key to guiding social distancing orders and containing emerging disease clusters by contact tracing and isolation. However, communities throughout the US do not yet have adequate access to tests. Pharmacies are already engaged in testing, but there is capacity to greatly increase coverage. Using a facility location optimization model and willingness-to-travel estimates from US National Household Travel Survey data, we find that if COVID-19 testing became available in all US pharmacies, an estimated 94% of the US population would be willing to travel to obtain a test, if warranted. Whereas the largest chain provides high coverage in densely populated states, like Massachusetts, Rhode Island, New Jersey, and Connecticut, independent pharmacies would be required for sufficient coverage in Montana, South Dakota, and Wyoming. If only 1,000 pharmacies in the US are selected to provide testing, judicious selection, using our optimization model, provides estimated access to 29 million more people than selecting pharmacies simply based on population density. COVID-19 testing through pharmacies can improve access across the US. Even if only few pharmacies offer testing, judicious selection of specific sites can simplify logistics and improve access.
Examining Health Sector Stakeholder Perceptions on the Efficiency of County Health Systems in Kenya
Authors: Nyawira Lizah , Mbau Rahab , Jemutai Julie , Hanson Kara , Molyneux Sassy , Normand Charles , Tsofa Benjamin , Maina Isabel , Mulwa Andrew , Barasa Edwine
Published: September 2020

Efficiency gains is a potential strategy to expand Kenya’s fiscal space for health. We explored health sector stakeholders’ understanding of efficiency and their perceptions of the factors that influence the efficiency of county health systems in Kenya. We collected data during a stakeholder engagement workshop. Workshop participants included health sector stakeholders from the national ministry of health and 10 (out 47) county health departments, and non-state actors in Kenya. We divided stakeholders into three groups and carried out facilitated group discussions followed by whole group feedback and discussion session. A total of 25 health sector stakeholders participated. We analysed data using a thematic approach. Health sector stakeholders indicated the need for the outputs and outcomes of a health system to be aligned to community health needs. They felt that both hardware aspects of the system (such as the financial resources, infrastructure, human resources for health) and software aspects of the system (such as health sector policies, public finance management systems, actor relationships) should be considered as inputs in the analysis of county health system efficiency. They also felt that while traditional indicators of health system performance such as intervention coverage or outcomes for infectious diseases, and reproductive, maternal, neonatal and child health (RMNCH) are still relevant, emerging epidemiological trends characterized by an increase in the burden of non-communicable diseases (NCDs) should also be considered. The stakeholders identified public finance management, human resources for health, political interests, corruption, management capacity, and poor coordination as factors that influence the efficiency of county health systems. An in-depth examination of the factors that influence the efficiency of county health systems could illuminate potential policy levers for generating efficiency gains. Mixed methods approaches could facilitate the study of both hardware and software factors that are considered inputs, outputs or factors that influence health system efficiency.
Risk Factors for Progression to Alzheimer’s Disease in African Americans in a Large National Cohort
Authors: Kim Yejin , Savitz Sean , Lee Jessica , Schulz Paul E , Chen Luyao , Jiang Xiaoqian
Published: September 2020

Objectives

To investigate risk factors for progression to Alzheimer’s disease and related dementias (ADRD) in African Americans and non-Hispanic Caucasians in a large US cohort.

Design

A matched case-control design using electronic health records (EHRs) from 2000 – 2017.

Setting

Cerner EHRs database covering more than 600 Cerner client hospitals. Participants: 79,120 patients aged 65 and older (#ADRD=39,560, #non ADRD older adults=39,560) from an initial cohort of 49,826,000 patients.

Measurements

We converted ICD9 or ICD10 diagnosis codes into PheWas codes to increase clinical relevance. Then we detected ADRD as having both ADRD diagnosis codes and medications. We considered PheWas codes for Alzheimer’s disease, dementia with cerebral degenerations, senile dementia, and vascular dementia. We considered ADRD medications including acetylcholine and memantine.

