bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbial community composition interacts with local abiotic conditions to drive colonization resistance in human gut microbiome samples
Authors: Baumgartner Michael , Pfrunder-Cardozo Katia R. , Hall Alex R.
Published: March 2021

Biological invasions can alter ecosystem stability and function, and predicting what happens when a new species or strain arrives remains a major challenge in ecology. In the mammalian gastrointestinal tract, susceptibility of the resident microbial community to invasion by pathogens has important implications for host health. However, at the community level, it is unclear whether susceptibility to invasion depends mostly on resident community composition (which microbes are present), or also on local abiotic conditions (such as nutrient status). Here, we used a gut microcosm system to disentangle some of the drivers of susceptibility to invasion in microbial communities sampled from humans. We found resident microbial communities inhibited an invading
Escherichia coli
strain, compared to community-free control treatments, sometimes excluding the invader completely (colonization resistance). These effects were stronger at later time points, when we also detected altered community composition and nutrient availability. By separating these two components (microbial community and abiotic environment), we found taxonomic composition played a crucial role in suppressing invasion, but this depended critically on local abiotic conditions (adapted communities were more suppressive in nutrient-depleted conditions). This helps predict when resident communities will be most susceptible to invasion, with implications for optimizing treatments based on microbiota management.
Ecological opportunity and the rise and fall of crocodylomorph evolutionary innovation
Authors: Stubbs Thomas L. , Pierce Stephanie E. , Elsler Armin , Anderson Philip S. L. , Rayfield Emily J. , Benton Michael J.
Published: March 2021

Understanding the origin, expansion and loss of biodiversity is fundamental to evolutionary biology. The approximately 26 living species of crocodylomorphs (crocodiles, caimans, alligators and gharials) represent just a snapshot of the group's rich 230-million-year history, whereas the fossil record reveals a hidden past of great diversity and innovation, including ocean and land-dwelling forms, herbivores, omnivores and apex predators. In this macroevolutionary study of skull and jaw shape disparity, we show that crocodylomorph ecomorphological variation peaked in the Cretaceous, before declining in the Cenozoic, and the rise and fall of disparity was associated with great heterogeneity in evolutionary rates. Taxonomically diverse and ecologically divergent Mesozoic crocodylomorphs, like marine thalattosuchians and terrestrial notosuchians, rapidly evolved novel skull and jaw morphologies to fill specialized adaptive zones. Disparity in semi-aquatic predatory crocodylians, the only living crocodylomorph representatives, accumulated steadily, and they evolved more slowly for most of the last 80 million years, but despite their conservatism there is no evidence for long-term evolutionary stagnation. These complex evolutionary dynamics reflect ecological opportunities, that were readily exploited by some Mesozoic crocodylomorphs but more limited in Cenozoic crocodylians.
Light environment influences mating behaviours during the early stages of divergence in tropical butterflies
Authors: Hausmann Alexander E. , Kuo Chi-Yun , Freire Marília , Rueda-M Nicol , Linares Mauricio , Pardo-Diaz Carolina , Salazar Camilo , Merrill Richard M.
Published: March 2021

Speciation is facilitated when traits under divergent selection also act as mating cues. Fluctuations in sensory conditions can alter signal perception independently of adaptation to the broader sensory environment, but how this fine-scale variation may constrain or promote behavioural isolation has received little attention. The warning patterns ofHeliconiusbutterflies are under selection for aposematism and act as mating cues. Using computer vision, we extracted behavioural data from 1481 h of video footage, for 387 individuals. We show that the putative hybrid speciesH. heurippaand its close relativeH. timareta linaresidiffer in their response to divergent warning patterns, but that these differences are strengthened with increased local illuminance. Trials with live individuals reveal low-level assortative mating that is sufficiently explained by differences in visual attraction. Finally, results from hybrid butterflies are consistent with linkage between a major warning pattern gene and the corresponding behaviour, though the differences in behaviour we observe are unlikely to cause rapid reproductive isolation as predicted under a model of hybrid trait speciation. Overall, our results reveal that the contribution of ecological mating cues to reproductive isolation may depend on the immediate sensory conditions during which they are displayed to conspecifics.
Allometric analysis of brain cell number in Hymenoptera suggests ant brains diverge from general trends
Authors: Godfrey R. Keating , Swartzlander Mira , Gronenberg Wulfila
Published: March 2021

Many comparative neurobiological studies seek to connect sensory or behavioural attributes across taxa with differences in their brain composition. Recent studies in vertebrates suggest cell number and density may be better correlated with behavioural ability than brain mass or volume, but few estimates of such figures exist for insects. Here, we use the isotropic fractionator (IF) method to estimate total brain cell numbers for 32 species of Hymenoptera spanning seven subfamilies. We find estimates from using this method are comparable to traditional, whole-brain cell counts of two species and to published estimates from established stereological methods. We present allometric scaling relationships between body and brain mass, brain mass and nuclei number, and body mass and cell density and find that ants stand out from bees and wasps as having particularly small brains by measures of mass and cell number. We find that Hymenoptera follow the general trend of smaller animals having proportionally larger brains. Smaller Hymenoptera also feature higher brain cell densities than the larger ones, as is the case in most vertebrates, but in contrast with primates, in which neuron density remains rather constant across changes in brain mass. Overall, our findings establish the IF as a useful method for comparative studies of brain size evolution in insects.
The roles of T cell competition and stochastic extinction events in chimeric antigen receptor T cell therapy
Authors: Kimmel Gregory J. , Locke Frederick L. , Altrock Philipp M.
Published: March 2021

