bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral Nerve Stimulation for the 21st Century: Sural, Superficial Peroneal, and Tibial Nerves
Authors: Hanyu-Deutmeyer Aaron , Pritzlaff Scott G
Published: May 2020

Objective

Peripheral nerve stimulation (PNS) of the lower extremity has progressed significantly over the last decade. From the proof of concept that ultrasound-guided, percutaneous implantation was possible to advances in waveforms, the field has been rapidly evolving. While most nerves in the lower extremity can be PNS targets, consideration must be given to the ergonomics of pulse generator placement, patient comfort, and avoidance of lead migration. For this paper, we examine some of the conditions amenable to lower extremity PNS, review the evidence and history behind PNS for these conditions, and describe approaches for the tibial, sural, and superficial peroneal nerves.

Methods

A literature search was conducted using PubMed. Search terms used were “peripheral nerve stimulation,” “lower extremity entrapment neuropathies,” “sural nerve,” “superficial peroneal nerve,” “tibial nerve,” and “tarsal tunnel syndrome.” Emphasis was placed on randomized controlled studies, anatomical dissections, and comprehensive review articles. Approaches to nerves and ultrasound images were based on anecdotal PNS cases from an experienced implanter (SP).

Conclusions

The development of ultrasound as a viable method of image guidance for percutaneous peripheral nerve stimulation has led to an exponential growth in the field. Lower extremity percutaneous lead placement is both feasible and an appropriate treatment modality for certain pain conditions.
MEASUREMENT AND ANALYSIS OF THE NEUTRON ENERGY SPECTRUM AND ASSOCIATED OCCUPATIONAL EXPOSURE FROM A SHIELDED241AM-BE SOURCE
Authors: Stringer Jimmy Steele , Spitz Henry , Glover Samuel
Published: May 2020

A set of five Bonner spheres was used to measure the ambient neutron H*(10) dose around an orphan 241Am-Be neutron source shielded with different arrangements and types of neutron-absorbing materials. These results were compared to measurements obtained using a portable radiation dosemeter. The Bonner sphere measurement results identified the presence of a large thermal and intermediate neutron component from the shielded 241Am-Be source that was not revealed using the portable instrument.
Hallucinations in Older Adults: A Practical Review
Authors: Badcock Johanna C , Larøi Frank , Kamp Karina , Kelsall-Foreman India , Bucks Romola S , Weinborn Michael , Begemann Marieke , Taylor John-Paul , Collerton Daniel , O’Brien John T , El Haj Mohamad , Ffytche Dominic , Sommer Iris E
Published: May 2020

Older adults experience hallucinations in a variety of social, physical, and mental health contexts. Not everyone is open about these experiences, as hallucinations are surrounded with stigma. Hence, hallucinatory experiences in older individuals are often under-recognized. They are also commonly misunderstood by service providers, suggesting that there is significant scope for improvement in the training and practice of professionals working with this age group. The aim of the present article is to increase knowledge about hallucinations in older adults and provide a practical resource for the health and aged-care workforce. Specifically, we provide a concise narrative review and critique of (1) workforce competency and training issues, (2) assessment tools, and (3) current treatments and management guidelines. We conclude with a brief summary including suggestions for service and training providers and future research.
Brief Report: Hormonal Contraception Use and Cabotegravir Pharmacokinetics in HIV-Uninfected Women Enrolled in HPTN 077
Authors: Blair Cheríe S. , Li Sue , Chau Gordon , Cottle Leslie , Richardson Paul , Marzinke Mark A. , Eshleman Susan H. , Adeyeye Adeola , Rinehart Alex R. , Margolis David , McCauley Marybeth , Hendrix Craig W. , Landovitz Raphael J. ,   on behalf of the HPTN 077 Study Team
Published: May 2020

Objectives:

To evaluate whether hormonal contraceptive use among cisgender women is associated with differences in pharmacokinetic (PK) parameters of a long-acting injectable formulation of the integrase strand transfer inhibitor, cabotegravir (CAB-LA).

Setting:

This is a secondary analysis of 85 cisgender women enrolled in HPTN 077, a phase 2a multicenter study that enrolled HIV-uninfected, low-risk individuals in Malawi, Brazil, South Africa, and the United States.

Methods:

Participants received 4-week daily oral cabotegravir lead-in, followed by CAB-LA 800 mg injection every 12 weeks (cohort 1) or 600 mg every 8 weeks (after 4-week initial interval between injections, cohort 2), over 41 weeks. Participants were followed 52–76 weeks subsequent to final injection. Generalized estimating equations and linear regression were used to evaluate differences in CAB-LA PK parameters (peak concentration, trough concentration, area under the curve, apparent terminal half-life, and time to lower limit of quantification) and self-reported hormonal contraceptive stratified by type (oral, injectable, implants, and other), controlling for body mass index and cohort.

Results:

Compared to women reporting no hormonal contraception (n = 6), oral contraceptive use (n = 18) was associated with lower CAB-LA peak concentration but was not associated with differences in other PK parameters. No other hormonal contraceptive type (injectable, implants, and other) was associated with significant differences in CAB-LA PK parameters.