Results

Using two-step propensity score matching, we built an African American cohort of 4,429 and a 4,570-person matched Caucasian cohort that was similar in terms of onset age, observation length, sex, and known ADRD risks (diabetes, vascular disease, heart disease, head injury, and obesity). Older African Americans had a statistically significant progression from cerebrovascular risk (transient ischemic attack) to ADRD incidence (treatment effect coefficient = 0.0978, p-value <0.000) whereas the matched Caucasians did not (treatment effect coefficient = 0.403, p-value = 0.196).

Conclusion

Our extensive causal analysis using a nationwide EHR discovered disease progression pathways to ADRD. The carefully matched cohorts from different racial groups showed different progression, which partly explains the racial disparities in ADRD incidence.

IMPACT STATEMENT

We certify that this work is confirmatory of recent novel clinical research. We confirmed that cerebrovascular disease increases the risk of ADRD incidence more in older African Americans than in non-Hispanic Caucasians when diabetes is controlled.1,2 This research adds large-scale and nationwide epidemiological evidence on racial disparities due to cerebrovascular risk.
The Accuracy of Healthcare Worker versus Self Collected (2-in-1) Oropharyngeal and Bilateral Mid-Turbinate (OPMT) Swabs and Saliva Samples for SARS-CoV-2
Authors: Tan Seow Yen , Tey Hong Liang , Lim Ernest Tian Hong , Toh Song Tar , Chan Yiong Huak , Tan Pei Ting , Lee Sing Ai , Tan Cheryl Xiaotong , Koh Gerald Choon Huat , Tan Thean Yen , Siau Chuin
Published: September 2020

Background

Self-sampling for SARS-CoV-2 would significantly raise testing capacity and reduce healthcare worker (HCW) exposure to infectious droplets personal, and protective equipment (PPE) use.

Methods

We conducted a diagnostic accuracy study where subjects with a confirmed diagnosis of COVID-19 (n=401) and healthy volunteers (n=100) were asked to self-swab from their oropharynx and mid-turbinate (OPMT), and self-collect saliva. The results of these samples were compared to an OPMT performed by a HCW in the same patient at the same session.

Results

In subjects confirmed to have COVID-19, the detection rates of the HCW-swab, self-swab, saliva, and combined self-swab plus saliva samples were 82.8%, 75.1%, 74.3% and 86.5% respectively. All samples obtained from healthy volunteers were tested negative. Compared to HCW-swab, the detection rates of a self-swab sample and saliva sample were inferior by 8.7% (95%CI: 2.4% to 15.0%, p=0.006) and 9.5% (95%CI: 3.1% to 15.8%, p=0.003) respectively. The combined detection rate of self-swab and saliva had a higher detection rate of 2.7% (95%CI: −2.6% to 8.0%, p=0.321). The sensitivity of both the self-collection methods are higher when the Ct value of the HCW swab is less than 30. The negative correctness of both the self-swab and saliva testing was 100% (95% CI 96.4% to 100%).

Conclusion

Our study provides evidence that detection rates of self-collected OPMT swab and saliva samples were inferior to a HCW swab, but they could still be useful testing tools in the appropriate clinical settings.
Extended kinship analysis of historical remains using SNP capture
Authors: Gorden Erin M. , Greytak Ellen M. , Sturk-Andreaggi Kimberly , Cady Janet , McMahon Timothy P. , Armentrout Steven , Marshall Charla
Published: September 2020

