bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTObjectivesTo 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.DesignA matched case-control design using electronic health records (EHRs) from 2000 – 2017.SettingCerner 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.MeasurementsWe 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.ResultsUsing 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).ConclusionOur 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 STATEMENTWe 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

AbstractBackgroundSelf-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.MethodsWe 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.ResultsIn 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%).ConclusionOur 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

AbstractDNA-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

ABSTRACTThe 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

SummaryThe 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

ABSTRACTGlia 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

AbstractObjectiveTo understand the underlying pathways that promote cardiotoxicity following chemotherapy.BackgroundAnthracyclines 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.Methodsβ1 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.ResultsSelective 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.ConclusionsElevated β1AR density may be the key common underlying mechanism which is altered in response to chemotherapy promoting cardiac dilation of otherwise healthy hearts.HighlightsIn 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

ABSTRACTIntroductionLarge 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).MethodsThe 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).ResultsBetween 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.ConclusionsWe 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

AbstractMales 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 StatementClinical 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

AbstractWe 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

AbstractBackgroundLaboratory 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.MethodsLower 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.ResultsThe 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.ConclusionsDetectability 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

ABSTRACTBackgroundBecause 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.MethodsTo 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.ResultsOlder 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.ConclusionDoing 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

ABSTRACTThe 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