Conclusion:

Although oral contraceptive use was associated with differences in CAB-LA peak concentration, no differences were observed in other PK parameters, suggesting that this association is not likely to be clinically significant. However, these data highlight the need for further research exploring potential drug–drug interactions between CAB-LA and hormonal contraceptives.
Can a herd immunity strategy become a viable option against COVID-19? A model-based analysis on social acceptability and feasibility
Authors: Akamatsu Takashi , Nagae Takeshi , Osawa Minoru , Satsukawa Koki , Sakai Takara , Mizutani Daijiro
Published: May 2020

This paper studies the social acceptability and feasibility of “herd immunity” strategies against coronavirus disease 2019 (COVID-19). To this end, we propose a control scheme that aims to develop herd immunity while satisfying the following two basic requirements for a viable policy option. The first requirement is social acceptability: the overall deaths should be minimized for social acceptance. The second is feasibility: the healthcare system should not be overwhelmed to avoid diverse adverse effects. Exploiting the fact that the severity of the disease increases considerably with age, the proposed control scheme protects high-risk individuals that mainly consist of the elderly. The protection of high-risk individuals reduces the average severity of the disease in the unprotected population, thereby substantially reducing mortality and avoiding the collapse of the healthcare system. Social acceptability (in terms of the resulting mortality) and feasibility (in terms of the healthcare system capacity) of the proposed herd immunity strategy are summarized into two respective, easily computable conditions by building on a simple susceptible–infected–recovered (SIR) model. For its parsimony, the proposed framework can provide a rule of thumb that applies to various populations for studying the viability of herd immunity strategies against COVID-19. For Japan, herd immunity may be developed by the considered control scheme ifand the severity rates of the disease are 1/10 times smaller than the previously reported value, although as high mortality as seasonal influenza is expected.
The misleading illusion of COVID-19 confirmed case data: alternative estimates and a monitoring tool
Authors: Macías-Ordóñez Rogelio , Villaseñor-Amador Damián
Published: May 2020

Confirmed Case Data have been widely cited during the current COVID-19 pandemic as an estimate of the spread of the SARS-CoV-2 virus. However, their central role in media, official reports and decision-making may be undeserved and misleading. Previously published Infection Fatality Rates were weighted by age structure in the 50 countries with more reported deaths to obtain country-specific rates. For each country, the number of infections up to the Infection Date (23 days ago = Incubation Period + Onset to Death period) and the present percentage of immune population were estimated using Infection Fatality Rate, the number of reported deaths (which is less prone to undersampling), and projecting back to Infection Date. We then estimated a Detection Index for each country as the percentage of estimated infections that confirmed cases represent. Assuming that detection remains constant after Infection Date, we estimated the number of deaths and the estimated percentage of the population of each country expected to be immune up to 23 days into the future. Estimated Infection Fatality Rates are higher in Europe. In most countries, confirmed cases currently represent less than 30% of estimated infections on Infection Date, and this value decreases with time. Countries with flat curves throughout the pandemic show the lowest immunity percentages and these values seem unlikely to change in the near future, suggesting that they remain vulnerable to new outbreaks. Estimates for some countries with low Infection Fatality Rates suggest a still steep increase in the number of casualties in the next three weeks. Countries that did not control initial outbreaks seem to have reached higher immunity percentages, although mostly still under 5%. We provide the code to monitor the trajectories of these estimates in 178 countries throughout the COVID-19 pandemic.
SARS-CoV-2 epitopes are recognized by a public and diverse repertoire of human T-cell receptors
Authors: Shomuradova Alina S. , Vagida Murad S. , Sheetikov Savely A. , Zornikova Ksenia V. , Kiryukhin Dmitry , Titov Aleksei , Peshkova Iuliia O. , Khmelevskaya Alexandra , Dianov Dmitry V. , Malasheva Maria , Shmelev Anton , Serdyuk Yana , Bagaev Dmitry V. , Pivnyuk Anastasia , Shcherbinin Dmitrii S. , Maleeva Alexandra V. , Shakirova Naina T. , Pilunov Artem , Malko Dmitry B. , Khamaganova Ekaterina G. , Biderman Bella , Ivanov Alexander , Shugay Mikhail , Efimov Grigory A.
Published: May 2020

Understanding the hallmarks of the adaptive immune response to SARS-CoV-2 is critical for fighting the COVID-19 pandemic. We assessed the antibody and T-cell reactivity in COVID-19 convalescent patients and healthy donors sampled both prior to and during the pandemic. The numbers of SARS-CoV-2-specific T cells were increased in healthy donors examined during COVID-19. Combined with the absence of symptoms and humoral response across that group, this finding suggests that some individuals might be protected by T-cell cross-reactivity. In convalescent patients we observed public and diverse T-cell response to SARS-CoV-2 epitopes, revealing T-cell receptor motifs with germline-encoded features. Bulk CD4+ and CD8+ T-cell responses to Spike glycoprotein were mediated by groups of homologous T-cell receptors, some of them shared across multiple donors. Overall, our results demonstrate that T-cell response to SARS-CoV-2, including the identified set of specific T-cell receptors, can serve as a useful biomarker for surveying viral exposure and immunity.
Spread dynamics of SARS-CoV-2 epidemic in China: a phylogenetic analysis
Authors: GuoHu Hong , Qing Guan , Qing Mao
Published: May 2020

Background

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic and infected millions of people. As the first country proclaimed the SARS-CoV-2 outbreak, China implemented travel ban measure, and curbed the epidemic quickly. We performed a phylogenetic analysis to reveal the spread dynamics detail of SARS-CoV-2 in China and the impact of travel ban on SARS-CoV-2.

