bluuebunny/crossref_metadata_2025 huggingface dataset:
Locally Adaptive Inversions Modulate Genetic Variation at Different Geographic Scales in a Seaweed Fly
Authors: Mérot Claire , Berdan Emma L , Cayuela Hugo , Djambazian Haig , Ferchaud Anne-Laure , Laporte Martin , Normandeau Eric , Ragoussis Jiannis , Wellenreuther Maren , Bernatchez Louis
Published: May 2021

Across a species range, multiple sources of environmental heterogeneity, at both small and large scales, create complex landscapes of selection, which may challenge adaptation, particularly when gene flow is high. One key to multidimensional adaptation may reside in the heterogeneity of recombination along the genome. Structural variants, like chromosomal inversions, reduce recombination, increasing linkage disequilibrium among loci at a potentially massive scale. In this study, we examined how chromosomal inversions shape genetic variation across a species range and ask how their contribution to adaptation in the face of gene flow varies across geographic scales. We sampled the seaweed fly Coelopa frigida along a bioclimatic gradient stretching across 10° of latitude, a salinity gradient, and a range of heterogeneous, patchy habitats. We generated a chromosome-level genome assembly to analyze 1,446 low-coverage whole genomes collected along those gradients. We found several large nonrecombining genomic regions, including putative inversions. In contrast to the collinear regions, inversions and low-recombining regions differentiated populations more strongly, either along an ecogeographic cline or at a fine-grained scale. These genomic regions were associated with environmental factors and adaptive phenotypes, albeit with contrasting patterns. Altogether, our results highlight the importance of recombination in shaping adaptation to environmental heterogeneity at local and large scales.
Unravelling the mechanisms of Type 1A topoisomerases using single-molecule approaches
Authors: Spakman Dian , Bakx Julia A M , Biebricher Andreas S , Peterman Erwin J G , Wuite Gijs J L , King Graeme A
Published: May 2021

Topoisomerases are essential enzymes that regulate DNA topology. Type 1A family topoisomerases are found in nearly all living organisms and are unique in that they require single-stranded (ss)DNA for activity. These enzymes are vital for maintaining supercoiling homeostasis and resolving DNA entanglements generated during DNA replication and repair. While the catalytic cycle of Type 1A topoisomerases has been long-known to involve an enzyme-bridged ssDNA gate that allows strand passage, a deeper mechanistic understanding of these enzymes has only recently begun to emerge. This knowledge has been greatly enhanced through the combination of biochemical studies and increasingly sophisticated single-molecule assays based on magnetic tweezers, optical tweezers, atomic force microscopy and Förster resonance energy transfer. In this review, we discuss how single-molecule assays have advanced our understanding of the gate opening dynamics and strand-passage mechanisms of Type 1A topoisomerases, as well as the interplay of Type 1A topoisomerases with partner proteins, such as RecQ-family helicases. We also highlight how these assays have shed new light on the likely functional roles of Type 1A topoisomerases in vivo and discuss recent developments in single-molecule technologies that could be applied to further enhance our understanding of these essential enzymes.
Marker-free quantification of repair pathway utilization at Cas9-induced double-strand breaks
Authors: Feng Wanjuan , Simpson Dennis A , Cho Jang-Eun , Carvajal-Garcia Juan , Smith Chelsea M , Headley Kathryn M , Hathaway Nate , Ramsden Dale A , Gupta Gaorav P
Published: May 2021

Genome integrity and genome engineering require efficient repair of DNA double-strand breaks (DSBs) by non-homologous end joining (NHEJ), homologous recombination (HR), or alternative end-joining pathways. Here we describe two complementary methods for marker-free quantification of DSB repair pathway utilization at Cas9-targeted chromosomal DSBs in mammalian cells. The first assay features the analysis of amplicon next-generation sequencing data using ScarMapper, an iterative break-associated alignment algorithm to classify individual repair products based on deletion size, microhomology usage, and insertions. The second assay uses repair pathway-specific droplet digital PCR assays (‘PathSig-dPCR’) for absolute quantification of signature DSB repair outcomes. We show that ScarMapper and PathSig-dPCR enable comprehensive assessment of repair pathway utilization in different cell models, after a variety of experimental perturbations. We use these assays to measure the differential impact of DNA end resection on NHEJ, HR and polymerase theta-mediated end joining (TMEJ) repair. These approaches are adaptable to any cellular model system and genomic locus where Cas9-mediated targeting is feasible. Thus, ScarMapper and PathSig-dPCR allow for systematic fate mapping of a targeted DSB with facile and accurate quantification of DSB repair pathway choice at endogenous chromosomal loci.
Preselector.uni-jena.de: optimize your cloning—a resource for identifying restriction enzymes for preselection reactions
Authors: Gühmann Martin , Reuter Stefanie , Hartung Jan , Mrowka Ralf
Published: May 2021

Preselection digests are a common strategy to reduce the background in the ligation step of molecular cloning. However, choosing fitting restriction enzymes by hand is not trivial and may lead to errors, potentially costing a lot of time and work. We therefore created preselector.uni-jena.de (https://preselector.uni-jena.de/), a free online tool to find such restriction enzymes. The tool uses regular expressions to find recognition sites of restriction enzymes in the DNA sequences provided by the user. This new tool compares the sets of restriction sites and reports the enzymes that cut one sequence but not the other sequences to the user. These enzymes are then the ones suitable for a preselection digest. Thus, preselector.uni-jena.de is a fast, reliable, and free-to-use tool to help researchers designing preselection digestion strategies for their cloning.
DeepFun: a deep learning sequence-based model to decipher non-coding variant effect in a tissue- and cell type-specific manner
Authors: Pei Guangsheng , Hu Ruifeng , Jia Peilin , Zhao Zhongming
Published: May 2021

