bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer cells optimize elasticity for efficient migration
Authors: Kashani Ahmad Sohrabi , Packirisamy Muthukumaran
Published: October 2020

Cancer progression is associated with alternations in the cytoskeletal architecture of cells and, consequently, their mechanical properties such as stiffness. Changing the mechanics of cells enables cancer cells to migrate and invade to distant organ sites. This process, metastasis, is the main reason for cancer-related mortality. Cell migration is an essential step towards increasing the invasive potential of cells. Although many studies have shown that the migratory speed and the invasion of cells can be inversely correlated to the stiffness of cells, some other investigations indicate opposing results. In the current work, based on the strain energy stored in cells due to the contractile forces, we defined an energy-dependent term, migratory index, to approximate how changes in the mechanical properties of cells influence cell migration required for cancer progression. Cell migration involves both cell deformation and force transmission within cells. The effects of these two parameters can be represented equally by the migratory index. Our mechanical modelling and computational study show that cells depending on their shape, size and other physical parameters have a maximum migratory index taking place at a specific range of cell bulk elasticity, indicating the most favourable conditions for invasive mobility. This approximate model could be used to explain why the stiffness of cells varies during cancer progression. We believe that the stiffness of cancer or malignant cells depending on the stiffness of their normal or non-malignant counterparts is either decreased or increased to reach the critical condition in which the mobility potential of cells is approximated to be maximum.
The role of oxidative stress in postcopulatory selection
Authors: Friesen Christopher R. , Noble Daniel W. A. , Olsson Mats
Published: October 2020

Two decades ago, von Schantz
et al
. (von Schantz T, Bensch S, Grahn M, Hasselquist D, Wittzell H. 1999 Good genes, oxidative stress and condition-dependent sexual signals.
Proc. R. Soc. B
266, 1–12. (
doi:10.1098/rspb.1999.0597
)) united oxidative stress (OS) biology with sexual selection and life-history theory. This set the scene for analysis of how evolutionary trade-offs may be mediated by the increase in reactive molecules resulting from metabolic processes at reproduction. Despite 30 years of research on OS effects on infertility in humans, one research area that has been left behind in this integration of evolution and OS biology is postcopulatory sexual selection—this integration is long overdue. We review the basic mechanisms in OS biology, why mitochondria are the primary source of ROS and ATP production during oxidative metabolism, and why sperm, and its performance, is uniquely susceptible to OS. We also review how postcopulatory processes select for antioxidation in seminal fluids to counter OS and the implications of the net outcome of these processes on sperm damage, sperm storage, and female and oocyte manipulation of sperm metabolism and repair of DNA to enhance offspring fitness.

This article is part of the theme issue ‘Fifty years of sperm competition’.
Seminal fluid and accessory male investment in sperm competition
Authors: Ramm Steven A.
Published: October 2020

Sperm production and allocation strategies have been a central concern of sperm competition research for the past 50 years. But during the ‘sexual cascade’ there may be strong selection for alternative routes to maximizing male fitness. Especially with the evolution of internal fertilization, a common and by now well-studied example is the accessory ejaculate investment represented by seminal fluid, the complex mixture of proteins, peptides and other components transferred to females together with sperm. How seminal fluid investment should covary with sperm investment probably depends on the mechanism of seminal fluid action. If seminal fluid components boost male paternity success by directly enhancing sperm function or use, we might often expect a positive correlation between the two forms of male investment, whereas trade-offs seem more likely if seminal fluid acts independently of sperm. This is largely borne out by a broad taxonomic survey to establish the prevailing patterns of seminal fluid production and allocation during animal evolution, in light of which I discuss the gaps that remain in our understanding of this key ejaculate component and its relationship to sperm investment, before outlining promising approaches for examining seminal fluid-mediated sperm competitiveness in the post-genomic era.

This article is part of the theme issue ‘Fifty years of sperm competition’.
TheDrosophilaseminal proteome and its role in postcopulatory sexual selection
Authors: Wigby Stuart , Brown Nora C. , Allen Sarah E. , Misra Snigdha , Sitnik Jessica L. , Sepil Irem , Clark Andrew G. , Wolfner Mariana F.
Published: October 2020

Postcopulatory sexual selection (PCSS), comprised of sperm competition and cryptic female choice, has emerged as a widespread evolutionary force among polyandrous animals. There is abundant evidence that PCSS can shape the evolution of sperm. However, sperm are not the whole story: they are accompanied by seminal fluid substances that play many roles, including influencing PCSS. Foremost among seminal fluid models isDrosophila melanogaster, which displays ubiquitous polyandry, and exhibits intraspecific variation in a number of seminal fluid proteins (Sfps) that appear to modulate paternity share. Here, we first consolidate current information on the identities ofD. melanogasterSfps. Comparing betweenD. melanogasterand human seminal proteomes, we find evidence of similarities between many protein classes and individual proteins, including someD. melanogasterSfp genes linked to PCSS, suggesting evolutionary conservation of broad-scale functions. We then review experimental evidence for the functions ofD. melanogasterSfps in PCSS and sexual conflict. We identify gaps in our current knowledge and areas for future research, including an enhanced identification of PCSS-related Sfps, their interactions with rival sperm and with females, the role of qualitative changes in Sfps and mechanisms of ejaculate tailoring.