Chimeric antigen receptor (CAR) T cell therapy is a remarkably effective immunotherapy that relies on
in vivo
expansion of engineered CAR T cells, after lymphodepletion (LD) by chemotherapy. The quantitative laws underlying this expansion and subsequent tumour eradication remain unknown. We develop a mathematical model of T cell–tumour cell interactions and demonstrate that expansion can be explained by immune reconstitution dynamics after LD and competition among T cells. CAR T cells rapidly grow and engage tumour cells but experience an emerging growth rate disadvantage compared to normal T cells. Since tumour eradication is deterministically unstable in our model, we define cure as a stochastic event, which, even when likely, can occur at variable times. However, we show that variability in timing is largely determined by patient variability. While cure events impacted by these fluctuations occur early and are narrowly distributed, progression events occur late and are more widely distributed in time. We parameterized our model using population-level CAR T cell and tumour data over time and compare our predictions with progression-free survival rates. We find that therapy could be improved by optimizing the tumour-killing rate and the CAR T cells' ability to adapt, as quantified by their carrying capacity. Our tumour extinction model can be leveraged to examine why therapy works in some patients but not others, and to better understand the interplay of deterministic and stochastic effects on outcomes. For example, our model implies that LD before a second CAR T injection is necessary.
Variable dosage compensation is associated with female consequences of an X-linked, male-beneficial mutation
Authors: Rayner Jack G. , Hitchcock Thomas J. , Bailey Nathan W.
Published: March 2021

Recent theory has suggested that dosage compensation mediates sexual antagonism over X-linked genes. This process relies on the assumption that dosage compensation scales phenotypic effects between the sexes, which is largely untested. We evaluated this by quantifying transcriptome variation associated with a recently arisen, male-beneficial, X-linked mutation across tissues of the field cricketTeleogryllus oceanicus, and testing the relationship between the completeness of dosage compensation and female phenotypic effects at the level of gene expression. Dosage compensation inT. oceanicuswas variable across tissues but usually incomplete, such that relative expression of X-linked genes was typically greater in females. Supporting the assumption that dosage compensation scales phenotypic effects between the sexes, we found tissues with incomplete dosage compensation tended to show female-skewed effects of the X-linked allele. In gonads, where expression of X-linked genes was most strongly female-biased, ovaries-limited genes were much more likely to be X-linked than were testes-limited genes, supporting the view that incomplete dosage compensation favours feminization of the X. Our results support the expectation that sex chromosome dosage compensation scales phenotypic effects of X-linked genes between sexes, substantiating a key assumption underlying the theoretical role of dosage compensation in determining the dynamics of sexual antagonism on the X.
Whole tissue homogenization preferable to mucosal scraping in determining the temporal profile of segmented filamentous bacteria in the ileum of weanling rats
Authors: Oemcke Linda A. , Anderson Rachel C. , Rakonjac Jasna , McNabb Warren C. , Roy Nicole C.
Published: March 2021

Segmented filamentous bacteria (SFB) are thought to play a role in small intestine immunological maturation. Studies in weanling mice have shown a positive correlation between ileal SFB abundance and plasma and faecal interleukin 17 (IL-17) and immunoglobulin A (IgA) concentrations. Although the first observation of SFB presence was reported in rats, most studies use mice. The size of the mouse ileum is a limitation whereas the rat could be a suitable alternative for sufficient samples. Changes in SFB abundance over time in rats were hypothesized to follow the pattern reported in mice and infants. We characterized the profile of SFB colonization in the ileum tissue and contents and its correlation with two immune markers of gastrointestinal tract (GIT) maturation. We also compared two published ileum collection techniques to determine which yields data on SFB abundance with least variability. Whole ileal tissue and ileal mucosal scrapings were collected from 20- to 32-day-old Sprague-Dawley rats. SFB abundance was quantified from proximal, middle and distal ileal tissues, contents and faeces by quantitative PCR using SFB-specific primers. Antibody-specific ELISAs were used to determine IL-17 and IgA concentrations. Significant differences in SFB abundance were observed from whole and scraped tissues peaking at day 22. Variability in whole ileum data was less, favouring it as a better collection technique. A similar pattern of SFB abundance was observed in ileum contents and faeces peaking at day 24, suggesting faeces can be a proxy for ileal SFB abundance. SFB abundance at day 26 was higher in females than males across all samples. There were significant differences in IgA concentration between days 20, 30 and 32 and none in IL-17 concentration, which was different from reports in mice and infants.
Using Random Forests with Asymmetric Costs to Predict Hospital Readmissions
Authors: Bleich Justin , Cole Brian , Kapelner Adam , Baillie Charles A. , Gupta Rohit , Hanish Asaf , Calgua Erwin , Umscheid Craig A. , Berk Richard
Published: March 2021

Background

Sufficiently accurate predictions of hospital readmissions are necessary for the allocation of scare clinical resources to reduce preventable readmissions. We describe the use of a data-driven approach that relies on machine learning algorithms to predict readmission at the time of discharge.