More than 90% of the genetic variants identified from genome-wide association studies (GWAS) are located in non-coding regions of the human genome. Here, we present a user-friendly web server, DeepFun (https://bioinfo.uth.edu/deepfun/), to assess the functional activity of non-coding genetic variants. This new server is built on a convolutional neural network (CNN) framework that has been extensively evaluated. Specifically, we collected chromatin profiles from ENCODE and Roadmap projects to construct the feature space, including 1548 DNase I accessibility, 1536 histone mark, and 4795 transcription factor binding profiles covering 225 tissues or cell types. With such comprehensive epigenomics annotations, DeepFun expands the functionality of existing non-coding variant prioritizing tools to provide a more specific functional assessment on non-coding variants in a tissue- and cell type-specific manner. By using the datasets from various GWAS studies, we conducted independent validations and demonstrated the functions of the DeepFun web server in predicting the effect of a non-coding variant in a specific tissue or cell type, as well as visualizing the potential motifs in the region around variants. We expect our server will be widely used in genetics, functional genomics, and disease studies.
The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination
Authors: Ramos-Morales Elizabeth , Bayam Efil , Del-Pozo-Rodríguez Jordi , Salinas-Giegé Thalia , Marek Martin , Tilly Peggy , Wolff Philippe , Troesch Edouard , Ennifar Eric , Drouard Laurence , Godin Juliette D , Romier Christophe
Published: May 2021

Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic wobble adenosine-to-inosine modification is catalysed by the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring a full tRNA for activity. Yet, ADAT catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood. Here, we have characterized mouse ADAT and provide the molecular basis for tRNAs deamination by ADAT2 as well as ADAT3 inactivation by loss of catalytic and tRNA-binding determinants. We show that tRNA binding and deamination can vary depending on the cognate tRNA but absolutely rely on the eukaryote-specific ADAT3 N-terminal domain. This domain can rotate with respect to the ADAT catalytic domain to present and position the tRNA anticodon-stem-loop correctly in ADAT2 active site. A founder mutation in the ADAT3 N-terminal domain, which causes intellectual disability, does not affect tRNA binding despite the structural changes it induces but most likely hinders optimal presentation of the tRNA anticodon-stem-loop to ADAT2.
The Flavor Train: The Nature and Extent of Flavored Cigarettes in Low- and Middle-Income Countries
Authors: Cohen Joanna E , Welding Kevin , Erinoso Olufemi , Saraf Sejal , Iacobelli Michael , Smith Katherine C
Published: May 2021

Introduction

Flavors and depictions of flavors are attractive and facilitate initiation and use of tobacco products. However, little is known about the types of flavored products on the market, particularly in low- and middle-income countries. We describe the nature and extent of flavored cigarettes sold in nine low- and middle-income countries from four of the six World Health Organization (WHO) regions.

Aims and Methods

We employed a systematic protocol to purchase unique cigarette packs in Bangladesh, Brazil, China, India, Indonesia, Philippines, Russia, Thailand, and Vietnam. Packs were double coded for flavor descriptors and imagery using a standard codebook. Frequencies and crosstabs were conducted to examine the proportion of packs with flavor descriptors and/or flavor imagery, and flavor capsules, by country and by major manufacturer.

Results

Overall, 15.4% of the country-unique cigarette packs had flavor descriptors and/or imagery, representing a variety of flavors: menthol or mint (8.2%), “concept” descriptors (3.5%) (eg, Fusion blast), fruit or citrus (3.3%), beverages (1.4%), and others (1.4%). Flavor was mostly communicated using descriptors (15.2%), with flavor imagery being less common (2.2%). Flavor capsules were prevalent (6.2%), with almost half having “concept” descriptors. All major tobacco companies produced cigarettes with flavors, and with capsules.

Conclusions

A range of flavored cigarettes remain on the market in the low- and middle-income countries with the greatest number of smokers. This finding is particularly concerning given the appeal of flavored cigarettes among youth and their potential to circumvent country bans on flavored tobacco products if those laws are not sufficiently comprehensive. Laws addressing flavored tobacco products need to account for flavor capsules and concept descriptors.