This article is part of the theme issue ‘Fifty years of sperm competition’.
Sperm competition when transfer is dangerous
Authors: Tuni Cristina , Schneider Jutta , Uhl Gabriele , Herberstein Marie E.
Published: October 2020

Aggressive and cannibalistic female spiders can impose strong selection on male mating and fertilization strategies. Furthermore, the distinctive reproductive morphology of spiders is predicted to influence the outcome of sperm competition. Polyandry is common in spiders, leading to defensive male strategies that include guarding, plugging and self-sacrifice. Paternity patterns are highly variable and unlikely to be determined solely by mating order, but rather by relative copulation duration, deployment of plugs and cryptic female choice. The ability to strategically allocate sperm is limited, either by the need to refill pedipalps periodically or owing to permanent sperm depletion after mating. Further insights now rely on unravelling several proximate mechanisms such as the process of sperm activation and the role of seminal fluids.

This article is part of the theme issue ‘Fifty years of sperm competition’.
Sperm competition in squamate reptiles
Authors: Friesen Christopher R. , Kahrl Ariel F. , Olsson Mats
Published: October 2020

Multiple paternity is ubiquitous within the polyphyletic group called ‘reptiles', especially within the lizards and snakes. Therefore, the probability of sperm competition occurring, and being intense, is high. Squamates exhibit a diversity of tactics to ensure fertilization success in the face of sperm competition. The duration of female sperm storage, which can be many months and even years in some species, remains an enigma. Here, we emphasize some mechanisms that might affect patterns of paternity, the source and function of ejaculates and features of the female reproductive tract that may aid in long-term sperm storage. In doing so, we present a new analysis of the relationship between sperm size, the strength of sperm competition and the duration of female sperm storage. Lizards and snakes are a diverse group that has provided many excellent models for the study of an array of life-history strategies. However, when it comes to postcopulatory sexual selection, there is much left to discover.

This article is part of the theme issue ‘Fifty years of sperm competition'.
Baculum shape and paternity success in house mice: evidence for genital coevolution
Authors: André Goncalo I. , Firman Renée C. , Simmons Leigh W.
Published: October 2020

Sexual selection is believed to be responsible for the rapid divergence of male genitalia, which is a widely observed phenomenon across different taxa. Among mammals, the stimulatory role of male genitalia and female ‘sensory perception’ has been suggested to explain these evolutionary patterns. Recent research on house mice has shown that baculum (penis bone) shape can respond to experimentally imposed sexual selection. Here, we explore the adaptive value of baculum shape by performing two experiments that examine the effects of male and female genitalia on male reproductive success. Thus, we selected house mice (
Mus musculus domesticus
) from families characterized by extremes in baculum shape (relative width) and examined paternity success in both non-competitive (monogamous) and competitive (polyandrous) contexts. Our analyses revealed that the relative baculum shape of competing males influenced competitive paternity success, but that this effect was dependent on the breeding value for baculum shape of the family from which females were derived. Our data provide novel insight into the potential mechanisms underlying the evolution of the house mouse baculum and lend support to the stimulatory hypothesis for the coevolution of male and female genitalia.

This article is part of the theme issue ‘Fifty years of sperm competition’.
Distribution of RecBCD and AddAB recombination-associated genes among bacteria in 33 phyla
Authors: Gurung Deepti , Blumenthal Robert M.
Published: October 2020

Homologous recombination plays key roles in fundamental processes such as recovery from DNA damage and in bacterial horizontal gene transfer, yet there are still open questions about the distribution of recognized components of recombination machinery among bacteria and archaea. RecBCD helicase-nuclease plays a central role in recombination among Gammaproteobacteria likeEscherichia coli; while bacteria in other phyla, like the FirmicuteBacillus subtilis, use the related AddAB complex. The activity of at least some of these complexes is controlled by short DNA sequences called crossover hotspot instigator (Chi) sites. When RecBCD or AddAB complexes encounter an autologous Chi site during unwinding, they introduce a nick such that ssDNA with a free end is available to invade another duplex. If homologous DNA is present, RecA-dependent homologous recombination is promoted; if not (or if no autologous Chi site is present) the RecBCD/AddAB complex eventually degrades the DNA. We examined the distribution ofrecBCDandaddABgenes among bacteria, and sought ways to distinguish them unambiguously. We examined bacterial species among 33 phyla, finding some unexpected distribution patterns.RecBCDandaddABare less conserved thanrecA, with the orthologousrecBandaddAgenes more conserved than therecCoraddBgenes. We were able to classify RecB vs. AddA and RecC vs. AddB in some bacteria where this had not previously been done. We used logo analysis to identify sequence segments that are conserved, but differ between the RecBC and AddAB proteins, to help future differentiation between members of these two families.
Predictors of severe symptomatic laboratory-confirmed SARS-COV-2 reinfection
Authors: Murillo-Zamora Efrén , Mendoza-Cano Oliver , Delgado-Enciso Iván , Hernandez-Suarez Carlos M.
Published: October 2020

Background

There is a major concern regarding the prognosis of coronavirus disease 2019 (COVID-19) in patients who recovered to first-time illness.

Objective

To evaluate factors predicting severe symptomatic laboratory-confirmed (reverse transcription-quantitative polymerase chain reaction, RT-qPCR) SARS-COV-2 (severe acute coronavirus-2) reinfection.