Methods

We employ random forests to clinical and administrative electronic health record data available from a cohort of 103,688 patients discharged from the acute inpatient settings of the University of Pennsylvania Health System between June 25th, 2011 and June 30th, 2013. We predict both 30-day all-cause readmissions and 7-day unplanned readmissions using only predictors available by the time of discharge. Using oversampling and undersampling of the different outcome classes of readmission and no readmission, we incorporate into our models the asymmetric costs of a false negative relative to a false positive from the perspective of a hospital. We calculate variable importance scores for included predictors. Our approach was derived and validated using split-sample internal validation.

Results

We developed a machine learning-based model using random forests with a 5:1 relative cost ratio for 30-day all-cause readmissions that achieves a sensitivity of 65% and specificity of 71% on validation data, as well as a random forests model with a 20:1 cost ratio for 7-day unplanned readmissions that achieves a sensitivity of 62% and specificity of 66% on validation data. Prior health system utilization, clinical discharging service, and vital sign information were most predictive of readmissions.

Conclusion

By modeling the complex relationships between many predictor variables and readmission data for a large health system, we demonstrate successful predictive models that can be used upon discharge to flag patients at high risk of readmission.
SARS-CoV-2 pandemic dynamics and infection tracing in Denmark
Authors: Jørgensen Morten W.N. , Høiby Niels , Ziock Hans J. , Rasmussen Steen
Published: March 2021

We model and simulate the COVID-19 infection and healthcare dynamics in Denmark from the onset till March 5, 2021. The simulation is matched and calibrated to hospital and death data as well as antibody population measurement. In this work we focus on comparing the time evolution of the estimated infection level with the daily identified infected individuals based on the national testing and contact tracing program. We find that the national testing program on average identifies 1/3 of the infected individuals July 1, 2020 - March 5, 2021. Our investigations indicate the current program does not have a proper balance between random probing, focused contact tracing, and testing prioritization. Too much of the program operates as a semi-random daily sampling of part of the population. We propose a policy with a focus on local infection tracing and interventions.
Curtailing Covid-19 on a Dollar-a-Day in Malawi: Implications for the Ongoing Pandemic
Authors: Kohler Iliana V. , Kämpfen Fabrice , Ciancio Alberto , Mwera James , Mwapasa Victor , Kohler Hans-Peter
Published: March 2021

Utilizing population-based data from the Covid-19 phone survey (N = 2, 262) of the Malawi Longitudinal Study of Families and Health (MLSFH) collected during June 2nd–August 17th, 2020, we investigate behavioral, economic and social responses to Covid-19 and focus on the crucial role that community leadership and trust in institutions play towards shaping these responses. We argue that the effective response of Malawi to limit the spread of the virus was facilitated by the engagement of local leaders to mobilize communities to adapt and adhere to Covid-19 prevention strategies. Village heads (VHs) played pivotal role in shaping individual’s knowledge about the pandemic and the adaption of preventive health behaviors and were crucial for mitigating the negative economic and health consequences of the pandemic. We further show that trust in institutions is of particular importance in shaping individuals’ behavior during the pandemic, and these findings highlight the pivotal role of community leadership in fostering better compliance and adoption of public health measures essential to contain the virus. Overall, our findings point to distinctive patterns of pandemic response in a low-income sub-Saharan African rural population that emphasized local leadership as mediators of public health messages and policies. These lessons from the first pandemic wave remain relevant as in many low-income countries behavioral responses to Covid-19 will remain the primary prevention strategy for a foreseeable future.
Community mobilisation approaches to preventing and reducing adolescent multiple risk behaviour: a realist review protocol
Authors: Tinner Laura , Caldwell Deborah , Campbell Rona
Published: March 2021

Background

Adolescent multiple risk behaviour (MRB) continues to be a global health issue, contributing to the burden of non-communicable diseases. Most interventions have focused on the proximal causes of adolescent MRB such as peer or family influence, rather than targeting the wider environmental or structural context. There is increasing recognition that community mobilisation approaches that extend beyond individually-focused educational programmes could be beneficial for adolescent health. Despite this, there are gaps in the current literature, theory and implementation that would benefit from a realist approach due to the suitability of this methodology to analysing complex interventions. In this protocol, we outline our study that aims to understand ‘how, why, for whom and in what circumstances and time periods do community mobilisation interventions work to prevent and/or reduce adolescent multiple risk behaviour?’

Methods

A realist review was chosen as the most suitable review method as it is theory-driven and seeks to understand how, why and for whom interventions work to produce intended and unintended outcomes. A six-stage iterative process is outlined, which includes initial development of a programme theory, systematic searching, study selection and appraisal, data extraction and data synthesis. We will engage with stakeholders at different stages in this process to aid the development of the programme theory.