Implications

While a number of countries have restricted flavors in tobacco products to reduce their appeal and attractiveness, a range of flavors continue to be on the market in low- and middle-income countries, putting people in these countries at increased risk for tobacco use and subsequent tobacco-caused death and disease. The presence of capsules and concept descriptors is particularly concerning given their appeal among youth and their potential to circumvent country bans on flavored tobacco products if those laws are not sufficiently comprehensive.
Aquaporin family lactic acid channel NIP2;1 promotes plant survival under low oxygen stress in Arabidopsis
Authors: Beamer Zachary G , Routray Pratyush , Choi Won-Gyu , Spangler Margaret K , Lokdarshi Ansul , Roberts Daniel M
Published: May 2021

Under anaerobic stress, Arabidopsis thaliana induces the expression of a collection of core hypoxia genes that encode proteins for an adaptive response. Among these genes is NIP2;1, which encodes a member of the “Nodulin 26-like Intrinsic Protein” (NIP) subgroup of the aquaporin superfamily of membrane channel proteins. NIP2;1 expression is limited to the “anoxia core” region of the root stele under normal growth conditions, but shows substantial induction (up to 1,000-fold by 2–4 h of hypoxia) by low oxygen stress, and accumulation in all root tissues. During hypoxia, NIP2;1-GFP accumulates predominantly on the plasma membrane by 2 h, is distributed between the plasma and internal membranes during sustained hypoxia, and remains elevated in root tissues through 4 h of reoxygenation recovery. In response to hypoxia challenge, T-DNA insertion mutant nip2;1 plants exhibit elevated lactic acid within root tissues, reduced efflux of lactic acid, and reduced acidification of the external medium compared to wild-type plants. Previous biochemical evidence demonstrates that NIP2;1 has lactic acid channel activity, and our work supports the hypothesis that NIP2;1 prevents lactic acid toxicity by facilitating release of cellular lactic acid from the cytosol to the apoplast, supporting eventual efflux to the rhizosphere. In evidence, nip2;1 plants demonstrate poorer survival during argon-induced hypoxia stress. Expressions of the ethanolic fermentation transcript Alcohol Dehydrogenase1 and the core hypoxia-induced transcript Alanine Aminotransferase1 are elevated in nip2;1, and expression of the Glycolate Oxidase3 transcript is reduced, suggesting NIP2;1 lactic acid efflux regulates other pyruvate and lactate metabolism pathways.
Differential regulation of the calcium-dependent protein kinase CPK28 by site-specific modification
Authors: Bredow Melissa , Monaghan Jacqueline
Published: May 2021

A protein kinase with roles in immune homeostasis and stem elongation is regulated by site-specific phosphorylation.
Framing action to reduce health inequalities: what is argued for through use of the ‘upstream–downstream’ metaphor?
Authors: McMahon Naoimh E
Published: May 2021

Background

Public health insights struggle to compete with dominant ideas which frame health inequalities as a problem of individual behaviour. There is consequently a need to critically reflect upon and question the effectiveness of different strategies for framing and communicating key insights. Taking the example of the ‘upstream–downstream’ metaphor, this literature review contributes to a necessary first step by asking what exactly is being argued for through its use.

Methods

An iterative search strategy was used to identify peer-reviewed articles which could contribute to the review question. A discourse analysis framework informed data extraction and synthesis of 24 articles. Articles were subsequently categorized into groups which reflected the different uses of the metaphor identified.

Results

All authors used the metaphor to promote a particular causal understanding of health inequalities, leading some to recommend policies and programmes, and others to focus on implementation processes. This seemingly simple metaphor has evolved beyond differentiating ‘upstream’ from ‘downstream’ determinants, to communicate an ambitious politically engaged agenda for change.

Conclusions

The metaphor is not without its critics and in light of the complexity of the arguments encapsulated in its use, work is needed to establish if it can, and does, resonate as intended with wider audiences.
COVID-19 deaths in the USA: Benford’s law and under-reporting
Authors: Campolieti Michele
Published: May 2021

Background

I use Benford’s law to assess whether there is misreporting of coronavirus disease of 2019 (COVID-19) deaths in the USA.

Methods

I use three statistics to determine whether the reported deaths for US states are consistent with Benford’s law, where the probability of smaller digits is greater than the probability of larger digits.

Results

My findings indicate that there is under-reporting of COVID-19 deaths in the USA, although the evidence for and the extent of under-reporting does depend on the statistic one uses to assess conformity with Benford’s law.

Conclusions

Benford’s law is a useful diagnostic tool for verifying data and can be used before a more detailed audit or resource intensive investigation.
Investigating Patient Acceptability of Stratified Medicine for Schizophrenia: A Mixed Methods Study
Authors: Jilka Sagar , Odoi Clarissa Mary , Meran Sazan , MacCabe James H , Wykes Til
Published: May 2021

Background

Health services have advocated a stratified medicine approach in mental health, but little is known about whether service users would accept this approach.

Aims

To explore service users’ views of the acceptability of stratified medicine for treatment-resistant schizophrenia compared to the traditional “trial-and-error” approach.

Methods

A mixed methods observational study that explored questionnaire responses on acceptability and whether these responses were affected by demographic or clinical variables. We also investigated whether treatment responsiveness or experience of invasive tests (brain scans and blood tests) affected participants’ responses. Questionnaire generated qualitative data were analyzed thematically. Participants (N108) were aged 18–65, had a diagnosis of schizophrenia, and were adherent to antipsychotic medication.

Results

Acceptability of a stratified approach was high, even after participants had experienced invasive tests. Most rated it as safer (62% vs 43%; P < .01 [CI: −1.69 to 2.08]), less risky (77% vs 44%; P < .01 [CI: −1.75 to 1.10]), and less painful (90% vs 73%; P < 0.01 [CI: −0.84 to 0.5]) and this was not affected by treatment responsiveness or test experience. Although not statistically significant, treatment nonresponders were more willing to undergo invasive tests. Qualitatively, all participants raised concerns about the risks, discomfort, and potential side effects associated with the invasive tests.