Method

We conducted a nationwide retrospective cohort study in Mexico and data from 258 reinfection cases (at least 28 days between both episodes onset) were analyzed. We used risk ratios (RR) and 95% confidence intervals (CI) to evaluate predictors of severe (dyspnea requiring hospital admission) secondary SARS-COV-2 infection.

Results

The risk of severe disease was 14.7% and the observed overall fatality rate was 4.3%. Patients with more serious primary disease were more likely to develop severe symptoms (39.5% vs. 5.5%, p < 0.001) during reinfection. In multiple analysis, factors associated with an increased risk of severe symptomatic SARS-COV-2 reinfection were increasing age (RR per year = 1.007, 95% CI 1.003-1.010), comorbidities (namely obesity [RR = 1.12, 95% CI 1.01-1.24], asthma [RR = 1.26, 95% CI 1.06-1.50], type 2 diabetes mellitus [RR = 1.22, 95% CI 1.07 - 1.38] and previous severe laboratory-confirmed COVID-19 (RR = 1.20, 95% CI 1.03-1.39).

Conclusions

To the best of our knowledge this is the first study evaluating disease outcomes in a large set of laboratory-positive cases of symptomatic SARS-COV-2 reinfection and factors associated with illness severity was characterized. Our results may contribute to the current knowledge of SARS-COV-2 pathogenicity and to identify populations at increased risk of a poorer outcome after reinfection.
Tracking SARS-CoV-2 RNA through the wastewater treatment process
Authors: Ali Hala Abu , Yaniv Karin , Bar-Zeev Edo , Chaudhury Sanhita , Shaga Marilou , Lakkakula Satish , Ronen Zeev , Kushmaro Ariel , Nir Oded
Published: October 2020

The municipal sewage carries the new coronavirus (SARS-CoV-2), shed by COVID-19 patients, to wastewater treatment plants. Proper wastewater treatment can provide an important barrier for preventing uncontrolled discharged of the virus into the environment. However, the role of the different wastewater treatment stages in reducing virus concentrations was, thus far, unknown. In this work, we quantified SARS-CoV-RNA in the raw sewage and along the main stages of the wastewater process from two different plants in Israel during this COVID-19 outbreak. We found that ca. 2 Log removal could be attained after primary and secondary treatment. Despite this removal, significant concentrations of SARS-CoV-RNA (>100 copies per mL) could still be detected in the treated wastewater. However, after treatment by chlorination, SARS-CoV-RNA was detected only once, likely due to insufficient chlorine dose. Our results highlight the need to protect wastewater treatment plants operators, as well as populations living near areas of wastewater discharge, from the risk of infection. In addition, our results emphasize the capabilities and limitations of the conventional wastewater treatment process in reducing SARS-CoV-RNA concentration, and present preliminary evidence for the importance of tertiary treatment and chlorination in reducing SARA-CoV-2 dissemination.
Metapopulation connectivity in Voles (Microtussp.) as a gauge for tallgrass prairie restoration in midwestern North America
Authors: Douglas Marlis R. , Anthonysamy Whitney J.B. , Davis Mark A. , Mulligan Matthew P. , Schooley Robert L. , Louis Wade , Douglas Michael E.
Published: October 2020

Applying quantifiable metrics to validate the success of restoration efforts is crucial for ongoing management programs in anthropogenically fragmented habitats. Estimates of dispersal can provide such baseline data because they measure not only the extent to which restored patches are colonized and interconnected, but also their metapopulation source/sink dynamics. In this context, we estimated dispersal and population connectivity among prairie (Microtus ochrogaster; N=231) and meadow vole (M. pennsylvanicus; N=83), sampled from eight restored plots at five tallgrass prairie sites embedded within the agricultural matrix of midwestern North America. Our expectation was that extensive distances separating these restored habitats (i.e., 48–246 km) would spatially isolate vole metapopulations, resulting in significant genetic differentiation. We first used molecular taxonomy to validate the field-identifications of all sampled individuals, then used pairwiseFSTderived from 15 microsatellite DNA loci to estimate genetic connectivity among the species-delimited study populations. Metapopulation stability was gauged by assessing migration rates and deriving effective population sizes (Ne). We also calculated relatedness values (r) as a potential surrogate for contact in prairie vole, a primary vector for Lyme disease. Molecular species-assignments contravened field-identifications in 25% of samples (11 prairie/67 meadow) and identified two instances of species-hybridization (0.6%). Local effects (i.e., population crash/drought) were manifested at two sites, as documented by significant temporal declines inNeandr. Overall, high migration rates and non-significant (10/15) pairwiseFSTvalues underscored elevated metapopulation connectivity. A single site that recorded five significantFSTvalues also displayed significantr-values indicating the inadvertent sampling of closely related individuals. This highlights the close social groupings among cooperatively-breeding prairie vole that can exacerbate Lyme disease transmission. Thus, while elevated population connectivity aligns with prairie restoration goals, it also reinforces a need in adaptive management to evaluate environmental matrices for their permeability to vector-borne diseases.
Explore the Potential of a Plant Phospholipase as an Antimicrobial
Authors: Chen Curtis , Xu Shanhui , Li Yanran
Published: October 2020