Discussion

The goal of this realist review is to identify and refine a programme theory for community mobilisation approaches to the prevention and/or reduction of adolescent multiple risk behaviour. Our aim is that the findings surrounding the programme theory refinement can be used to develop and implement adolescent multiple risk behaviour interventions and maintain collaboration between local policy makers, researchers and community members.

Registration

This realist review is registered on the PROSPERO database (registration number: CRD42020205342).
Modelling the laminar connectome of the human brain
Authors: Shamir Ittai , Tomer Omri , Krupnik Ronnie , Assaf Yaniv
Published: March 2021

The human connectome is the complete structural description of the network of connections and elements that form the ‘wiring diagram’ of the brain. Due to the current scarcity of information regarding laminar end points of white matter tracts inside cortical grey matter, tractography remains focused on cortical partitioning into regions, while ignoring radial partitioning into laminar components. To overcome this biased representation of the cortex as a single homogenous unit, we use a recent data-derived model of cortical laminar connectivity, which has been further explored and corroborated in the macaque brain by comparison to published studies. The model integrates multimodal MRI imaging datasets of both white matter connectivity and grey matter laminar composition into a laminar-level connectome. In this study we model the laminar connectome of healthy human brains (N=30) and explore them via a set of neurobiologically meaningful complex network measures. Our analysis demonstrates a subdivision of network hubs that appear in the standard connectome into each individual component of the laminar connectome, giving a fresh look into the role of laminar components in cortical connectivity and offering new prospects in the fields of both structural and functional connectivity.
Weak humoral immune reactivity among residents of long-term care facilities following one dose of the BNT162b2 mRNA COVID-19 vaccine
Authors: Brockman Mark A. , Mwimanzi Francis , Sang Yurou , Ng Kurtis , Agafitei Olga , Ennis Siobhan , Lapointe Hope , Young Landon , Umviligihozo Gisele , Burns Laura , Brumme Chanson , Leung Victor , Montaner Julio S.G. , Holmes Daniel , DeMarco Mari , Simons Janet , Niikura Masa , Pantophlet Ralph , Romney Marc G. , Brumme Zabrina L.
Published: March 2021

Background

Several Canadian provinces are extending the interval between COVID-19 vaccine doses to increase population vaccine coverage more rapidly. However, immunogenicity of these vaccines after one dose is incompletely characterized, particularly among the elderly, who are at greatest risk of severe COVID-19.

Methods

We assessed SARS-CoV-2 humoral responses pre-vaccine and one month following the first dose of BNT162b2 mRNA vaccine, in 12 COVID-19 seronegative residents of long-term care facilities (median age, 82 years), 18 seronegative healthcare workers (HCW; median age, 36 years) and 4 convalescent HCW. Total antibody responses to SARS-CoV-2 nucleocapsid (N) and spike protein receptor binding domain (S/RBD) were assessed using commercial immunoassays. We quantified IgG and IgM responses to S/RBD and determined the ability of antibodies to block S/RBD binding to ACE2 receptor using ELISA. Neutralizing antibody activity was also assessed using pseudovirus and live SARS-CoV-2.

Results

After one vaccine dose, binding antibodies against S/RBD were ∼4-fold lower in residents compared to HCW (p<0.001). Inhibition of ACE2 binding was 3-fold lower in residents compared to HCW (p=0.01) and pseudovirus neutralizing activity was 2-fold lower (p=0.003).While six (33%) seronegative HCW neutralized live SARS-CoV-2, only one (8%) resident did (p=0.19). In contrast, convalescent HCW displayed 7- to 20-fold higher levels of binding antibodies and substantial ability to neutralize live virus after one dose.

Interpretation

Extending the interval between COVID-19 vaccine doses may pose a risk to the elderly due to lower vaccine immunogenicity in this group. We recommend that second doses not be delayed in elderly individuals.
Characterising post-COVID syndrome more than 6 months after acute infection in adults; prospective longitudinal cohort study, England
Authors: Amin-Chowdhury Zahin , Harris Ross J , Aiano Felicity , Zavala Maria , Bertran Marta , Borrow Ray , Linley Ezra , Ahmad Shazaad , Parker Ben , Horsley Alex , Hallis Bassam , Flood Jessica , Brown Kevin E , Amirthalingam Gayatri , Ramsay Mary E , Andrews Nick , Ladhani Shamez N
Published: March 2021

Background

Most individuals with COVID-19 will recover without sequelae, but some will develop long- term multi-system impairments. The definition, duration, prevalence and symptoms associated with long COVID, however, have not been established.

Methods

Public Health England (PHE) initiated longitudinal surveillance of clinical and non-clinical healthcare workers for monthly blood sampling for SARS-CoV-2 antibodies in March 2020. Eight months after enrolment, participants completed an online questionnaire including 72 symptoms in the preceding month. Symptomatic mild-to-moderate cases with confirmed COVID-19 were compared with asymptomatic, seronegative controls. Multivariable logistic regression was used to identify independent symptoms associated with long COVID.