DNA-assisted identification of historical remains requires the genetic analysis of highly degraded DNA, along with a comparison to DNA from known relatives. This can be achieved by targeting single nucleotide polymorphisms (SNPs) using a hybridization capture and next-generation sequencing approach suitable for degraded skeletal samples. In the present study, two SNP capture panels were designed to target ~25,000 (25K) and ~95,000 (95K) nuclear SNPs, respectively, to enable distant kinship estimation (up to 4thdegree relatives). Low-coverage SNP data were successfully recovered from 14 skeletal elements 75 years postmortem, with captured DNA having mean insert sizes ranging from 32-170 bp across the 14 samples. SNP comparison with DNA from known family references was performed in the Parabon Fx Forensic Analysis Platform, which utilizes a likelihood approach for kinship prediction that was optimized for low-coverage sequencing data with cytosine deamination. The 25K panel produced 15,000 SNPs on average, which allowed for accurate kinship prediction in 17 of the 21 pairwise comparisons. The 95K panel increased the average SNPs to 42,000 and resulted in two additional pairwise comparisons (19 of 21). This study provides the groundwork for the expansion of research involving compromised samples to include SNP hybridization capture.
Thalamus and claustrum control parallel layer 1 circuits in retrosplenial cortex
Authors: Brennan Ellen K.W. , Jedrasiak-Cape Izabela , Kailasa Sameer , Rice Sharena P. , Sudhakar Shyam Kumar , Ahmed Omar J.
Published: September 2020

The granular retrosplenial cortex (RSG) is critical for both spatial and non-spatial behaviors, but the underlying neural codes remain poorly understood. Here, we use optogenetic circuit mapping in mice to reveal a double dissociation that allows parallel circuits in superficial RSG to process disparate inputs. The anterior thalamus and dorsal subiculum, sources of spatial information, strongly and selectively recruit small low-rheobase (LR) pyramidal cells in RSG. In contrast, neighboring regular-spiking (RS) cells are preferentially controlled by claustral and anterior cingulate inputs, sources of mostly non-spatial information. Precise sublaminar axonal and dendritic arborization within RSG layer 1, in particular, permits this parallel processing. Observed thalamocortical synaptic dynamics enable computational models of LR neurons to compute the speed of head rotation, despite receiving head direction inputs that do not explicitly encode speed. Thus, parallel input streams identify a distinct principal neuronal subtype ideally positioned to support spatial orientation computations in the RSG.
Local projections of layer Vb-to-Va are more effective in lateral than in medial entorhinal cortex
Authors: Ohara Shinya , Blankvoort Stefan , Nair Rajeevkumar R. , Nigro Maximiliano J. , Nilssen Eirik S. , Kentros Clifford , Witter Menno P.
Published: September 2020

The entorhinal cortex, in particular neurons in layer V, allegedly mediate transfer of information from the hippocampus to the neocortex, underlying long-term memory. Recently, this circuit has been shown to comprise a hippocampal output recipient layer Vb and a cortical projecting layer Va. With the use ofin vitroelectrophysiology in transgenic mice specific for layer Vb, we assessed the presence of the thus necessary connection from layer Vb-to-Va in the functionally distinct medial (MEC) and lateral (LEC) subdivisions; MEC, particularly its dorsal part, processes allocentric spatial information, whereas the corresponding part of LEC processes information representing elements of episodes. Using identical experimental approaches, we show that connections from layer Vb-to-Va neurons are more effective in LEC compared with dorsal MEC. This indicates that the hippocampal-cortex output circuit is more effective in LEC, suggesting that episodic systems-consolidation may use LEC-derived information more than allocentric spatial information from MEC.
Bidirectional regulation of glial potassium buffering: glioprotectionversusneuroprotection
Authors: Li Hailun , Lones Lorenzo , DiAntonio Aaron
Published: September 2020

Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A SIK3-regulated gene expression program controls the glial capacity to buffer K+and water, however upstream regulatory mechanisms are unknown. Here we identify an octopaminergic circuit linking neuronal activity to glial ion and water buffering. Under basal conditions, octopamine functions through the inhibitory octopaminergic GPCR OctβR to upregulate glial buffering capacity, while under pathological K+stress, octopamine signals through the stimulatory octopaminergic GPCR OAMB1 to downregulate the glial buffering program. Failure to downregulate this program leads to intracellular glia swelling and stress signaling, suggesting that turning down this pathway is glioprotective. In theeag shaker Drosophilaseizure model, the SIK3-mediated buffering pathway in inactivated. Re-activation of the glial buffering program dramatically suppresses neuronal hyperactivity, seizures, and shortened lifespan in this mutant. These findings highlight the therapeutic potential of a glial-centric therapeutic strategy for diseases of hyperexcitability.
Chemotherapeutic cardiotoxicity is associated with elevated β1-adrenergic receptor density
Authors: Gupta Manveen K , Martelli Elizabeth E. , Stenson Kate T. , Naga Prasad Sathyamangla V.
Published: September 2020

Objective

To understand the underlying pathways that promote cardiotoxicity following chemotherapy.