Global public health is increasingly threatened by the fast emergence of antibiotic resistance, and novel types of antibiotics are urgently needed. Metazoans have evolved their own antimicrobial mechanism, such as human group IIA secreted phospholipase A (sPLA2), which can efficiently inhibit the growth of gram-positive bacteria, but with much lower efficiency toward gram-negative bacteria. Here, we verified the antibacterial activity of a plant lipase, PLIP1 fromArabidopsis thaliana, against the gram-negative bacteriaEscherichia coli, which belongs to the WHO priority 1 (critical) pathogenEnterobacteriaceaefamily. We also explored the potential of evolving PLIP1 as a more potent antimicrobial agent towardsE. coli. Our results imply the possibility of using plant lipases as a potential antimicrobial and shed light on the future exploration of plant enzymes for novel and more efficient antibacterial agents.
Distal CA1 maintains a more coherent spatial representation than proximal CA1 when local and global cues conflict
Authors: Deshmukh Sachin S.
Published: October 2020

Entorhinal cortical projections show segregation along the transverse axis of CA1, with the medial entorhinal cortex (MEC) sending denser projections to proximal CA1 (pCA1) and the lateral entorhinal cortex (LEC) sending denser projections to distal CA1 (dCA1). Previous studies have reported functional segregation along the transverse axis of CA1 correlated with the functional differences in MEC and LEC. pCA1 shows higher spatial selectivity than dCA1 in these studies. We employ a double rotation paradigm, which creates an explicit conflict between local and global cues, to understand differential contributions of these reference frames to the spatial code in pCA1 and dCA1. We show that pCA1 and dCA1 respond differently to this local-global cue conflict. pCA1 shows incoherent response consistent with the strong conflicting inputs it receives from MEC and distal CA3 (dCA3). In contrast, dCA1 shows a more coherent rotation with global cues. In addition, pCA1 and dCA1 display comparable levels of spatial selectivity in this study. This finding differs from the previous studies, perhaps due to richer sensory information available in our behavior arena. Together these observations indicate that the functional segregation along proximodistal axis of CA1 is not merely of the amount of spatial selectivity but that of the nature of the different inputs utilized to create and anchor spatial representations.
Stromal cells regulate malignant B-cell spatial organization, survival, and drug response in a new 3D model mimicking lymphoma tumor niche
Authors: Lamaison Claire , Latour Simon , Hélaine Nelson , Morvan Valérie Le , Monvoisin Céline , Mahouche Isabelle , Dussert Christelle , Dessauge Elise , Pangault Céline , Seffals Marine , Broca-Brisson Léa , Alessandri Kévin , Soubeyran Pierre , Mourcin Frédéric , Nassoy Pierre , Recher Gaëlle , Tarte Karin , Bresson-Bepoldin Laurence
Published: October 2020

Non-Hodgkin B-cell lymphomas (B-NHL) mainly develop within lymph nodes as densely packed aggregates of tumor cells and their surrounding microenvironment, creating a tumor niche specific to each lymphoma subtypes. Until now,in vitropreclinical models mimicking biomechanical forces, cellular microenvironment, and 3D organization of B lymphomas remain scarce while all these parameters constitute key determinants of lymphomagenesis and drug resistance. Using a microfluidic method based on the encapsulation of cells inside permeable, elastic, and hollow alginate microspheres, we developed a new tunable 3D-model incorporating extracellular matrix and/or stromal cells. Lymphoma B cells and stromal cells dynamically formed self-organized 3D spheroids, thus initiating a coevolution of these two cell types, reflecting their bidirectional crosstalk, and recapitulating the heterogeneity of B-NHL subtypes. In addition, this approach makes it suitable to assess in a relevantin vitromodel the activity of new therapeutic agents in B-NHL.
CRISPR-guided programmable self-assembly of artificial virus-like nucleocapsids
Authors: Calcines-Cruz Carlos , Finkelstein Ilya J. , Hernandez-Garcia Armando
Published: October 2020

Designer virus-inspired proteins drive the manufacturing of more effective and safer gene-delivery systems as well as simpler models to study viral assembly. However, the self-assembly of engineered viromimetic proteins on specific nucleic acid templates, a distinctive viral property, has proved difficult. Inspired by viral packaging signals, we harness the programmability of CRISPR-Cas12a to direct the nucleation and growth of a self-assembling synthetic polypeptide into virus-like particles (VLP) on specific DNA molecules. Positioning up to ten nuclease-dead Cas12a (dCas12a) proteins along a 48.5 kbp DNA template triggers particle growth and full DNA encapsidation at limiting polypeptide concentrations. Particle growth rate was further increased when dCas12a was dimerized with a polymerization silk-like domain. Such improved self-assembly efficiency allows for discrimination between cognate versus non-cognate DNA templates by the synthetic polypeptide. Our CRISPR-guided VLPs could help develop programmable bio-inspired nanomaterials with applications in biotechnology as well as viromimetic scaffolds to improve our understanding of viral self-assembly.
Causal discovery identifies posttraumatic stress as a driver of internalizing symptoms across independent veteran and civilian populations
Authors: Pierce Benjamin , Kirsh Thomas , Ferguson Adam R. , Neylan Thomas C. , Ma Sisi , Kummerfeld Erich , Cohen Beth E. , Nielson Jessica L.
Published: October 2020

Background

Approximately half of patients with posttraumatic stress disorder (PTSD) also meet criteria for internalizing disorders, yet few studies assess reciprocal longitudinal relations among these symptoms.

Methods

We used longitudinal causal discovery in a veteran cohort for hypothesis-generation about PTSD and internalizing symptom drivers (n=240), followed by hypothesis-testing in two independent civilian cohorts with similar symptom assessments over time (n=79 and n=116).