Results

All 2,147 participants were contacted and 1,671 (77.8%) completed the questionnaire, including 140 (8.4%) cases and 1,160 controls. At a median of 7.5 (IQR 7.1-7.8) months after infection, 20 cases (14.3%) had ongoing (4/140, 2.9%) or episodic (16/140, 11.4%) symptoms. We identified three clusters of symptoms associated with long COVID, those affecting the sensory (ageusia, anosmia, loss of appetite and blurred vision), neurological (forgetfulness, short-term memory loss and confusion/brain fog) and cardiorespiratory (chest tightness/pain, unusual fatigue, breathlessness after minimal exertion/at rest, palpitations) systems. The sensory cluster had the highest association with being a case (aOR 5.25, 95% CI 3.45-8.01). Dermatological, gynaecological, gastrointestinal or mental health symptoms were not significantly different between cases and controls.

Conclusions

Most persistent symptoms reported following mild COVID-19 were equally common in cases and controls. While all three clusters identified had a strong association with previous COVID-19 infection, the sensory cluster had the highest specificity and strength of association.

Key points

Compared to controls, we identified three clusters of symptoms affecting the sensory, neurological and cardiorespiratory systems that were more prevalent among cases. Notably, gastrointestinal and dermatological symptoms and symptoms related to mental health were as prevalent among cases as controls.
Alpha-1 blockers and susceptibility to COVID-19 in benign prostate hyperplasia patients : an international cohort study
Authors: Nishimura Akihiko , Xie Junqing , Kostka Kristin , Duarte-Salles Talita , Fernández Bertolín Sergio , Aragón María , Blacketer Clair , Shoaibi Azza , DuVall Scott L , Lynch Kristine , Matheny Michael E , Falconer Thomas , Morales Daniel R , Conover Mitchell M , You Seng Chan , Pratt Nicole , Weaver James , Sena Anthony G , Schuemie Martijn J , Reps Jenna , Reich Christian , Rijnbeek Peter R , Ryan Patrick B , Hripcsak George , Prieto-Alhambra Daniel , Suchard Marc A
Published: March 2021

Alpha-1 blockers, often used to treat benign prostate hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storms release. We conducted a prevalent-user active-comparator cohort study to assess association between alpha-1 blocker use and risks of three COVID-19 outcomes: diagnosis, hospitalization, and hospitalization requiring intensive services. Our study included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH therapy during the period between November 2019 and January 2020, found in electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We found no differential risk for any of COVID-19 outcome, pointing to the need for further research on potential COVID-19 therapies.
Inferring livestock movement networks from archived data to support infectious disease control in developing countries
Authors: Muwonge A. , Bessell P.R. , Porphyre T. , Motta P. , Rydevik G. , Devailly G. , Egbe N.F. , Kelly R.F. , Handel I.G. , Mazeri S. , Bronsvoort B.M.deC.
Published: March 2021

The use of network analysis to support livestock disease control in low middle-income countries (LMICs) has historically been hampered by the cost of generating empirical data in the absence of animal movement recording schemes. To fill this gap, methods which exploit freely available demographic and archived molecular data can be used to generate livestock networks based on gravity and phylogeographic modelling techniques, respectively. However, questions remain on the performance of these methods in capturing the topology of empirical networks. Here, we compare output from these network methodologies to a network constructed from either empirical data or randomly generated data. To facilitate this comparison, the spread of infectious diseases was simulated, it is this evaluation that demonstrates their potential utility to inform robust livestock disease control strategies.

The molecular network was the closest approximation to the empirical network, both in relation to topological and epidemic characteristics, whereas size of epidemics in the gravity network tended to be larger, better agreement across all three networks was observed when; a) total nodes infected, b) percentage infection take off were compared. These methods consistently identified the same important animal movement and trade hotspots as the empirical networks. We therefore consider this proof-of-concept that demographic data such as censuses and archived molecular data could be repurposed to inform livestock disease management in LMICs.

Author summary

Live animal movements in Africa represent a significant risk of transmission and spread of infectious diseases in livestock populations, and therefore, have direct implications on the food security of the continent. Here we explore the potential utility of available data to support control strategies, by comparing movement networks inferred from such data i.e. census and pathogen molecular data using gravity modelling and phylogeography respectively. Their utility is evaluated by comparing their topology and disease spread characteristics to empirical live animal movement. Based on our results, we posit that archived data can be repurposed to support infectious disease control on the African continent.
Diet-derived antioxidants do not decrease the risk of ischemic stroke: a Mendelian Randomization Study in over 1 million participants
Authors: Martens Leon G , Luo Jiao , Dijk Ko Willems van , Jukema J Wouter , Noordam Raymond , Heemst Diana van
Published: March 2021

Background

Intake, either as dietary components or as supplements, and blood concentrations of vitamin E, C, lycopene and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot not be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically-influenced antioxidant levels in blood and ischemic stroke using Mendelian Randomization (MR).