Method

Focusing on SARS-CoV-2 sequences collected from China in public database released as of March 31, 2020, we performed a Bayesian inference phylogenetic analyses to estimate the effective population size (Ne) curve of SARS-CoV-2 epidemic. Furthermore, we displayed the geographic spread mode of SARS-CoV-2 among different China regions by using Bayesian stochastic search variable selection (BSSVS) method.

Results

The most recent common ancestor (tMRCA) of SARS-CoV-2 in China was traced back to December 9, 2019. According the Ne estimation and geographic spread reconstruction, January 25, 2020 was considered as the crucial time point during the SARS-CoV-2 epidemic in China,which was 2 days after the travel ban implemented. On the point, the tendency of viral population size changed from ascending to decreasing, and the cross-regional spread paths were blocked.

Conclusions

Travel ban is an effective measure to intervene in the spread of SARS-CoV-2, It is necessary to continue efforts in research for prevention and control measures.
Coronavirus (COVID-19) infection in children at a specialist centre: outcome and implications of underlying ‘high-risk’ comorbidities in a paediatric population
Authors: Issitt RW , Booth J , Bryant WA , Spiridou A , Taylor AM , du Pré P , Ramnarayan P , Hartley J , Cortina-Borja M , Moshal K , Dunn H , Hemingway H , Sebire NJ
Published: May 2020

Background

There is evolving evidence of significant differences in severity and outcomes of coronavirus disease 2019 (COVID-19) in children compared to adults. Underlying medical conditions associated with increased risk of severe disease are based on adult data, but have been applied across all ages resulting in large numbers of families undertaking social ‘shielding’ (vulnerable group). We conducted a retrospective analysis of children with suspected COVID-19 at a Specialist Children’s Hospital to determine outcomes based on COVID-19 testing status and underlying health vulnerabilities.

Methods

Routine clinical data were extracted retrospectively from the Institution’s Electronic Health Record system and Digital Research Environment for patients with suspected and confirmed COVID-19 diagnoses. Data were compared between Sars-CoV-2 positive and negative patients (CoVPos / CoVNeg respectively), and in relation to presence of underlying health vulnerabilities based on Public Health England guidance.

Findings

Between 1st March and 15th May 2020, 166 children (<18 years of age) presented to a specialist children’s hospital with clinical features of possible COVID-19 infection. 65 patients (39.2%) tested positive for SARS-CoV-2 virus. CoVPos patients were older (median 9 [0.9 - 14] years vs median 1 [0.1 - 5.7.5] years respectively, p<0.001). There was a significantly reduced proportion of vulnerable cases (47.7% vs 72.3%, p=0.002), but no difference in proportion of vulnerable patients requiring ventilation (61% vs 64.3%, p = 0.84) between CoVPos and CoVNeg groups. However, a significantly lower proportion of CoVPos patients required mechanical ventilation support compared to CoVNeg patients (27.7 vs 57.4%, p<0.001). Mortality was not significantly different between CoVPos and CoVNeg groups (1.5 vs 4% respectively, p=0.67) although there were no direct COVID-19 related deaths in this highly preselected paediatric population.

Interpretation

COVID-19 infection may be associated with severe disease in childhood presenting to a specialist hospital, but does not appear significantly different in severity to other causes of similar clinical presentations. In children presenting with pre-existing ‘COVID-19 vulnerable’ medical conditions at a specialist centre, there does not appear to be significantly increased risk of either contracting COVID-19 or severe complications, apart from those undergoing chemotherapy, who are over-represented.
Heat Shock Protein 27 Immune Complex Upregulates LDLR Expression Thereby Reducing Plasma Cholesterol and Atherogenesis
Authors: Chen Yong-Xiang , Shi Chunhuai , Deng Jingti , Diao Catherine , Maarouf Nadia , Rosin Matthew , Shrivastava Vipul , Hu Angie A. , Bharadwa Sonya , Adijiang Ayinuer , Ulke-Lemee Annegret , Gwilym Brenig , Hellmich Alexandria , Malozzi Christopher , Batulan Zarah , Dean Jonathan L. E. , Ramirez F. Daniel , Liu Jingwen , Gerthoffer William T. , O’Brien Edward R.
Published: May 2020

Elevated Heat Shock Protein 27 levels predict relative freedom from cardiovascular events. In ApoE-/-mice HSP27 over-expression or twice daily subcutaneous injections reduce blood and plaque cholesterol levels, inflammation and atherogenesis. While natural antibodies to HSP27 are present in human blood their role is unknown. Here, we show that blood levels of both HSP27 and anti-HSP27 IgG antibodies are elevated in healthy controls compared to patients with cardiovascular disease. ApoE-/-mice vaccinated with recombinant HSP25 (murine ortholog) develop elevated anti-HSP25 IgG antibodies and reduced levels of cholesterol, inflammation and atherosclerosis. The effects on cholesterol metabolism were divergent: increased hepatic LDLR expression and reduced plasma PCSK9 levels.In vitro, a polyclonal anti-HSP27 IgG antibody combined with rHSP27 to upregulate hepatocyte LDLR expression via an NF-kB-dependent pathway that is independent of SREBP2 expression and intracellular cholesterol levels. HSP27 immunotherapy represents a novel means of lowering not only cholesterol but also PCSK9.
Validation of an LC-MS/MS Assay for the Simultaneous Determination of Bictegravir, Doravirine, and Raltegravir in Human Plasma
Authors: Schauer Amanda P. , Sykes Craig , Cottrell Mackenzie L , Kashuba Angela DM
Published: May 2020