Results

In the veteran cohort, causal discovery revealed PTSD symptoms drove internalizing symptoms, which subsequently impacted social functioning; all independent of problematic alcohol use. This replicated in treatment-seeking anxiety disorders (AD, n = 79) and substance abuse (SA, n = 116) samples with significantly better model fit for PTSD symptoms driving internalizing symptoms, versus internalizing symptoms driving PTSD symptoms (BIC change for AD sample = 175.1, p<.001; BIC change for SA sample = 571.6, p<.001). We also found better model fit with PTSD symptoms driving anxiety symptoms, versus anxiety symptoms driving PTSD symptoms (BIC change for AD sample = 71.8, p < .001; BIC change for SA sample = 568.9, p < .001). Posthoc analysis in the veteran sample revealed that hyperarousal and cognitive and affective disturbance bridged between other PTSD symptoms and internalizing symptoms.

Conclusions

Our findings suggest that internalizing symptoms that emerge in the context of PTSD are more likely to be driven by PTSD symptoms. These results highlight the need for a PTSD- and trauma-informed approach to treating internalizing symptoms, and provide preliminary evidence for cognition and mood disruption as a factor driving comorbidity.
Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield
Authors: van der Sanden Bart P.G.H. , Corominas Jordi , de Groot Michelle , Pennings Maartje , Meijer Rowdy P.P. , Verbeek Nienke , van de Warrenburg Bart , Schouten Meyke , Yntema Helger G. , Vissers Lisenka E.L.M. , Kamsteeg Erik-Jan , Gilissen Christian
Published: October 2020

Purpose

The expansion of specific short tandem repeats (STRs) can lead to approximately 30 different human genetic disorders. Despite extensive application of exome sequencing (ES) in routine diagnostic genetic testing, STRs are not routinely identified from these data.

Methods

We assessed diagnostic utility by applying ExpansionHunter to 2,867 exomes from movement disorder patients and 35,228 other clinical exomes.

Results

We identified 36 movement disorder patients with a possible aberrant STR length. Validation by PCR and/or repeat-primed PCR technologies confirmed the presence of aberrant expansion alleles for 11 (31%). For seven of these patients the genotype was compatible with the phenotypic description, and resulted in a molecular diagnosis. We subsequently tested the remainder of our diagnostic ES cohort, including over 30 clinically and genetically heterogeneous disorders. Optimized manual curation yielded 140 samples with a likely aberrant STR length. Validations confirmed 70/140 (50%) aberrant expansion alleles, of which 48 were in the pathogenic range and 22 in the premutation range.

Conclusions

Our work provides guidance for the implementation of STR analysis in clinical ES. Our results show that systematic STR evaluation may increase diagnostic ES yield by 0.2%, and recommend to make STR evaluation a routine part of ES interpretation in genetic testing laboratories.
Accuracy of Healthcare Professionals’ Nasopharyngeal Swab Technique in SARS-CoV-2 Specimen Collection
Authors: Woods Robbie S. R. , Nwaokorie Kellie , Crowley Jana , Walsh Michael , de Barra Eoghan , Lacy Peter D.
Published: October 2020

Background

The COVID-19 pandemic has caused huge pressure on healthcare systems worldwide. Public health measures to control the virus are reliant on testing, including appropriate collection of specimens for analysis.

Methods

A prospective study of nasopharyngeal swab technique by staff in an academic tertiary referral centre was carried out. Nasopharyngeal swab technique was evaluated by a novel design of a navigated swab on a three-dimensional model head.

Results

Swab technique of 228 participants was assessed. Technique was poor, with a success rate of nasopharyngeal swabbing at 38.6%. Angle and length of insertion were significantly different between those with successful and unsuccessful technique. Doctors were significantly more accurate than nurses and non-healthcare professionals (p<0.01).

Conclusion

Inaccurate specimen collection from poor swab technique could contribute to a false negative rate of testing for SARS-CoV-2. Specific training in nasopharyngeal anatomy and swab technique may improve the accuracy of nasopharyngeal swabbing.
Percentage HScore confirms low incidence of secondary haemophagocytic lymphohistiocytosis in hospitalised COVID-19 patients
Authors: Ardern-Jones Michael R , Stammers Matt , Phan Hang T.T. , Borca Florina , Koutalopoulou Anastasia , Teo Ying , Batchelor James , Smith Trevor , Duncombe Andrew S
Published: October 2020

Objective

It has been assumed that a significant proportion of COVID-19 patients show evidence of hyperinflammation of which secondary haemophagocytic lymphohistiocytosis (sHLH) is the most severe manifestation. To facilitate diagnosis of sHLH the HScore has been developed and validated. We set out to examine the prevalence of sHLH-like hyperinflammation in COVID-19.

Methods

We retrospectively examined HScore parameters in 626 COVID-19 cases admitted to our institute of which 567 were suitable for analysis and compared these to a cohort of confirmed infection associated sHLH cases. To account for missing data, we calculated the maximum possible HScore of the recorded parameters (%HScore).

Results

Early measurement of HScore parameters (day -1 to 4 from diagnosis) strongly predicted the %HScore over the course of the admission (p <0.0001). The retrospective cohort of sHLH showed significantly higher %HScores as compared to COVID-19 (median 73.47 vs 18.13 respectively, p <0.0001). The overall prevalence of individuals with an 80% probability of sHLH in our COVID-19 cohort was 1.59% on admission and only rose to 4.05% during the whole disease course. In the small cohort with scores suggestive of sHLH, there was no excess mortality compared with the whole cohort. %HScores were higher in younger patients (p<0.0001) and did not reliably predict outcome at any cut-off value (AUROC 0.533, p=0.211; OR 0.99).