Conclusions

Service users were positive about a stratified approach for choosing treatments but were wary of devolving clinical decisions to purely data-driven algorithms. These results reinforce the value of service user perspectives in the development and evaluation of novel treatment approaches.
Effects of changes in temperature on Zika dynamics and control
Authors: Ngonghala Calistus N. , Ryan Sadie J. , Tesla Blanka , Demakovsky Leah R. , Mordecai Erin A. , Murdock Courtney C. , Bonds Matthew H.
Published: May 2021

When a rare pathogen emerges to cause a pandemic, it is critical to understand its dynamics and the impact of mitigation measures. We use experimental data to parametrize a temperature-dependent model of Zika virus (ZIKV) transmission dynamics and analyse the effects of temperature variability and control-related parameters on the basic reproduction number (
R
0
) and the final epidemic size of ZIKV. Sensitivity analyses show that these two metrics are largely driven by different parameters, with the exception of temperature, which is the dominant driver of epidemic dynamics in the models. Our
R
0
estimate has a single optimum temperature (≈30°C), comparable to other published results (≈29°C). However, the final epidemic size is maximized across a wider temperature range, from 24 to 36°C. The models indicate that ZIKV is highly sensitive to seasonal temperature variation. For example, although the model predicts that ZIKV transmission cannot occur at a constant temperature below 23°C (≈ average annual temperature of Rio de Janeiro, Brazil), the model predicts substantial epidemics for areas with a mean temperature of 20°C if there is seasonal variation of 10°C (≈ average annual temperature of Tampa, Florida). This suggests that the geographical range of ZIKV is wider than indicated from static
R
0
models, underscoring the importance of climate dynamics and variation in the context of broader climate change on emerging infectious diseases.
Introducing a graph topology for robust cooperation
Authors: Locodi A. M. , O’Riordan C.
Published: May 2021

Identifying the conditions that support cooperation in spatial evolutionary game theory has been the focus of a large body of work. In this paper, the classical Prisoner's Dilemma is adopted as an interaction model; agents are placed on graphs and their interactions are constrained by a graph topology. A simple strategy update mechanism is used where agents copy the best performing strategy of their neighbourhood (including themselves). In this paper, we begin with a fully cooperative population and explore the robustness of the population to the introduction of defectors. We introduce a graph structure that has the property that the initial fully cooperative population is robust to any one perturbation (a change of any cooperator to a defector). We present a proof of this property and specify the necessary constraints on the graph. Furthermore, given the standard game payoffs, we calculate the smallest graph which possesses this property. We present an approach for increasing the size of the graph and we show empirically that this extended graph is robust to an increasing percentage of perturbations. We define a new class of graphs for the purpose of future work.
Diversity aboard a Tudor warship: investigating the origins of theMary Rosecrew using multi-isotope analysis
Authors: Scorrer Jessica , Faillace Katie E. , Hildred Alexzandra , Nederbragt Alexandra J. , Andersen Morten B. , Millet Marc-Alban , Lamb Angela L. , Madgwick Richard
Published: May 2021

The great Tudor warship, theMary Rose, which sank tragically in the Solent in 1545 AD, presents a rare archaeological opportunity to research individuals for whom the precise timing and nature of death are known. A long-standing question surrounds the composition of the Tudor navy and whether the crew were largely British or had more diverse origins. This study takes a multi-isotope approach, combining strontium (87Sr/86Sr), oxygen (δ18O), sulfur (δ34S), carbon (δ13C) and nitrogen (δ15N) isotope analysis of dental samples to reconstruct the childhood diet and origins of eight of theMary Rosecrew. Forensic ancestry estimation was also employed on a subsample. Provenancing isotope data tentatively suggests as many as three of the crew may have originated from warmer, more southerly climates than Britain. Five have isotope values indicative of childhoods spent in western Britain, one of which had cranial morphology suggestive of African ancestry. The general trend of relatively high δ15N and low δ13C values suggests a broadly comparable diet to contemporaneous British and European communities. This multi-isotope approach and the nature of the archaeological context has allowed the reconstruction of the biographies of eight Tudor individuals to a higher resolution than is usually possible.
Potential syntrophic relationship between coral-associated Prosthecochloris and its companion sulfate-reducing bacterium unveiled by genomic analysis
Authors: Chen Yu-Hsiang , Yang Shan-Hua , Tandon Kshitij , Lu Chih-Ying , Chen Hsing-Ju , Shih Chao-Jen , Tang Sen-Lin
Published: May 2021

Endolithic microbial symbionts in the coral skeleton may play a pivotal role in maintaining coral health. However, compared to aerobic micro-organisms, research on the roles of endolithic anaerobic micro-organisms and microbe–microbe interactions in the coral skeleton are still in their infancy. In our previous study, we showed that a group of coral-associated

Prosthecochloris

(CAP), a genus of anaerobic green sulphur bacteria, was dominant in the skeleton of the coral Isopora palifera. Though CAP is diverse, the 16S rRNA phylogeny presents it as a distinct clade separate from other free-living

Prosthecochloris

. In this study, we build on previous research and further characterize the genomic and metabolic traits of CAP by recovering two new high-quality CAP genomes – Candidatus Prosthecochloris isoporae and Candidatus Prosthecochloris sp. N1 – from the coral I. palifera endolithic cultures. Genomic analysis revealed that these two CAP genomes have high genomic similarities compared with other