Bictegravir (BIC), an integrase inhibitor, and doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor, were recently approved by the US FDA for HIV treatment and are recommended first line treatment options. Because certain clinical scenarios warrant using them in combination, we developed a fully validated LC-MS/MS method for simultaneous measurement of BIC and DOR, along with a legacy integrase inhibitor, raltegravir (RAL), in human plasma over a clinically relevant 1000-fold range for each analyte. These analytes were extracted from the plasma by protein precipitation with their stable, isotopically labeled internal standards (BIC-d5,13C6-DOR, and RAL-d6). Following extraction, samples were analyzed by reverse phase chromatography on a Waters Atlantis T3 C18 (50×2.1mm, 3um particle size) column with subsequent detection by electrospray ionization in positive ion mode on an AB Sciex API-5000 triple quadrupole mass spectrometer. The assay was linear (R2>0.994) over the selected calibration ranges (20.0-20,000ng/mL (BIC), 3.00-3,000ng/mL (DOR), and 10.0-10,000 (RAL)). The assay was accurate (inter-assay %Bias ≤±8.5) and precise (inter-assay %CV ≤11.4). This method was validated according to FDA guidance for industry and can be used to assess the pharmacokinetics of two newly approved antiretrovirals, or to support therapeutic drug monitoring for modern antiretroviral therapy.
Tracking cortical representations of facial attractiveness using time-resolved representational similarity analysis
Authors: Kaiser Daniel , Nyga Karen
Published: May 2020

When we see a face, we rapidly form an impression of its attractiveness. Here, we investigated how rapidly representations of facial attractiveness emerge in the human brain. In an EEG experiment, participants viewed 100 face photographs and rated them for their attractiveness. Using time-resolved representational similarity analysis on the EEG data, we reveal representations of facial attractiveness after 150-200ms of cortical processing. Interestingly, we show that these representations are related to individual participants’ personal attractiveness judgments, suggesting that already early perceptual representations of facial attractiveness convey idiosyncratic attractiveness preferences. Further, we show that these early representations are genuinely related to attractiveness, as they are neither explained by other high-level face attributes, such as face sex or age, nor by features extracted by an artificial deep neural network model of face processing. Together, our results demonstrate early, individually specific, and genuine representations of facial attractiveness, which may underlie fast attractiveness judgments.
Network Preservation Reveals Shared and Unique Biological Processes Associated with Chronic Alcohol Abuse in NAc and PFC
Authors: Vornholt Eric , Mamdani Mohammed , Drake John , McMichael Gowon , Taylor Zachary N. , Bacanu Silviu-Alin , Miles Michael F. , Vladimirov Vladimir I.
Published: May 2020

Background

Excessive alcohol consumption has become a growing public health concern worldwide due to the potential development of alcohol dependence (AD). Prolonged alcohol abuse leads to dysregulation of the mesocorticolimbic pathway (MCL), effectively disrupting executive functioning and the allostatic conditioning of reward response.

Methods

We utilized weighted gene co-expressed network analysis (WGCNA) and network preservation using a case/control study design (n=35) to identify unique and shared biological processes dysregulated in AD in the prefrontal cortex (PFC) and nucleus accumbens (NAc). We used correlation and regression analyses to identify mRNA/miRNA interactions and local expression quantitative trait loci (cis-eQTL) to identify genetic regulatory mechanisms for networks significantly associated with AD.

Results

Network analyses revealed 6 and 3 significant mRNA modules from the NAc and PFC, respectively. Network preservation revealed immune response upregulation in both regions, whereas cellular morphogenesis/localization and cilia-based cell projection processes were upregulated only in the NAc. We observed 4 significantly correlated module eigengenes (ME) between the significant mRNA and miRNA modules in PFC, and 6 significant miRNA/mRNA ME correlations in NAc, with the mir-449a/b cluster emerging as a potential regulator for cellular morphogenesis/localization dysregulation in this brain region. Finally, we identified cis-eQTLs (37 mRNA and 9 miRNA in NAc, and 17 mRNA and 16 miRNA in PFC) which potentially mediate alcohol’s effect in a brain region-specific manner.