Conclusion

Surprisingly, these findings show that sHLH-type hyperinflammation is not prevalent in COVID-19, and %HScores do not predict outcome. Therefore, new algorithms are required to optimise case selection for clinical trials of targeted anti-inflammatory interventions.
Could nutrition modulate COVID-19 susceptibility and severity of disease? A systematic review
Authors: James Philip T. , Ali Zakari , Armitage Andrew E. , Bonell Ana , Cerami Carla , Drakesmith Hal , Jobe Modou , Jones Kerry S. , Liew Zara , Moore Sophie E. , Morales-Berstein Fernanda , Nabwera Helen M. , Nadjm Behzad , Pasricha Sant-Rayn , Scheelbeek Pauline , Silver Matt J. , Teh Megan R. , Prentice Andrew M.
Published: October 2020

Background

Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to COVID-19 infection, progression to symptoms, likelihood of severe disease and survival. The pandemic has fostered many nutrition-related theories, sometimes backed by a biased interpretation of evidence.

Objectives

To provide a systematic review of the latest evidence on how malnutrition across all its forms (under- and over-nutrition and micronutrient status) may influence both susceptibility to, and progression and severity of, COVID-19.

Methods

We synthesised information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity and diabetes; protein-energy malnutrition; anaemia; vitamins A, C, D, and E; poly-unsaturated fatty acids; iron; selenium; zinc; anti-oxidants, and nutritional support. For each section we provide: a) a landscape review of pertinent material; b) a systematic search of the literature in PubMed and EMBASE databases, including a systematic search of a wide range of pre-print servers; and c) a screen of six clinical trial registries. Two reviewers were assigned per section for data extraction. All original research was considered, without restriction to study design, and included if it covered: 1) SARS-CoV-2, MERS-CoV or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16thMay and 11thAugust, 2020. PROSPERO registration CRD42020186194.

Results

Across the 13 searches, a total of 2732 articles from PubMed and EMBASE, 4164 articles from the pre-print servers, and 433 trials were returned. A total of 288 published articles and 278 pre-print articles were taken to full text screening. In the final narrative synthesis, we cover 22 published articles, 39 pre-print articles and 79 trials. The review highlights a range of mechanistic and observational evidence to highlight the role nutrition can play in susceptibility and progression of COVID-19. However, to date, there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery, although results of clinical trials are eagerly awaited.

Conclusions

To date there is no conclusive evidence supporting adoption of novel nutritional therapies. However, given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. There is strong evidence that prevention of obesity, and its consequent type-2 diabetes, will reduce the risk of serious COVID-19 outcomes.
A Multidisciplinary Approach: Teaching Medical Spanish to Medical Students Using Role-play
Authors: Mozaffari Khashayar , Kolodner Rebecca , Chalif Eric , Ruiz Victor Valdivia , Blatt Benjamin
Published: October 2020

Introduction

The Hispanic community is the most rapidly growing minority group in the United States, making up 18.1% of the population, with 40% reporting limited English proficiency. To address this need, many health sciences institutions have implemented medical Spanish courses to increase Spanish proficiency among future healthcare providers. Although interactive courses have shown efficacy in teaching field-related terminology, barriers to medical Spanish curriculum implementation persist. Our study investigated the benefit of role-play, an underutilized teaching modality, in a medical Spanish course.

Methods

19 second year medical students were recruited to participate. Based on their placement test performance, students were assigned to a beginner or intermediate group and met weekly for one-hour sessions over five consecutive weeks. Students assumed the roles of Spanish-speaking patient, English-speaking provider, and interpreter to practice various medical scenarios. Students completed pre- and post-course examinations to assess Spanish proficiency improvement. Statistical significance was determined using a p-value < 0.05.

Results

Seven students, all members of the intermediate group, completed the course. Attendance among this group was 77.4%. When comparing examination scores, there was statistically significant improvement in oral translation of phrases from Spanish to English (p-value= 0.03).

Discussion

Statistically significant improvement in oral translation of phrases from Spanish to English was accomplished through a minimal time requirement of one hour per week utilizing role-play. Given the fact that limited time poses a barrier to implementing medical Spanish curricula, our findings highlight the potential benefit of this teaching methodology and call for further evaluation.
The cross-sectional area of the vagus nerve is not reduced in Parkinson’s Disease patients
Authors: Sijben Laura C.J. , Mess Werner H. , Walter Uwe , Janssen A. Miranda L. , Kuijf Mark , Oosterloo Mayke , Weber Wim M. , Janssen Marcus L.F.
Published: October 2020

Objective

Recent studies have revealed the importance of the gut brain axis in the development of Parkinson’s disease (PD). It has also been suggested that the cross-sectional area (CSA) of the vagus nerve can be used in the diagnosis of PD. Here, we hypothesize that the CSA of the vagus nerve is decreased in PD patients compared to control subjects.

Methods

In this study we measured the CSA of the vagus nerve on both sides in 31 patients with PD and 51 healthy controls at the level of the common carotid artery using high-resolution ultrasound.