Methods

For each circulating antioxidant (vitamin E, C, lycopene, β-carotene and retinol), which were assessed as either absolute blood levels and/or high-throughput metabolite levels, genetic instrumental variables were generated from earlier genome wide association studies. We used summary statistics for SNP-stroke associations from three European-ancestry cohorts (cases/controls): MEGASTROKE (67,162/454,450), UK Biobank (2,404/368,771) and FinnGen study (8,046/164,286). MR analyses were performed on each exposure per outcome cohort using inverse-variance weighted analyses, and subsequently meta-analyzed.

Results

In a combined sample of 1,065,119 individuals (77,612 cases), none of the genetically-influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (95% CI) ranged between 0.94 (95% CI: 0.85 to 1.05) for vitamin C and 1.04 (95% CI: 0.99 to 1.08) for lycopene. For metabolites, odds ratios ranged between 1.01 (95% CI: 0.98 to 1.03) for retinol and 1.12 (95% CI: 0.88 to 1.42) for vitamin E.

Conclusion

This study did not provide evidence for a causal association between dietary-derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke.
Quantifying structural connectivity in brain tumor patients
Authors: Wei Yiran , Li Chao , Price Stephen John
Published: March 2021

Brain tumors are characterised by infiltration along the white matter tracts, posing significant challenges to precise treatment. Mounting evidence shows that an infiltrative tumor can interfere with the brain network diffusely. Therefore, quantifying structural connectivity has potential to identify tumor invasion and stratify patients more accurately. The tract-based statistics (TBSS) is widely used to measure the white matter integrity. This voxel-wise method, however, cannot directly quantify the connectivity of brain regions. Tractography is a fiber tracking approach, which has been widely used to quantify brain connectivity. However, the performance of tractography on the brain with tumors is biased by the tumor mass effect. A robust method of quantifying the structural connectivity in brain tumor patients is still lacking. Here we propose a method which could provide robust estimation of tract strength for brain tumor patients. Specifically, we firstly construct an unbiased tract template in healthy subjects using tractography. The voxel projection procedure of TBSS is employed to quantify the tract connectivity in patients, based on the location of each tract fiber from the template. To further improve the standard TBSS, we propose an approach of iterative projection of tract voxels, under the guidance of tract orientation measured by voxel-wise eigenvectors. Compared to the conventional tractography methods, our approach is more sensitive in reflecting functional relevance. Further, the different extent of network disruption revealed by our approach correspond to the clinical prior knowledge of tumor histology. The proposed method could provide a robust estimation of the structural connectivity for brain tumor patients.
Recalibrating SARS-CoV-2 antigen rapid lateral flow test relative sensitivity from validation studies to absolute sensitivity for detecting individuals with live virus
Authors: Petersen Irene , Crozier Alexander , Buchan Iain , Mina Michael , Bartlett Jonathan W
Published: March 2021

Testing for SARS-CoV-2 internationally has focused on COVID-19 diagnosis among symptomatic individuals using reverse transcriptase polymerase chain reaction (PCR) tests. Recently, however, SARS-CoV-2 antigen rapid lateral flow tests (LFT) have been rolled out in several countries for testing asymptomatic individuals in public health programmes. Validation studies for LFT have been largely cross-sectional, reporting sensitivity, specificity and predictive values of LFT relative to PCR. However, because PCR detects genetic material left behind for a long period when the individual is no longer infectious, these statistics can under-represent sensitivity of LFT for detecting infectious individuals, especially when sampling asymptomatic populations. LFTs (intended to detect individuals with live virus) validated against PCR (intended to diagnose infection) are not reporting against a gold standard of equivalent measurements. Instead, these validation studies have reported relative performance statistics that need recalibrating to the purpose for which LFT is being used. We present an approach to this recalibration.

We derive a formula for recalibrating relative performance statistics from LFT vs PCR validation studies to give likely absolute sensitivity of LFT for detecting individuals with live virus. We show the differences between widely reported apparent sensitivities of LFT and its absolute sensitivity as a test of presence of live virus. After accounting for within-individual viral kinetics and epidemic dynamics within asymptomatic populations we show that a highly performant test of live virus should show a LFT-to-PCR relative sensitivity of less than 50% in conventional validation studies, which after re-calibration would be an absolute sensitivity of more than 80%.

Further studies are needed to ascertain the absolute sensitivity of LFT as a test of infectiousness in COVID-19 responses. These studies should include sampling for viral cultures and longitudinal series of LFT and PCR, ideally in cohorts sampled from both contacts of cases and the general population.
COVID-19 Infection Risk amongst 14,104 Vaccinated Care Home Residents: A national observational longitudinal cohort study in Wales, United Kingdom, December 2020 to March 2021
Authors: Hollinghurst Joe , North Laura , Perry Malorie , Akbari Ashley , Gravenor Mike B , Lyons Ronan A , Fry Richard
Published: March 2021

Background

Vaccinations for COVID-19 have been prioritised for older people living in care homes. However, vaccination trials included limited numbers of older people.

Aim

We aimed to study infection rates of SARS-CoV-2 for older care home residents following vaccination and identify factors associated with increased risk of infection.