Conclusion

In agreement with previous reports, we observed a generalized upregulation of immune response processes in subjects with AD, that highlights alcohol’s neurotoxic properties, while simultaneously demonstrating distinct molecular changes in subcortical brain regions as a result of chronic alcohol abuse. Such changes further support previous neuroimaging and physiological studies that emphasize the distinct roles PFC and NAc play in the development of addictive behaviors.
Inclusion of Variants Discovered from Diverse Populations Improves Polygenic Risk Score Transferability
Authors: Cavazos Taylor B. , Witte John S.
Published: May 2020

The majority of polygenic risk scores (PRS) have been developed and optimized in individuals of European ancestry and may have limited generalizability across other ancestral populations. Understanding aspects of PRS that contribute to this issue and determining solutions is complicated by disease-specific genetic architecture and limited knowledge of sharing of causal variants and effect sizes across populations. Motivated by these challenges, we undertook a simulation study to assess the relationship between ancestry and the potential bias in PRS developed in European ancestry populations. Our simulations show that the magnitude of this bias increases with increasing divergence from European ancestry, and this is attributed to population differences in linkage disequilibrium and allele frequencies of European discovered variants, likely as a result of genetic drift. Importantly, we find that including into the PRS variants discovered in African ancestry individuals has the potential to achieve unbiased estimates of genetic risk across global populations and admixed individuals. We confirm our simulation findings in an analysis of HbA1c, asthma, and prostate cancer in the UK Biobank. Given the demonstrated improvement in PRS prediction accuracy, recruiting larger diverse cohorts will be crucial—and potentially even necessary—for enabling accurate and equitable genetic risk prediction across populations.
Effect of methanol fixation on single-cell RNA sequencing data
Authors: Wang Xinlei , Yu Lei , Wu Angela
Published: May 2020

Single-cell RNA sequencing (scRNA-seq) has led to remarkable progress in our understanding of tissue heterogeneity in health and disease. Recently, the need for scRNA-seq sample fixation has emerged in many scenarios, such as when samples need long-term transportation, or when experiments need to be temporally synchronized. Methanol fixation is a simple and gentle method that has been routinely applied in scRNA-seq. Yet, concerns remain that fixation may result in biases which may change the RNA-seq outcome. We adapted an existing methanol fixation protocol and performed scRNA-seq on both live and methanol fixed cells. Analyses of the results show methanol fixation can faithfully preserve biological related signals, while the discrepancy caused by fixation is subtle and relevant to library construction methods. By grouping transcripts based on their lengths and GC content, we find that transcripts with different features are affected by fixation to different degrees in full-length sequencing data, while the effect is alleviated in Drop-seq result. Our deep analysis reveals the effects of methanol fixation on sample RNA integrity and elucidates the potential consequences of using fixation in various scRNA-seq experiment designs.
Global Infodemiology of COVID-19: Focus on Google Web Searches and Instagram Hashtags
Authors: Rovetta Alessandro , Bhagavathula Akshaya Srikanth
Published: May 2020

Background

Though ‘infodemiological’ methods have been used in COVID-19 research, an examination of the extent of infodemic monikers (misinformation) use on the Internet remains limited.

Objective

To investigate Internet search behavior related to COVID-19 and examine the circulation of infodemic monikers through two platforms—Google and Instagram—during the current global pandemic.

Methods

Using Google Trends and Instagram hashtags (#), we explored Internet search activities and behaviors related to the COVID-19 pandemic from February 20, 2020, to May 06, 2020. We investigated the names used to identify the virus, health and risk perception, life during the lockdown, and information related to the adoption of COVID-19 infodemic monikers. We computed the average peak volume (APC) with a 95% confidence interval (CI) during the study period for the monikers.

Results

The top five COVID-19-related terms in the Google searches were “coronavirus”, “corona”, “COVID”, “virus”, “corona virus”, and “COVID-19”. Countries with a higher number of COVID-19 cases had a higher number of COVID-19 queries on Google. The monikers “coronavirus ozone”, “coronavirus laboratory”, “coronavirus 5G”, “coronavirus conspiracy” and “coronavirus bill gates” were widely circulated on the Internet. Searches about ‘tips and cures’ for COVID-19 spiked in relation to the U.S. president speculating about a ‘miracle cure’ and suggesting the injection of disinfectant to treat the virus. Around two-thirds (66.1%) of Instagram users used the hashtags “COVID-19”, and “coronavirus” to disperse virus-related information.

Conclusion

Globally, there is a growing interest in COVID-19, and numerous infodemic monikers continue to circulate on the Internet. Based on our findings, we hope to encourage mass media regulators and health organizers to be vigilant and diminish the use and circulation of these infodemic monikers on the Internet, to decrease the spread of misinformation.
Assessment of Workers’ Personal Vulnerability to COVID-19 Using “COVID-AGE”
Authors: Coggon David , Croft Peter , Cullinan Paul , Williams Anthony
Published: May 2020