Prosthecochloris

and harbour several CAP-unique genes. Interestingly, different CAP species harbour various pigment synthesis and sulphur metabolism genes, indicating that individual CAPs can adapt to a diversity of coral microenvironments. A novel high-quality genome of sulfate-reducing bacterium (SRB)– Candidatus Halodesulfovibrio lyudaonia – was also recovered from the same culture. The fact that CAP and various SRB co-exist in coral endolithic cultures and coral skeleton highlights the importance of SRB in the coral endolithic community. Based on functional genomic analysis of Ca. P. sp. N1, Ca. P. isoporae and Ca. H. lyudaonia, we also propose a syntrophic relationship between the SRB and CAP in the coral skeleton.
Automated vision screening of children using a mobile graphic device
Authors: Kane Steven A. , Gaspich Mark , Kane Julia , Weitzman Sarah , Hofeldt Albert
Published: May 2021

Background/Objective

Can measures of interocular brightness disparity, acuity, and colour vision identify children with amblyopia?

Subjects/Methods

208 subjects from 3 to 14 years were recruited for a prospective, observational protocol to measure interocular brightness disparity, acuities with and without a pinhole, and colour vision using an iPad. Interocular brightness disparity was assessed as the subject looked through a system of polarizing filters and chose the brighter of two spaceships. The differential brightness of image pairs was varied according to a staircase algorithm until equal brightness was perceived. Acuities were tested with tumbling Es. Colour vision was tested with AO-HRR colour plates. 2 subjects (1%) were later confirmed to have unilateral amblyopia.

Results

Binocular brightness balance on the iPad detected both amblyopes and excluded all 202 non-amblyopes, in this study with sensitivity and specificity of 100%. By using 20/30 as cutoff for normal acuity, 1 of the 2 amblyopes was detected and all non-amblyopes were excluded by visual acuity testing with pinhole. The mean difference between iPad and E-Chart visual acuities with pinhole was 0.02 logMAR with limits of agreement from -0.08 to +0.11 logMAR. Colour vision testing with iPad and printed plates gave identical results. Testing times were brief and exit pleasure poll responses were positive.

Conclusions

Interocular brightness disparity, acuity, and colour vision can be measured in children as young as 3 years playing a fun game on a mobile graphic device. Interocular brightness disparity may be a sensitive and specific method to detect unilateral amblyopia.
Prevalence use of nonsteroidal anti-inflammatory drugs in the general population with COVID-19 and associated COVID-19 risk, hospitalization, severity, death, and safety outcomes: A systematic review and meta-analysis
Authors: Zhao Huilei , Huang Shanshan , Mei Kaibo , Shao Wen , Zhang Jing , Ma Jianyong , Zhu Wengen , Jiang Yuan , Yu Peng , Liu Xiao
Published: May 2021

Introduction

Recent reports of potential harmful effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with Corona Virus Disease 2019 (COVID-19) have provoked great concern. Therefore, the safety of NSAIDs is still questioned.

Methods

We searched the PubMed, EMBASE, Cochrane Library and Web of Science databases from December 2019 to January 2021 to examine use prevalence for NSAIDs in general, as well as associated COVID-19 risk and outcomes. This study has been registered with PROSPERO (CRD42019132063)

Results

We included 25 studies with a total of 101,215 COVID-19 patients. The use of NSAIDs in COVID-19 patients reached 19%. Exposure to NSAIDs was not associated with significantly increased risk of developing COVID-19 (odds ratio [OR]=0.98, 95% confidence interval [CI]: 0.78-1.24; I2=82%), hospitalization (OR=1.06, 95%CI: 0.76-1.48; I2=81%), mechanical ventilation (OR=0.71, 95%CI: 0.47-1.06; I2=38%), and length of hospital stay. Moreover, use of NSAIDs was significantly associated with better outcomes, including severity of COVID-19 (OR=0.79, 95%CI: 71-0.89; I2=0%) and death (OR=0.68, 95%CI: 0.52-0.89; I2=85%) in patients with COVID-19. Regarding safety outcomes, exposure to NSAIDs was associated with increased risk of stroke (OR=2.32, 95%CI: 1.04-5.2; I2=0%), but not with myocardial infraction (OR=1.49; p=0.66; I2=0%), overt thrombosis (OR=0.76, p=0.50; I2=28%) and major bleeding (p=0.61).

Conclusion

Based on current evidence, exposure to NSAIDs is not linked to increased odds or exacerbation of COVID-19 in the general COVID-19 population. Furthermore, administration of NSAIDs might have better outcomes and survival benefits in the general COVID-19 population, although potentially increasing the risk of stroke. Use of NSAIDs might be safe and beneficial in COVID-19. Future observational and randomized control trials are needed for further confirmation.
Changes in work and health of Australians during the COVID-19 pandemic: a longitudinal cohort study
Authors: Griffiths Daniel , Sheehan Luke , van Vreden Caryn , Petrie Dennis , Whiteford Peter , Sim Malcolm R , Collie Alex
Published: May 2021

Objectives

To determine the long-term effects of work loss on health during the COVID-19 pandemic, and whether any effects are persistent upon returning to work.

Methods

A prospective longitudinal cohort study of 2603 participants across Australia monitored changes in health and work during between March and December 2020, with participants completing surveys at baseline and 1, 3 and 6 months later. Outcomes described psychological distress, and mental and physical health. Linear mixed regression models examined associations between changes in health and experiences of work loss, and return to work, over time.