Results

The CSA of the vagus nerve was not reduced in PD patients compared to controls (p = 0.391. The mean CSA of the left vagus nerve was significantly smaller than the right (p < 0.001). There was no significant correlation between age, gender and autonomic symptoms with the CSA of the left (p = 0.128) and right vagus nerve (p = 0.166).

Conclusion

These findings show that the CSA of the vagus nerve using ultrasonography is not a reliable diagnostic tool in the diagnosis of PD.

Highlights

The cross-sectional area of the vagus nerve is not decreased in Parkinson disease patients.

The cross-sectional area of the vagus nerve does not correlate with autonomic symptoms.

Measurement of the vagus nerve cross-sectional area has a high inter-observer correlation.
Spatiotemporal Response Heterogeneity Across Metastatic Lesions Informs Drug Efficacy and Patient Survival in Colorectal Cancer
Authors: Zhou Jiawei , Li Quefeng , Cao Yanguang
Published: October 2020

The sum of target lesions is routinely used to evaluate patient objective responses to treatment in the RECIST criteria, but it neglects the response heterogeneity across metastases. This study argues that the spatiotemporal response heterogeneity across metastases informs drug efficacy and patient survival. We analyzed the longitudinal data of 11,404 metastatic lesions in 2,802 colorectal cancer patients and examined their response heterogeneity. The response dynamics of metastatic lesions varied broadly across anatomical locations and therapies. High inter-lesion heterogeneity is associated with worse survival (p < 0.001), while targeted therapies (bevacizumab or panitumumab) reduced the inter-lesion heterogeneity (p < 0.05) and elicited more favorable effects on liver lesions (p < 0.001) than chemotherapy alone. The responses of liver lesions predicted patient survival more significantly than the lesions in the lungs and lymph nodes. Altogether, the high spatiotemporal heterogeneity across metastases should be integrated into current methods for treatment evaluation and patient prognosis.

Significance

The spatiotemporal heterogeneity across metastases in response to first-line therapies in colorectal cancer is informative for drug efficacy and patient survival, particularly in targeted therapy. Our findings provide evidence to support the inclusion of individual lesion response in the RECIST to improve the assessment of drug efficacy and patient survival.
Low-Cost Manually Assembled Open Source Reader for Isothermal Pathogen Detection from Saliva using RT-LAMP: SARS-CoV-2 Use Case
Authors: Bramley John C. , Waligorski Jason E. , Kremitzki Colin L. , Liebeskind Mariel J. , Yenkin Alex L. , Xu Xinyuan E. , Lalli Matthew A. , O’Halloran Jane A. , Mudd Philip A. , House Stacey L. , Mitra Robi D. , Milbrandt Jeffrey D. , Buchser William J.
Published: October 2020

Distributed “Point-of-Care” or “at-Home” testing is an important component for a complete suite of testing solutions. This manuscript describes the construction and operation of a platform technology designed to meet this need. The ongoing COVID-19 pandemic will be used as the proof-of-concept for the efficacy and deployment of this platform. The technology outlined consists of a one-pot, reverse-transcription loop-mediated isothermal amplification (RT-LAMP) chemistry coupled with a low-cost and user-assembled reader using saliva as input. This platform is readily adapted to a wide range of pathogens due to the genetic basis of the reaction. A complete guide to the construction of the reader as well as the production of the reaction chemistry are provided here. Additionally, analytical limit of detection data and the results from saliva testing of SARS-CoV-2, are presented. The platform technology outlined here demonstrates a rapid, distributed, molecular point-of-care solution for pathogen detection using crude sample input.
Prevalence of antibodies to SARS-CoV-2 in healthy blood donors in New York
Authors: Kamath Kathy , Baum-Jones Elisabeth , Jordan Gregory , Haynes Winston , Waitz Rebecca , Shon John , Kujawa Steve , Fitzgibbons Lyn , Kessler Debra , Luchsinger Larry ,   Yale IMPACT Team, Daugherty Patrick
Published: October 2020

Despite the high level of morbidity and mortality worldwide, there is increasing evidence for asymptomatic carriers of the novel coronavirus SARS-CoV-2. We analyzed blood specimens from 1,559 healthy blood donors, collected in the greater New York metropolitan area between the months of March and July 2020 for antibodies to SARS-CoV-2 virus. Using our proprietary technology, SERA (Serum Epitope Repertoire Analysis), we observed a significant increase in SARS-CoV-2 seropositivity rates over the four-month period, from 0% [95% CI: 0 - 1.5%] (March) to 11.6% [6.0 - 21.2%] (July). Follow-up ELISA tests using S1 and nucleocapsid viral proteins confirmed most of these results. Our findings are consistent with seroprevalence studies within the region and with reports that SARS-COV-2 infections can be asymptomatic or cause only mild symptoms.