Decisions on fitness for employment that entails a risk of contracting Covid-19 require an assessment of the worker’s personal vulnerability should infection occur. Using recently published UK data, we have developed a risk model that provides estimates of personal vulnerability to Covid-19 according to sex, age, ethnicity, and various comorbidities. Vulnerability from each risk factor is quantified in terms of its equivalence to added years of age. Addition of the impact from each risk factor to an individual’s true age generates their “Covid-age”, a summary measure representing the age of a healthy UK white male with equivalent vulnerability. We discuss important limitations of the model, including current scientific uncertainties and limitations on generalisability beyond the UK setting and its use beyond informing assessments of individual vulnerability in the workplace. As new evidence becomes available, some of these limitations can be addressed. The model does not remove the need for clinical judgement or for other important considerations when managing occupational risks from Covid-19.
Rising evidence of COVID-19 transmission potential to and between animals: do we need to be concerned?
Authors: Akhmetzhanov Andrei R. , Linton Natalie M. , Nishiura Hiroshi
Published: May 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—the virus that causes coronavirus disease (COVID-19)—has been detected in domestic dogs and cats, raising concerns of transmission from, to, or between these animals. There is currently no indication that feline- or canine-to-human transmission can occur, though there is rising evidence of the reverse. To explore the extent of animal-related transmission, we aggregated 17 case reports on confirmed SARS-CoV-2 infections in animals as of 15 May 2020. All but two animals fully recovered and had only mild respiratory or digestive symptoms. Using data from probable cat-to-cat transmission in Wuhan, China, we estimated the basic reproduction number R0 under this scenario at 1.09 (95% confidence interval: 1.05, 1.13). This value is much lower than the R0 reported for humans and close to one, indicating that the sustained transmission between cats is unlikely to occur. Our results support the view that the pet owners and other persons with COVID-19 in close contact with animals should be cautious of the way they interact with them.
AMP-activated-protein kinase (AMPK) is an essential sensor and metabolic regulator of retinal neurons and their integrated metabolism with RPE
Authors: Xu Lei , Brown Emily E. , Keuthan Casey J. , Gubbi Himani , Grellier Elodie-Kim , Roger Jerome , Swaroop Anand , Du Jianhai , Ash John D.
Published: May 2020

The retina has one of the highest energy demands in the human body, and proper regulation of metabolism among the cell types of the retina is required for functional vision. Recent studies have reported that retinal metabolism is disrupted during retinal degeneration and aging, while therapies designed to enhance metabolism can slow or prevent degeneration. Here, we show that multiple metabolic pathways, including those regulated by a key ATP sensor and regulator of metabolism, AMP-activated-kinase (AMPK), were dysregulated in a model of inherited retinal degeneration. In order to assess the direct role of AMPK in regulating retinal metabolism, we used mice with retina-specific knockout of AMPK activity. Conditional loss of AMPK resulted in impaired visual function at an early age, with slow photoreceptor loss observed in older mice. Moreover, we found that loss of AMPK resulted in decreased metabolic flux from glucose, decreased mitochondrial DNA copy number, decreased mitochondrial-related gene expression, and alterations in mitochondrial morphology in the photoreceptors, all of which preceded degeneration. Surprisingly, metabolic changes from the loss of AMPK in retinal neurons also resulted in secondary degeneration of retinal pigment epithelial (RPE) cells. Together, these data show that AMPK signaling is important for maintaining metabolic homeostasis of the retina and support the hypothesis that photoreceptors and RPE have a shared metabolic ecosystem that is controlled, in part, by AMPK.
Targeting the RHOA pathway improves learning and memory inKctd13and 16p11.2 deletion mouse models
Authors: Martin Lorenzo Sandra , Nalesso Valérie , Chevalier Claire , Birling Marie-Christine , Herault Yann
Published: May 2020

Gene copy number variants (CNV) have an important role in the appearance of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication ofKctd13genetic imbalance in the 16p11.2 deletion through the regulation of the RHOA pathway. Here, we target the pathway and rescue the cognitive phenotypes of the 16p11.2 deletion mouse models. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase (ROCK), in mouse models carrying a heterozygous inactivation ofKctd13, or the deletion of the entire 16p11.2 BP4-BP5 region. We focused our attention on the most robust cognitive phenotypes seen in the 16p11.2 models and we showed that a chronic fasudil treatment can restore object recognition memory in both mouse models but does not change other behavioural traits. These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the pertinence of the RHOA pathway as a therapeutic path and reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 CNV models.

HIGHLIGHTS

- Kctd13 haploinsufficiency recapitulates most of the behaviour phenotypes found in the 16p11.2Del/+ models

- Fasudil treatment restores Kctd13 and 16p11.2Del/+ mutant phenotypes in novel location and novel object recognition memory tests

- Fasudil treatment restores the RhoA pathway inKctd13+/-and 16p11.2Del/+ models
Untargeted metabolome- and transcriptome-wide association study identifies causal genes modulating metabolite concentrations in urine
Authors: Flitman Reyhan Sönmez , Khalili Bita , Kutalik Zoltan , Rueedi Rico , Bergmann Sven
Published: May 2020

In this study we investigate the results of a metabolome- and transcriptome-wide association study to identify genes influencing the human metabolome. We used RNAseq data from lymphoblastoid cell lines (LCLs) derived from 555 Caucasian individuals to characterize their transcriptome. As for the metabolome we took an untargeted approach using binned features from1H nuclear magnetic resonance spectroscopy (NMR) of urine samples from the same subjects allowing for data-driven discovery of associated compounds (rather than working with a limited set of quantified metabolites).