Results

Losing work during the early stages of the pandemic was associated with long-term poorer mental health, which began to recover over time as some returned to work. Physical health deteriorated over time, greater for people not working at baseline. Being out of work was associated with poorer mental health, but better physical health. These effects were larger for people that had recently lost work than for people with sustained work loss, and retaining employment played a protective role. Generally, returning to work resulted in poorer physical health and improvements in mental health, although this depended on the broader context of changes in work.

Conclusions

Work cessation during the pandemic led to poor health outcomes and had long-lasting effects. Returning to work benefits mental health but may reduce physical activity in the short-term. We encourage the provision of accessible mental health supports and services immediately following loss of work, and for people with prolonged forms of work loss.
Preventing COVID-19 Outbreaks Through Surveillance Testing in Healthcare Facilities - A Modelling Study
Authors: Litwin Tim , Timmer Jens , Berger Mathias , Wahl-Kordon Andreas , Müller Matthias J. , Kreutz Clemens
Published: May 2021

Surveillance testing within healthcare facilities provides an opportunity to prevent severe outbreaks of coronavirus disease 2019 (COVID-19). However, the quantitative impact of different available surveillance strategies is not well-understood. Our study adds to the available body of evidence by examining different strategies for their potential to decrease the probability of outbreaks in these facilities. Based on our findings, we propose determinants of successful surveillance measures. To this end, we establish an individual-based model representative of a mental health hospital yielding generalizable results. Attributes and features of this facility were derived from a prototypical hospital, which provides psychiatric, psychosomatic and psychotherapeutic treatment. We estimate the relative reduction of outbreak probability for three test strategies (entry test, once-weekly test and twice-weekly test) relative to a symptom-based baseline strategy. We found that fast diagnostic test results and adequate compliance of the clinic population are mandatory for conducting effective surveillance. The robustness of these results towards uncertainties is demonstrated via comprehensive sensitivity analyses. In summary, we robustly quantified the efficacy of different surveillance scenarios and conclude that active testing in mental health hospitals and similar facilities successfully reduces the number of COVID-19 outbreaks.
Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a phase 1, dose-escalating, randomised controlled study
Authors: Khoo Saye H , FitzGerald Richard , Fletcher Thomas , Ewings Sean , Jaki Thomas , Lyon Rebecca , Downs Nichola , Walker Lauren , Tansley-Hancock Olana , Greenhalf William , Woods Christie , Reynolds Helen , Marwood Ellice , Mozgunov Pavel , Adams Emily , Bullock Katie , Holman Wayne , Bula Marcin D , Gibney Jennifer L , Saunders Geoffrey , Corkhill Andrea , Hale Colin , Thorne Kerensa , Chiong Justin , Condie Susannah , Pertinez Henry , Painter Wendy , Wrixon Emma , Johnson Lucy , Yeats Sara , Mallard Kim , Radford Mike , Fines Keira , Shaw Victoria , Owen Andrew , Lalloo David G , Jacobs Michael , Griffiths Gareth
Published: May 2021

Background

AGILE is a phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection.

Methods

We undertook a dose-escalating, open-label, randomised-controlled (standard-of-care) Bayesian adaptive phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomised 2:1 in groups of 6 participants to 300mg, 600mg and 800mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was higher than 25%. Secondary outcomes included safety, clinical progression, pharmacokinetics and virologic responses.

Results

Of 103 volunteers screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 400, 600 or 800mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800mg molnupiravir respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800mg was estimated at 0.9%.

Conclusion

Molnupiravir was safe and well tolerated; a dose of 800mg twice-daily for 5 days was recommended for Phase II evaluation.
Almond Consumption for 8 Weeks Altered Host and Microbial Metabolism in Comparison to a Control Snack in Young Adults
Authors: Dhillon Jaapna , Newman John W. , Fiehn Oliver , Ortiz Rudy M.
Published: May 2021

Almond consumption can improve cardiometabolic (CM) health. However, the mechanisms underlying those benefits are not well characterized. This study explored the effects of consuming a snack of almonds vs. crackers for 8 weeks on changes in metabolomic profiles in young adults (clinicaltrials.gov ID: NCT03084003). Participants (n=73, age: 18-19 years, BMI: 18-41 kg/m2) were randomly assigned to consume either almonds (2 oz/d, n=38) or an isocaloric control snack of graham crackers (325 kcal/d, n=35) daily for 8 weeks. Blood samples were collected at baseline prior to and at 4 and 8 weeks after the intervention. Metabolite abundances in the serum were quantified by hydrophilic interaction chromatography quadrupole (Q) time-of-flight (TOF) mass spectrometry (MS/MS), gas chromatography (GC) TOF MS, CSH-ESI (electrospray) QTOF MS/MS, and targeted analyses for free PUFAs, total fatty acids, oxylipins and endocannabinoids. Linear mixed model analyses with baseline-adjustment were conducted, and those results were used for enrichment and network analyses. Microbial community pathway predictions from 16S rRNA sequencing of fecal samples was done using PICRUST2. Almond consumption enriched unsaturated triglycerides, unsaturated phosphatidylcholines, saturated and unsaturated lysophosphatidylcholines, tricarboxylic acids, and tocopherol clusters (p<0.05). Targeted analyses reveal lower levels of omega-3 total fatty acids (TFAs) overall in the almond group compared to the cracker group (p<0.05). Microbial amino acid biosynthesis, and amino sugar and nucleotide sugar metabolism pathways were also differentially enriched at the end of the intervention (p<0.05). The study demonstrates the differential effects of almonds on host tocopherol, lipid, and TCA cycle metabolism with potential changes in microbial metabolism, which may interact with host metabolism to facilitate the CM benefits.
Participatory prototyping of a tailored U=U (undetectable=untransmittable) message to increase HIV testing in men in Western Cape, South Africa
Authors: Smith Philip , Joseph Davey Dvora L. , Schmucker Laura , Bruns Cal , Bekker Linda-Gail , Medina-Marino Andrew , Thirumurthy Harsha , Buttenheim Alison
Published: May 2021