Study Design and Setting

We conducted an observational data-linkage study including 14,104 vaccinated older care home residents in Wales (UK) using anonymised electronic health records and administrative data.

Methods

We used Cox proportional hazards models to estimate hazard ratios (HRs) for the risk of testing positive for SARS-CoV-2 infection following vaccination, after landmark times of either 7 or 21-days post-vaccination. We adjusted hazard ratios for age, sex, frailty, prior SARS-CoV-2 infections and vaccination type.

Results

We observed a small proportion of care home residents with positive PCR tests following vaccination 1.05% (N=148), with 90% of infections occurring within 28-days. For the 7-day landmark analysis we found a reduced risk of SARS-CoV-2 infection for vaccinated individuals who had a previous infection; HR (95% confidence interval) 0.54 (0.30,0.95), and an increased HR for those receiving the Pfizer-BioNTECH vaccine compared to the Oxford-AstraZeneca; 3.83 (2.45,5.98). For the 21-day landmark analysis we observed high HRs for individuals with low and intermediate frailty compared to those without; 4.59 (1.23,17.12) and 4.85 (1.68,14.04) respectively.

Conclusions

Increased risk of infection after 21-days was associated with frailty. We found most infections occurred within 28-days of vaccination, suggesting extra precautions to reduce transmission risk should be taken in this time frame.
COVID-19 therapeutics for low- and middle-income countries: a review of re-purposed candidate agents with potential for near-term use and impact
Authors: Maxwell Daniel , Sanders Kelly C. , Sabot Oliver , Hachem Ahmad , Llanos-Cuentas Alejandro , Olotu Ally , Gosling Roly , Cutrell James B. , Hsiang Michelle S.
Published: March 2021

Low- and middle-income countries (LMICs) face significant challenges in the control of COVID-19, given limited resources, especially for inpatient care. In a parallel effort to that for vaccines, the identification of therapeutics that have near-term potential to be available and easily administered is critical. Using the United States, European Union, and World Health Organization clinical trial registries, we reviewed COVID-19 therapeutic agents currently under investigation. The search was limited to oral or potentially oral agents, with at least a putative anti-SARS-CoV-2 virus mechanism, and with at least 3 registered trials. We describe the available evidence regarding agents that met these criteria and additionally discuss the need for additional investment by the global scientific community in large well-coordinated trials of accessible agents and their combinations in LMICs. The search yielded 636, 175, and 930 trials, in the US, EU, and WHO trial registers, respectively. These trials covered 17 oral or potentially oral repurposed agents that are currently used as antimicrobials and immunomodulatory therapeutics and therefore have established safety. The available evidence regarding proposed mechanism of actions, clinical efficacy, and potential limitations is summarized. We also identified the need for large well-coordinated trials of accessible agents and their combinations in LMICs. Several repurposed agents have potential to be safe, available, and easily administrable to treat COVID-19. To prevent COVID-19 from becoming a neglected tropical disease, there is critical need for rapid and coordinated effort in their evaluation and the deployment of those found to be efficacious.
The Impact of Vaccination to Control COVID-19 Burden in the United States: A Simulation Modeling Approach
Authors: Alagoz Oguzhan , Sethi Ajay K. , Patterson Brian W. , Churpek Matthew , Alhanaee Ghalib , Scaria Elizabeth , Safdar Nasia
Published: March 2021

Introduction

Vaccination programs aim to control the COVID-19 pandemic. However, the relative impacts of vaccine coverage, effectiveness, and capacity in the context of nonpharmaceutical interventions such as mask use and physical distancing on the spread of SARS-CoV-2 are unclear. Our objective was to examine the impact of vaccination on the control of SARS-CoV-2 using our previously developed agent-based simulation model.

Methods

We applied our agent-based model to replicate COVID-19-related events in 1) Dane County, Wisconsin; 2) Milwaukee metropolitan area, Wisconsin; 3) New York City (NYC). We evaluated the impact of vaccination considering the proportion of the population vaccinated, probability that a vaccinated individual gains immunity, vaccination capacity, and adherence to nonpharmaceutical interventions. The primary outcomes were the number of confirmed COVID-19 cases and the timing of pandemic control, defined as the date after which only a small number of new cases occur. We also estimated the number of cases without vaccination.

Results

The timing of pandemic control depends highly on vaccination coverage, effectiveness, and adherence to nonpharmaceutical interventions. In Dane County and Milwaukee, if 50% of the population is vaccinated with a daily vaccination capacity of 0.1% of the population, vaccine effectiveness of 90%, and the adherence to nonpharmaceutical interventions is 65%, controlled spread could be achieved by July 2021 and August 2021, respectively versus in March 2022 in both regions without vaccine. If adherence to nonpharmaceutical interventions increases to 70%, controlled spread could be achieved by May 2021 and April 2021 in Dane County and Milwaukee, respectively.

Discussion

In controlling the spread of SARS-CoV-2, the impact of vaccination varies widely depending not only on effectiveness and coverage, but also concurrent adherence to nonpharmaceutical interventions. The effect of SARS-CoV-2 variants was not considered.