Using pairwise linear regression we identified 21 study-wide significant associations between metabolome features and gene expression levels. We observed the most significant association between the geneALMS1and two adjacent metabolome features at 2.0325 and 2.0375 ppm. By using our previously developed metabomatching methodology, we found N-Acetylaspartate (NAA) as the potential underlying metabolite whose urine concentration is correlated withALMS1expression. Indeed, a number of metabolome- and genome-wide association studies (mGWAS) had already suggested the locus of this gene to be involved in regulation of N-acetylated compounds, yet were not able to identify unambiguously the exact metabolite, nor to disambiguate betweenALMS1andNAT8, another gene found in the same locus as the mediator gene. The second highest significant association was observed betweenHPS1and two metabolome features at 2.8575 and 2.8725 ppm. Metabomatching of the association profile ofHPS1with all metabolite features pointed at trimethylamine (TMA) as the most likely underlying metabolite. mGWAS had previously implicated a locus containingHPS1to be associated with TMA concentrations in urine but could not disambiguate this association signal fromPYROXD2, a gene in the same locus. We used Mendelian randomization to show for bothALMS1andHPS1that their expression is causally linked to the respective metabolite concentrations.

Our study provides evidence that the integration of metabolomics with gene expression data can support mQTL analysis, helping to identify the most likely gene involved in the modulation of the metabolite concentration.
Chromatin stability generated by stochastic binding and unbinding of cross-linkers at looping sites revealed by Markov models
Authors: Papale Andrea , Holcman David
Published: May 2020

Chromatin loops inside the nucleus can be stable for a very long time, which remains poorly understood. Such a time is crucial for chromatin organization maintenance and stability. We explore here several physical scenarios, where loop maintenance is due to diffusing cross-linkers such as cohesin and CTCF that can bind and unbind at the base of chromatin loops. Using a Markov chain approach to coarse-grain the binding and unbinding, we consider that a stable loop disappears when the last cross-linker (CTCF or cohesin molecule) is unbound. We derive expressions for this last passage times that we use to quantify the loop stability for various value parameters, such as the chemical rate constant or the number of cross-linkers. The present analysis suggests that this binding and unbinding mechanism is sufficient to guarantee that there are always cross-linkers in place because they generate a positive feed-back mechanism that stabilizes the loop over long-time. To conclude, we propose that tens to hundreds cross-linkers per loop are sufficient to guarantee the loop stability in the genome over a cell cycle.
Potential consequences of the red blood cell storage lesion on cardiac electrophysiology
Authors: Reilly Marissa , Bruno Chantal , Prudencio Tomas , Ciccarelli Nina , Guerrelli Devon , Nair Raj , Ramadan Manelle , Luban Naomi L.C. , Posnack Nikki Gillum
Published: May 2020

The red blood cell (RBC) storage lesion is a series of morphological, functional and metabolic changes that RBCs undergo following collection, processing and refrigerated storage for clinical use. Since the biochemical attributes of the RBC unit shifts with time, transfusion of older blood products may contribute to cardiac complications, including hyperkalemia and cardiac arrest. We measured the direct effect of storage age on cardiac electrophysiology and compared with hyperkalemia, a prominent biomarker of storage lesion severity. Donor RBCs were processed using standard blood banking techniques. The supernatant was collected from RBC units (sRBC), 7-50 days post-donor collection, for evaluation using Langendorff-heart preparations (rat) or human stem-cell derived cardiomyocytes. Cardiac parameters remained stable following exposure to ‘fresh’ sRBC (day 7: 5.9+0.2 mM K+), but older blood products (day 40: 9.7+0.4 mM K+) caused bradycardia (baseline: 279±5 vs day 40: 216±18 BPM), delayed sinus node recovery (baseline: 243±8 vs day 40: 354±23 msec), and increased the effective refractory period of the atrioventricular node (baseline: 77+2 vs day 40: 93+7 msec) and ventricle (baseline: 50+3 vs day 40: 98+10 msec) in perfused hearts. Beating rate was also slowed in human cardiomyocytes after exposure to older sRBC (−75+9%, day 40 vs control). Similar effects on automaticity and electrical conduction were observed with hyperkalemia (10-12 mM K+). This is the first study to demonstrate that ‘older’ blood products directly impact cardiac electrophysiology, using experimental models. These effects are likely due to biochemical alterations in the sRBC that occur over time, including, but not limited to hyperkalemia. Patients receiving large volume and/or rapid transfusions may be sensitive to these effects.

New & noteworthy

We demonstrate that red blood cell storage duration time can have downstream effects on cardiac electrophysiology, likely due to biochemical alterations in the blood product. Hyperkalemia and cardiac arrest have been reported following blood transfusions, but this is the first experimental study to show a direct correlation between storage duration and cardiac function. Infant and pediatric patients, and those receiving large volume and/or rapid transfusions may be sensitive to these effects.
Genomic surveillance of SARS-CoV-2 in Thailand reveals mixed imported populations, a local lineage expansion and a virus with truncated ORF7a
Authors: Batty Elizabeth M , Kochakarn Theerarat , Panthan Bhakbhoom , Kümpornsin Krittikorn , Jiaranai Poramate , Wangwiwatsin Arporn , Kotanan Namfon , Jaruampornpan Peera , Watthanachockchai Treewat , Rakmanee Kingkan , Sensorn Insee , Sungkanuparph Somnuek , Pasomsub Ekawat , Chookajorn Thanat , Chantratita Wasun
Published: May 2020