Introduction

Taking daily ART eliminates sufficient virus so that HIV is undetectable via viral load (VL) testing within 24 weeks. HIV-positive individuals with an undetectable VL cannot transmit HIV to sexual partners or through giving birth, a message commonly referred to as U=U (undetectable equals untransmittable). Since South African men have poorer HIV outcomes than women, we used interactive human centred design co-creation workshops to ask men from high HIV burden communities in Cape Town, South Africa to create a U=U message aimed at increasing HIV testing and ART uptake in men.

Methods

Two facilitators explained the U=U message to the men (n =39) attending the workshop and asked them how to effectively communicate the message. Participants designed messages to assuage fears of testing HIV positive, explaining that ART enables HIV positive people to live normally and makes the virus “untransmittable” to their sexual partners.

Results

Participants developed three insights for the U=U message; 1) “Introduce” the modern antiretroviral pill, 2) positively redefine the man for whom the pill is intended, and 3) simplify the benefits of ART for men. Participants’ messages emphasised 1) “you cannot spread the virus (HIV) to the other person” 2) and “(the pill) keeps on killing the virus so I can live a normal life for the rest of my life.”

Discussion

Men in the workshops co-created a simple U=U message to address fears of testing HIV positive, emphasising the pill’s positive effects. Co-created, tailored messaging may improve the uptake of HIV services for South African men.
Impact of Dutasteride on PSA Kinetics and Time to Progression in Men with PSA-only Recurrent Prostate Cancer
Authors: Myers Charles E , McCarthy Michelle S
Published: May 2021

Background

AVODART After Radical Therapy For Prostate Cancer Study (ARTS) reported dutasteride reduced PSA doubling (PSADT) at two years by 66% and disease progression by 59%. The durability of the cancer control is unknown.

Objective

Explore the impact of dutasteride on PSADT and time to progression in men with PSA-only recurrent disease.

Design, Setting and Participants

Retrospective examination of the impact of dutasteride on PSA kinetics and time to progression with PSA-only recurrent prostate cancer.

Intervention

Dutasteride daily.

Outcome, Measurement and Statistical Analysis

Change in PSA over time was determined by linear regression of natural log of PSA versus time. The slope of that curve was used as a measure of exponential PSA progression. Impact of dutasteride on slope was analyzed using Wilcoxon signed-rank two-sided test. Time to progression was analyzed using Kaplan-Meier, univariant and multivariant Cox regression.

Results and Limitation

Compared to men with BPH, patients showed little change in PSA during the first 3 months. Thereafter, the PSA resumed an exponential increase. PSADT was 10.3 months pre dutasteride and 24.8 months post dutasteride. Multivariant analysis showed a strong correlation between post dutasteride PSA kinetics and time to progression, with close to 50% relapse free at 10 years. Post-dutasteride, patients with PSADT >9 months had significantly better survival.

Conclusions

Dutasteride slows PSADT in PSA-only recurrent prostate cancer. This decline correlated with time to disease progression with close to 50% progression free at 10 years.

Patient Summary

Men with PSA-only recurrent prostate cancer on dutasteride experience a significant drop in the rate at which the PSA increases. If the PSA does not double between months 3-12, they are likely to remain free of metastases for many years.
Mouse Adapted SARS-CoV-2 protects animals from lethal SARS-CoV challenge
Authors: Muruato Antonio , Vu Michelle N. , Johnson Bryan A. , Davis-Gardner Meredith E. , Vanderheiden Abigail , Lokugmage Kumari , Schindewolf Craig , Crocquet-Valdes Patricia A. , Langsjoen Rose M. , Plante Jessica A. , Plante Kenneth S. , Weaver Scott C. , Debbink Kari , Routh Andrew L. , Walker David , Suthar Mehul S. , Xie Xuping , Shi Pei-Yong , Menachery Vineet D.
Published: May 2021

The emergence of SARS-CoV-2 has resulted in a worldwide pandemic causing significant damage to public health and the economy. Efforts to understand the mechanisms of COVID-19 disease have been hampered by the lack of robust mouse models. To overcome this barrier, we utilized a reverse genetic system to generate a mouse-adapted strain of SARS-CoV-2. Incorporating key mutations found in SARSCoV-2 variants, this model recapitulates critical elements of human infection including viral replication in the lung, immune cell infiltration, and significantin vivodisease. Importantly, mouse-adaptation of SARS-CoV-2 does not impair replication in human airway cells and maintains antigenicity similar to human SARS-CoV-2 strains. Utilizing this model, we demonstrate that SARS-CoV-2 infected mice are protected from lethal challenge with the original SARS-CoV, suggesting immunity from heterologous CoV strains. Together, the results highlight the utility of this mouse model for further study of SARS-CoV-2 infection and disease.
Volumetric alteration of olfactory bulb and immune-related molecular changes in olfactory epithelium in first episode psychosis patients
Authors: Yang Kun , Hua Jun , Etyemez Semra , Paez Adrian , Prasad Neal , Ishizuka Koko , Sawa Akira , Kamath Vidyulata
Published: May 2021