Background

Anthracyclines are associated with cardiotoxicity which could be potentiated with use of complementary agents (like anti-ERBB2 inhibitors) which together afford robust anti-neoplastic effects. Anthracyclines lead to oxidative stress and thought to induce cardiotoxicity. However, interventions reducing oxidative stress in patients have been unsuccessful suggesting mechanisms beyond oxidative stress. Despite β-adrenergic receptors (βARs) being key regulators of cardiac function, nothing is known about their role in chemotherapy-mediated cardiotoxicity.

Methods

β1 and/or β2-AR density was assessed in end-stage human heart failure patient samples either due to anthracycline cardiotoxicity or non-anthracycline dilated cardiomyopathy (DCM). Since ERBB2 inhibition is integral to overall chemotherapeutic arsenal, we assessed β1- and/or β2-AR density, cardiac function by echocardiography and immunohistochemistry in mice following ERBB2-specific inhibitor AG825.

Results

Selective increase in cardiac β1AR density is observed in end-stage human heart failure patient samples due to anthracycline cardiotoxicity as well as in ERBB2 inhibitor-treated mice.

Conclusions

Elevated β1AR density may be the key common underlying mechanism which is altered in response to chemotherapy promoting cardiac dilation of otherwise healthy hearts.

Highlights

In contrast to downregulation of β1-adrenergic receptors (β1AR) in end-stage human heart failure, anthracycline cardiotoxicity-mediated failure is associated with selective increase in β1AR density.

ERBB2 inhibitor (AG825) treatment in mice results in cardiac dilation and selective rise in β1AR density showing that increased β1AR density in the heart could be a common mechanism underlying cardiotoxicity.
Urban rail transport and SARS-CoV-2 infections: an ecological study in Lisbon Metropolitan Area
Authors: Severo Milton , Ribeiro Ana Isabel , Lucas Raquel , Leão Teresa , Barros Henrique
Published: September 2020

Introduction

Large number of passengers, limited space and shared surfaces can transform public transportation into a hub of epidemic spread. This study was conducted to investigate whether proximity to railway stations, a proxy for utilization, was associated with higher rates of SARS-CoV-2 infection across small-areas of Lisbon Metropolitan Area (Portugal).

Methods

The number of SARS-CoV-2 confirmed infections from March 2 until July 5, 2020 at parish-level was obtained from the National Epidemiological Surveillance System. We used a Geographic Information System to estimate proximity to railway stations from the six railway lines operating in the area. Then, we fitted a quasi-Poisson generalized linear regression model to estimate the relative risks (RR) and corresponding 95% Confidence Intervals (95%CI).

Results

Between May 2 and July 5, 2020, there were a total of 17,168 SARS-CoV-2 infections in the Lisbon Metropolitan Area, with wide disparities between parishes.

Globally, parishes near one of the railway lines (Sintra) presented significantly higher SARS-CoV-2 infection rates (RR=1.42, 95%CI 1.16, 1.75) compared to those parishes located far away from railway stations, while the opposite happened for parishes near other railway lines (Sado/Fertagus), whose infection rates were significantly lower than those observed in parishes located far away from railway stations (RR=0.66, 95%CI 0.50, 0.87). However, the associations varied according to the stage of the epidemic and according to mitigation measures in place. Regression results also revealed an increasing influence of socioeconomic deprivation on SARS-CoV-2 infections.