Coronavirus Disease 2019 (COVID-19) is a global public health threat. Genomic surveillance of SARS-CoV-2 was implemented during March 2020 at a major diagnostic hub in Bangkok, Thailand. Several virus lineages supposedly originated in many countries were found, and a Thai-specific lineage, designated A/Thai-1, has expanded to be predominant in Thailand. A virus sample in the SARS-CoV-2 A/Thai-1 lineage contains a frame-shift deletion at ORF7a, encoding a putative host antagonizing factor of the virus.
Assessing the Performance of Machine Learning Models to Predict Neonatal Mortality Risk in Brazil, 2000-2016
Authors: Alves Luciana Correia , Beluzo Carlos Eduardo , Arruda Natália Martins , Bresan Rodrigo Campos , Carvalho Tiago
Published: May 2020

Neonatal mortality figures are an important health’s problem, as the first month of life is the most vulnerable time for survival. Factors associated with neonatal mortality are complexly and influenced by the maternal and newborn biological characteristics, social conditions and the care provided by the health services. The aim of this study was investigated the association between features related and neonatal mortality risk in Brazil. Data came from two surveys: The Mortality Information System and Information System on Live Births. The final sample was composed of 302,943 children between 2006 and 2016. We highlight the proposition of a new approach based on machine learning to address the problem of neonatal mortality death risk classification. The results using three different machine learning classifiers points toward expressiveness of features, being newborn weight, Apgar at the first and fifth minute, congenital malformations, gestational weeks and number of prenatal appointments the six more expressive.
Association between comorbidities and the risk of death in patients with COVID-19: sex-specific differences
Authors: Wu Mingyang , Huang Shuqiong , Liu Jun , Shu Yanling , Luo Yinbo , Wang Lulin , Li Mingyan , Wang Youjie
Published: May 2020

Background

The coronavirus disease 2019 (Covid-19) spreads rapidly around the world.

Objective

To evaluate the association between comorbidities and the risk of death in patients with COVID-19, and to further explore potential sex-specific differences.

Methods

We analyzed the data from 18,465 laboratory-confirmed cases that completed an epidemiological investigation in Hubei Province as of February 27, 2020. Information on death was obtained from the Infectious Disease Information System. The Cox proportional hazards model was used to estimate the association between comorbidities and the risk of death in patients with COVID-19.

Results

The median age for COVID-19 patients was 50.5 years. 8828(47.81%) patients were females. Severe cases accounted for 20.11% of the study population. As of March 7, 2020, a total of 919 cases deceased from COVID-19 for a fatality rate of 4.98%. Hypertension (13.87%), diabetes (5.53%), and cardiovascular and cerebrovascular diseases (CBVDs) (4.45%) were the most prevalent comorbidities, and 27.37% of patients with COVID-19 reported having at least one comorbidity. After adjustment for age, gender, address, and clinical severity, patients with hypertension (HR 1.55, 95%CI 1.35-1.78), diabetes (HR 1.35, 95%CI 1.13-1.62), CBVDs (HR 1.70, 95%CI 1.43-2.02), chronic kidney diseases (HR 2.09, 95%CI 1.47-2.98), and at least two comorbidities (HR 1.84, 95%CI 1.55-2.18) had significant increased risks of death. And the association between diabetes and the risk of death from COVID-19 was prominent in women (HR 1.69, 95%CI 1.27-2.25) than in men (HR 1.16, 95%CI 0.91-1.46) (P for interaction = 0.036).

Conclusion

Among laboratory-confirmed cases of COVID-19 in Hubei province, China, patients with hypertension, diabetes, CBVDs, chronic kidney diseases were significantly associated with increased risk of death. The association between diabetes and the risk of death tended to be stronger in women than in men. Clinicians should increase their awareness of the increased risk of death in COVID-19 patients with comorbidities.
Clinical Characteristics and Prognostic Factors for ICU Admission of Patients with Covid-19 Using Machine Learning and Natural Language Processing
Authors: Izquierdo Jose L. , Ancochea Julio ,   Savana COVID-19 Research Group, Soriano Joan B.
Published: May 2020

There remain many unknowns regarding the onset and clinical course of the ongoing COVID-19 pandemic. We used a combination of classic epidemiological methods, natural language processing (NLP), and machine learning (for predictive modeling), to analyse the electronic health records (EHRs) of patients with COVID-19.

We explored the unstructured free text in the EHRs within the SESCAM Healthcare Network (Castilla La-Mancha, Spain) from the entire population with available EHRs (1,364,924 patients) from January 1st to March 29th, 2020. We extracted related clinical information upon diagnosis, progression and outcome for all COVID-19 cases, focusing in those requiring ICU admission.

A total of 10,504 patients with a clinical or PCR-confirmed diagnosis of COVID-19 were identified, 52.5% males, with age of 58.2±19.7 years. Upon admission, the most common symptoms were cough, fever, and dyspnoea, but all in less than half of cases. Overall, 6% of hospitalized patients required ICU admission. Using a machine-learning, data-driven algorithm we identified that a combination of age, fever, and tachypnoea was the most parsimonious predictor of ICU admission: those younger than 56 years, without tachypnoea, and temperature <39°C, (or >39°C without respiratory crackles), were free of ICU admission. On the contrary, COVID-19 patients aged 40 to 79 years were likely to be admitted to the ICU if they had tachypnoea and delayed their visit to the ER after being seen in primary care.

Our results show that a combination of easily obtainable clinical variables (age, fever, and tachypnoea with/without respiratory crackles) predicts which COVID-19 patients require ICU admission.