Background

Olfactory dysfunction has been reproducibly reported in patients with psychosis, including first episode psychosis (FEP) patients. Consistently, structural abnormalities in the olfactory bulb (OB), a key region of the peripheral olfactory system, have also been reported in psychotic disorders. Meanwhile, air pollution and viral infections in the upper respiratory tract, including those of SARS-CoV-2, are reportedly risk factors for brain dysfunction and mental disorders. These risk factors can disturb the olfactory epithelium (OE) that is located adjacent to the OB and connected via direct neuronal projections. Nevertheless, it is unknown how a disturbance of the OE possibly affects the OB in the pathophysiological context of psychotic disorders.

Methods

We examined the volume of the OB in FEP patients and healthy controls from 3 Tesla magnetic resonance imaging and molecular expression profiles of olfactory neuronal cells (ONCs) enriched from freshly biopsied OE.

Results

We observed a reduction of the OB volume in FEP patients compared with healthy controls. We also observed a significant alteration in gene expression profiles in the ONCs from FEP patients, supporting the pathological changes in the OE. Among such molecular changes, immune-related molecules and pathways were underscored in association with the OB volume changes in FEP patients.

Conclusions

Our data support the OB and OE pathologies in FEP patients. Immune-related molecular changes in the OE can biologically link adverse factors in the nasal cavity, such as air pollution and viral infection, with the OB structural change, both of which have been reported for psychotic disorders.
SARS-CoV-2 Seroprevalence and Risk Factors among Convalescents in Sichuan Province, China: a retrospective cohort study
Authors: Zhou Lijun , Li Cheng , Yang Huiping , Yuan Heng , Pan Ming , Cheng Xiuwei , Xiao Chongkun , Su Xiaoyan , Zhu Yuanfang , Xu Jianan , Tang Jianxiang , Du Xunbo , Peng Huanwen , Xiao Chen , Huang Tao , Liao Hongxiu , Xian Deqiang , Liao Hongxiu , Wang HaoZhou , Liu Wenwu , Ping Zhou , Zhang Zhengdong , Juan Liu , Wu Xianping , Zhang Tao
Published: May 2021

Objectives

To understand SARS-CoV-2 seroprevalence of convalescents and assess their the immunity. Furthermore, we intend to explore the association between antibody levels and with demographic factors.

Methods

177 COVID-19 convalescents in Sichuan Province were voluntarily participated in our study. 363 serum samples were collected from June, 2020 to November, 2020. Duration of seroprevelance in these convalescents and their demographic characteristics were described, and the risk factors to antibody levels were analysed.

Results

Men had more than twice the odds of having IgM antibody positive compared with women (OR=2.419, 95% CI:[1.232, 4.751]). Participants without symptoms were nearly 0.5 times IgG seropositive than those with symptoms (OR=0.455, 95% CI: [0.220, 0.940]). People aged≥60 years were nearly 3 times IgG seropositive than those who aged < 20 years (OR=2.986, 95% CI: [1.058, 8.432]). Seroprevalence in asymptomatic declined quicker than symptomatic.

Conclusions

Age and gender may affect the antibody levels and seroprevalence. Asymptomatic appeared more easier to turn to seronegative than symptomatic.
Cell-type specific requirement for pyruvate dehydrogenase in hematopoiesis and leukemia development
Authors: Jun Sojeong , Mahesula Swetha , Mathews Thomas P. , Martin-Sandoval Misty S. , Zhao Zhiyu , Piskounova Elena , Agathocleous Michalis
Published: May 2021

Cancer cells have different metabolic requirements as compared to their corresponding normal tissues. This is thought to reflect metabolic reprogramming during transformation. An alternative possibility is that some metabolic requirements of cancer cells reflect a maintenance of the metabolism of the specific normal cell type from which cancer cells originate. Here, we investigate this hypothesis by comparing glucose use in normal hematopoiesis and in leukemia. T cell progenitors in the thymus were glucose avid and oxidized more glucose in the tricarboxylic acid (TCA) cycle through pyruvate dehydrogenase (PDH) as compared to hematopoietic stem cells (HSCs) or other hematopoietic cells. PDH deletion reduced the number of double positive (DP) T cell progenitors but had no effect on HSCs, myeloid progenitors and other hematopoietic cells we examined. PDH deletion blocked the development of T cell leukemia fromPten-deficient DP progenitors, but not the development of a myeloid neoplasm fromPten-deficient HSCs or myeloid progenitors. Therefore, the requirement of glucose oxidation for leukemia development is inherited from the normal cell of origin and occurs independently of the driver genetic lesion. PDH was not requiredin vivoto generate acetyl-CoA or maintain levels of TCA cycle metabolites but to prevent pyruvate accumulation and to maintain glutathione levels and redox homeostasis.