Conclusions

We found no consistent association between proximity to railway stations and SARS-CoV-2 infection rates in the most affected metropolitan area of the country, suggesting that other factors (e.g. socioeconomic deprivation) might play a more prominent role in the epidemic dynamics.
Sex differences in innate anti-viral immune responses to respiratory viruses
Authors: Regis Eteri , Fontanella Sara , Lin Lijing , Howard Rebecca , Haider Sadia , Curtin John A. , Edwards Michael R. , Rattray Magnus , Simpson Angela , Custovic Adnan , Johnston Sebastian L.
Published: September 2020

Males have excess morbidity and mortality from respiratory viral infections and especially so in COVID-19. The mechanisms explaining this excess in disease burden in males are unknown. Innate immune responses are likely critical in protection against a novel virus like SARS-CoV-2. We hypothesised that innate immune responses may be deficient in males relative to females. To test this we stimulated peripheral blood mononuclear cells (PBMCs) from participants in a population-based birth cohort with three respiratory viruses (rhinoviruses-RV-A16 and RV-A1, and respiratory syncytial virus-RSV) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2). We measured interferon (IFN) and IFN-induced chemokine responses and investigated sex differences in virus-induced responses. IFN-α, IFN-β and IFN-γ responses to RV-A16 were deficient in males compared to females, fold-inductions being 1.92-fold (P<0.001), 2.04-fold (P<0.001) and 1.77-fold (P=0.003) lower in males than females, respectively. Similar significant deficiencies in innate immune responses were observed in males for eleven other cytokine-stimulus pairs. Responses in males were greater than those in females in only one of 35 cytokine-stimulus pairs investigated. Review of healthcare records revealed that 12.1% of males but only 6.6% of females were admitted to hospital with respiratory infections in the first year of life (P=0.017). Impaired innate anti-viral immunity in males likely results in high morbidity and mortality from respiratory viruses including COVID-19. Males may preferentially benefit from therapies that boost innate anti-viral immune responses.

Significance Statement

Clinical outcomes including, mortality, Intensive care unit admissions and hospital admissions, during COVID-19 disease are consistently and substantially worse in males than in females. The mechanisms underlying this increased susceptibility to severe disease in males are not understood. We hypothesised that the differential outcomes between sexes could be a consequence of deficient innate interferon responses in males, and more robust innate interferon responses in females. We have investigated such responses in a large population-based cohort and found that indeed males have deficient innate interferon responses to viral stimuli, including stimuli that mimic SARS-CoV-2 infection, relative to females. Our findings have very important treatment implications as interferons are available for clinical use with immediate effect.
The COVID-19 Spread in the State of Assam, India
Authors: Baruah Hemanta K.
Published: September 2020

We have studied the current COVID-19 spread situation in Assam, a State of India. We have found that currently the spread pattern is indeed exponential and that it is not going to show a reducing trend soon. As a result, it is not possible yet to forecast about the time of peaking of the epidemic in Assam. It can be said that the COVID-19 situation in this Indian State is very alarming even after five and a half months of the start of the epidemic in the State. It may so happen that in Assam the spread would continue to grow exponentially even after the situation changes in India as a whole.
Detectability of the novel coronavirus (SARS-CoV-2) infection and rates of mortality for COVID-19 in different regions of the Russian Federation
Authors: Goldstein Edward
Published: September 2020

Background

Laboratory diagnosis of the novel coronavirus (SARS-CoV-2) infection combined with tracing/quarantine for contacts of infected individuals affects the spread of SARS-CoV-2 in the community and the levels of related mortality. Moreover, not all cases of SARS-CoV-2 infection in the population are detected (laboratory diagnosed). Here, we examine the relation between detectability of SARS-CoV-2 infection (i.e. the percent of detected COVID-19 cases among all cases of SARS-CoV-2 infection in the population) and levels of mortality for COVID-19 for the 85 different regions (federal subjects) of the Russian Federation.