IMPORTANCE

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has caused vast morbidity and mortality worldwide, yet several studies indicate that there may be a significant number of infected people who are asymptomatic or exhibit mild symptoms. In this study, samples were collected from healthy blood donors in a region of rapidly increasing disease burden (New York metropolitan area) and we hypothesized that a subset would be seropositive to SARS-CoV-2. People who experienced mild or no symptoms during SARS-CoV-2 infection may represent a source for convalescent plasma donors.
A community-engaged mHealth intervention to increase uptake of HIV Pre-Exposure Prophylaxis (PrEP) among gay, bisexual and other men who have sex with men in China: Study protocol for a pilot randomized controlled trial
Authors: Li Chunyan , Xiong Yuan , Muessig Kathryn E. , Tang Weiming , Huang Haojie , Mu Tong , Tong Xiaokai , Yu Jianxiong , Yang Zeyu , Sherer Renslow , Hazra Aniruddha , Lio Jonathan , Matthews Derrick D. , Fisher Edwin B. , Li Linghua , Tucker Joseph D.
Published: October 2020

Introduction

Emtricitabine-Tenofovir was officially approved as the first medicine for HIV pre-exposure prophylaxis (PrEP) in China on August 11, 2020. The large number of key populations who would benefit from PrEP in the context of limited health system capacity and public awareness will pose challenges for timely PrEP scale-up. This suggests an urgent need for innovative and accessible intervention tools for promoting PrEP. Our overall goal is to develop and pilot test a theory-informed, tailored mobile phone intervention to increase engagement in PrEP education and initiation among Chinese gay, bisexual, and other men who have sex with men (GBMSM). We also aim to generate hypotheses of potential behavioral pathways to PrEP uptake among Chinese GBMSM.

Methods and analysis

This two-phase study includes a formative assessment (Phase 1) using in-depth interviews (N=30) and a 12-week experimental pilot study (Phase 2) using a two-arm randomized controlled trial design (N=60). The primary intervention is delivered through a WeChat-based mini-app (a program built into a Chinese multipurpose social media application) developed by young GBMSM from a 2019 crowdsourcing hackathon. This participatory event brought together GBMSM, tech experts, health professionals, and other key stakeholders. This study will further investigate the specific needs and concerns among GBMSM in terms of using PrEP as an HIV prevention strategy, how their concerns and PrEP use behaviors may change with exposure to the mini-app intervention at 8-week and 12-week follow-up, and how we can further refine this intervention tool to better meet GBMSM ‘s needs for broader implementation.

Ethics and dissemination

This study and its protocols have been reviewed and approved by the Institutional Review Boards of the University of North Carolina at Chapel Hill, USA (IRB#19-3481), the Guangdong Provincial Dermatology Hospital, China (IRB#2020031), and the Guangzhou Eighth People ‘s Hospital, China (IRB#202022155). Study staff will work with local GBMSM community-based organizations to disseminate the study results to participants and the community via social media, offline workshops, and journal publication. This research addresses a critical need as GBMSM bear a disproportionate burden of HIV infections in China and remain underserved in the healthcare system.

Trial Registration

The study was registered on clinicaltrials.gov (Trial#: NCT04426656) on June 11, 2020. https://clinicaltrials.gov/ct2/show/NCT04426656. Prospectively registered.
Repeated introductions and intensive community transmission fueled a mumps virus outbreak in Washington State
Authors: Moncla Louise H. , Black Allison , DeBolt Chas , Lang Misty , Graff Nicholas R. , Pérez-Osorio Ailyn C. , Müller Nicola F. , Haselow Dirk , Lindquist Scott , Bedford Trevor
Published: October 2020

In 2016/2017, Washington State experienced a mumps outbreak despite high childhood vaccination rates, with cases more frequently detected among school-aged children and members of the Marshallese community. We sequenced 166 mumps virus genomes collected during outbreaks in Washington and other US states, and apply phylodynamic approaches to trace mumps introductions and transmission within Washington. We uncover that mumps was introduced into Washington at least 13 times, primarily from Arkansas, sparking multiple co-circulating transmission chains. Neither vaccination status nor age were strong determinants of transmission. Instead, the outbreak in Washington was overwhelmingly sustained by transmission within the Marshallese community. Our findings underscore the utility of genomic data to clarify epidemiologic factors driving transmission, and pinpoint contact networks as critical determinants of mumps transmission. These results imply that contact structures and historic disparities may leave populations at increased risk for respiratory virus disease even when a vaccine is effective and widely used.
Modifiable lifestyle factors and severe COVID-19 risk: Evidence from Mendelian randomization analysis
Authors: Li Shuai
Published: October 2020

Background

Lifestyle factors including obesity and smoking are suggested to be related to increased risk of COVID-19 severe illness or related death. However, little is known about whether these relationships are causal, or the relationships between COVID-19 severe illness and other lifestyle factors, such as alcohol consumption and physical activity.

Methods

Genome-wide significant genetic variants associated with body mass index (BMI), lifetime smoking, alcohol consumption and physical activity identified by large-scale genome-wide association studies (GWAS) were selected as instrumental variables. GWAS summary statistics of these genetic variants for relevant lifestyle factors and severe illness of COVID-19 were obtained. Two-sample Mendelian randomization (MR) analyses were conducted.

Results

Both genetically predicted BMI and lifetime smoking were associated with about 2-fold increased risks of severe respiratory COVID-19 and COVID-19 hospitalization (all P<0.05). Genetically predicted physical activity was associated with about 5-fold (95% confidence interval [CI], 1.4, 20.3; P=0.02) decreased risk of severe respiratory COVID-19, but not with COVID-19 hospitalization, though the majority of the 95% CI did not include one. No evidence of association was found for genetically predicted alcohol consumption, but associations were found when using pleiotropy robust methods.

Conclusion

Evidence is found that BMI and smoking causally increase and physical activity causally decreases the risk of COVID-19 severe illness. This study highlights the importance of maintaining a healthy lifestyle in protecting from COVID-19 severe illness and its public health value in fighting against COVID-19 pandemic.