Primary Funding Source

National Institute of Allergy and Infectious Diseases
Relationship between COVID-19 pandemic and ecological, economic, and social characteristics
Authors: Murányi Attila , Varga Bálint
Published: March 2021

COVID-19 pandemic had huge impacts on the global world, with both a negative impact on society and economy, but a positive one on nature. But this universal effect resulted in different infection rates from country to country. We analyzed the relationship between the pandemic and ecological, economic, and social characteristics. All of these data were collected in 140 countries at 6 time points. Correlations were studied using univariate and multivariate regression models.

The world was interpreted as a single global ecosystem consisting of ecosystem units representing countries. We first studied 140 countries around the world together, and infection rates were related to per capita GDP, Ecological Footprint, median age, urban population, and Biological Capacity, globally. We then ranked 140 countries by infection rate and created 4 equal groups, each with 35 countries. In the first group, the infection rate was very high and was related to the Ecological Footprint (consumption) and GDP per capita (production). This group is dominated by developed countries and their ecological characteristics have proven to be particularly significant. In groups 2, 3, and 4, infection rates were high, moderate, and low, and were primarily associated with median age and urban population.

In the scientific discussion, we have interpreted why infection is high in developed countries. Sustainable ecosystems are balanced, unlike the ecosystems of developed countries. According to science, the resilience and health of both natural ecosystems and humans are closely linked to the world of microbial communities. Our results suggest that both the economy and society need to be in harmony with nature, creating sustainable ecosystems in developed countries as well.
Genome-wide identification of the oatMLOfamily and identification of a candidateAsMLOassociated with powdery mildew susceptibility
Authors: Reilly Aisling , Gibriel Hesham A.Y. , Karki Sujit Jung , Twamley Anthony , Finnan John , Kildea Steven , Feechan Angela
Published: March 2021

Blumeria graminisf. spp.avenaeis the causal agent of powdery mildew disease in oats (Avena sativa). It is the most significant limiting factor to oat production, with yield losses ranging from 5%-40%, during high disease pressure conditions. Certain members of theMildew Locus O(MLO) gene family have been shown to act as powdery mildew susceptibility factors in many different plant species. A loss-of-function mutation of specificMLOgenes confers broad-spectrum resistance against powdery mildew pathogens. PotentialMLOcandidates have not yet been identified in oats. In this study, we identified oat MLOs by querying 341 known MLO protein sequences against the publicly available oat genome. 11 MLO-like sequences were identified in oats. Phylogenetic analysis grouped these candidates into four different clades, one of which, AsMLO1 was grouped together with other cereal MLOs functionally known to contribute to powdery mildew susceptibility. AsMLO1 showed the highest similarity to the known powdery mildew-associated MLO proteins from wheat and barley. Gene expression analysis revealedAsMLO1expression is up regulated at 12 hours post-infection withBgaand was inferred to be a candidate gene associated with powdery mildew susceptibility in oats. These results are an important step towards more durable strategies to control powdery mildew incidence and severity in oats.
Effects of green manure application on soil microbial communities and activities in the decontaminated sandy soil paddy field in Fukushima, Japan
Authors: Lee Chol Gyu , Mitsuda Yuko , Sugihara Soh , Ookawa Taiichiro , Tanaka Haruo
Published: March 2021

On March 11, 2011, Japan experienced an unprecedented earthquake off the Pacific coast of Tohoku, and suffered the direct and long-term effects of the earthquake and tsunami in the area. In Fukushima prefecture, agricultural land contaminated with radioactive Cesium from the Fukushima Daiichi Nuclear Power Plant. Therefore, surface soil were removed for deconamination, and low fertility sandy soil was covered. Organic matter input is necessary to increase soil organic matter and green manure application is an effective method to improve soil fertility in the paddy field. Soil microbes and enzyme activities are sensitively responded to organic matter addition, but their dynamics on the dressed field are not well investigated. In this study, we focused on changing the microbial community, diversity and enzyme activities along with the green manure decomposition process in the sandy soil dressed paddy field in Japan. The green manure of hairy vetch and oat were harvested and incorporated in May 2020 and their decomposition process as cellulose and hemicellulose contents were determined. Soil bacterial communities were analyzed using 16S amplicon sequencing. The green manure was rapidly decomposed within the first 13 days, and they did not remain 50 days after green manure incorporation. Soil microbial biomass carbon was higher in the M treatment after GM treatment, but was not significant between treatments after 50 days. Dehydrogenase and β-glucosidase activities changed during the harvesting period, but did not correlate with GM decomposition. Microbial diversity (OTU numbers and Shannon index) also changed with GM application, but they were not associated with GM decomposition. Soil prokaryotic communities and some bacteria (BaciiliandChlorolfexi) are significantly influenced by GM treatment. However,Clostridawas not affected by GM. Mixed green manure treatment showed significantly rapid hemicellulose decomposition than other treatments. In this process,Anaerolineaewere negatively correlated with the decreasing of hemicellulose in this treatment. These results showed that GM treatment affected microbial communities, and their response was active during the decomposition process.