Methods

Lower case-fatality rate (CFR, the proportion of deaths among reported COVID-19 cases in the population) corresponds to higher detectability of the SARS-COV-2 infection. We used data from the Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor) on the number of detected COVID-19 cases and the number of deaths from COVID-19 in the 85 different regions of the Russian Federation to examine the correlation between case-fatality rates and rates of mortality for COVID-19 in different regions of the Russian Federation.

Results

The correlation between case-fatality rates for cases/deaths reported by Sep. 17, 2020 and rates of mortality for COVID-19 per 100,000 for deaths reported by Sep. 17, 2020 in different regions of the Russian Federation is 0.68 (0.55,0.78). The region with both the highest COVID-19 mortality rate per 100,000 and the highest CFR (lowest detectability of SARS-CoV-2 infection) is the city of St. Petersburg.

Conclusions

Detectability of SARS-CoV-2 infection is one of the factors that affects the levels of mortality for COVID-19 in Russia. Regions of the Russian Federation with relatively low detectability of SARS-CoV-2 infection (e.g. those regions for which the case-fatality rate is above the median value of 1.2% for the case-fatality rate in different regions of the Russian Federation on Sep. 17, 2020 [3]) ought to increase testing for SARS-CoV-2 in order to mitigate the spread of SARS-CoV-2 and diminish the related mortality.
Challenges in conducting sexual health and violence research in older adults beyond GDPR: a Belgian case study
Authors: Nobels Anne , Inescu Adina Cismaru , Nisen Laurent , Hahaut Bastien , Lemmens Gilbert M.D. , Vandeviver Christophe , Keygnaert Ines
Published: September 2020

Background

Because of a growing older population, the sexual health (SH) of older adults, including sexual violence (SV), is becoming an increasingly important public health concern. Yet, reliable SV prevalence rates and risk factors are lacking, due to methodological shortcomings in current studies. SV research involves challenges regarding safety and disclosure, especially in older adults. In this paper we reflect on the methods used in a SH&V study in older adults balancing between GDPR imposed privacy rules and ethical and safety guidelines.

Methods

To ensure the acceptability of the questionnaire, it was tested in a two-phase pilot study. To maximize SV disclosure, the questionnaire built up gradually towards the more sensitive SV modules. Interviewers were trained to approach participants in a non-judgemental manner. Due to GDPR, our data collection method was changed from a random sampling via the National Register to a cluster random probability sampling with a random route finding approach.

Results

Older adults were willing to discuss SH&V during a face-to-face interview with trained interviewers. Following strict safety guidelines, no major incidents were reported. The cluster random probability sampling with random route finding approach provided an adequate sampling frame, but was inefficient and time-consuming.

Conclusion

Doing research on SH&V in older adults is feasible, but requires a substantial investment of time and the challenges involved may incur greater costs. Research institutions, donors, and policy makers should convene to investigate how problems related to GDPR can be solved, especially regarding research on sensitive topics and hard to reach populations.
Splice switching oligonucleotide mediated gene knockdown in B cells and plasma cells
Authors: Marchalot Anne , Lambert Jean-Marie , Boyer François , Pollet Justine , Moreau Jeanne , Feuillard Jean , Faumont Nathalie , Delpy Laurent
Published: September 2020

The need to identify new therapeutic approaches to the treatment of cancers of the B lymphoid lineage is crucial. Unlike CRISPR/Cas technology, antisense strategies result in transient modifications of gene expression and lack mutagenic effects at the DNA level. Here, we provide evidence for efficient knockdown of c-REL and RELA expression after treatment with splice switching antisense oligonucleotides (SSO) inducing exon skipping and reading frameshifts. We also developed a tool to facilitate the choice of exons for on purpose inhibition of mouse and human gene expression. Interestingly, treatments with morpholino SSO targeting the c-REL exon 2 donor splice site or RELA exon 5 acceptor splice site elicited very efficient knockdown in diffuse large B cell lymphoma (DLBCL) cell lines and antibody-secreting cells derived from primary human B cells. Consistent with the clinical relevance of c-REL activation in DLBCLs, treatment with c-REL SSO induced major alterations in NF-κB and TNF signalling pathways and strongly decreased cell viability. Altogether, SSO-mediated knockdown is a powerful approach to transiently inhibit the expression of given genes in B-lineage cells that should pave the way for cancer treatments, provided optimized ligand-conjugations forin vivodelivery.

Graphical Abstract
Primary case inference in viral outbreaks through analysis of intra-host variant population
Authors: Gussler J. Walker , Campo David S , Dimitrova Zoya , Skums Pavel , Khudyakov Yury
Published: September 2020

Investigation of outbreaks to identify the primary case is crucial for the interruption and prevention of transmission of infectious diseases. These individuals may have a higher risk of participating in near future transmission events when compared to the other patients in the outbreak, so directing more transmission prevention resources towards these individuals is a priority. Genetic characterization of intra-host viral populations, although highly efficient in the identification of transmission clusters, is not as efficient in routing transmissions during outbreaks, owing to complexity of viral evolution. Here, we present a new computational framework, PYCIVO:primarycaseinference inviraloutbreaks. This framework expands upon our earlier work in development of QUENTIN, which builds a probabilistic disease transmission tree based on simulation of evolution of intra-host hepatitis C virus (HCV) variants between cases involved in direct transmission during an outbreak. PYCIVO improves upon QUENTIN by also implementing a custom heterogeneity index which empowers PYCIVO to make the important ‘No primary case’ prediction. One or more samples, possibly including the primary case, may have not been sampled, and this designation is meant to account for these scenarios. These approaches were validated using a set of 105 sequence samples from 11 distinct HCV transmission clusters identified during outbreak investigations, in which the primary case was epidemiologically verified. Both models can detect the correct primary case in 9 out of 11 transmission clusters (81.8%). However, while QUENTIN issues erroneous predictions on the remaining 2 transmission clusters, PYCIVO issues a null output for these clusters, giving it an effective prediction accuracy of 100%. To further evaluate accuracy of the inference, we created 10 modified transmission clusters in which the primary case had been removed. In this scenario, PYCIVO was able to correctly identify that there was no primary case in 8/10 (80%) of these modified clusters. This model was validated with HCV; however, this approach may be applicable to other microbial pathogens.

A version of this software is publicly available at the following url:https://www.github.com/walkergussler/PYCIVO
Evolution of the Analytical Scattering Model of LiveEscherichia Coli
Authors: Semeraro Enrico F. , Marx Lisa , Mandl Johannes , Frewein Moritz P. K. , Scott Haden L. , Prévost Sylvain , Bergler Helmut , Lohner Karl , Pabst Georg
Published: September 2020

We have revised a previously reported multi-scale model for (ultra) small angle X-ray (USAXS/SAXS) and (very) small angle neutron scattering (VSANS/SANS) of liveEscherichia colibased on compositional/metabolomic and ultrastructural constraints. The cellular body is modelled, as previously described, by an ellipsoid with multiple shells. However, scattering originating from flagella was substituted by a term accounting for the oligosaccharide cores of the lipopolysaccharide leaflet of the outer membrane including its cross-term with the cellular body. This was mainly motivated by (U)SAXS experiments showing indistinguishable scattering for bacteria in the presence and absence of flagella or fimbrae. The revised model succeeded in fitting USAXS/SAXS and differently contrasted VSANS/SANS data ofE. coliATCC 25922 over four orders of magnitude in length scale, providing specifically detailed insight into structural features of the cellular envelope, including the distance of the inner and outer membranes, as well as the scattering length densities of all bacterial compartments. Consecutively, the model was also successfully applied toE. coliK12, used for our original modelling, as well as for two otherE. colistrains, detecting significant differences between the different strains in terms of bacterial size, intermembrane distance and its positional fluctuations. These findings corroborate the general applicability of our approach to quantitatively study the effect of bactericidal compounds on ultrastructural features of Gram-negative bacteria without the need to resort to any invasive staining or labelling agents.