bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trends in severe acute malnutrition admissions, characteristics, and treatment outcomes in Malawi from 2011 through 2019
Authors: Daniel Allison I. , Kathumba Sylvester , Mitambo Collins , Chasweka Dennis , Voskuijl Wieger , Kamanga Esther , Mbale Emmie , Bandsma Robert H.J. , Potani Isabel 
Published: June 2022

AbstractBackgroundCommunity-based Management of Acute Malnutrition (CMAM) has been successfully implemented across Malawi, yet trends in admissions, characteristics, and treatment outcomes in children with severe acute malnutrition (SAM) have not been examined. The objective was therefore to investigate trends in admissions, characteristics including percentage of children with SAM with HIV and oedema, and treatment outcomes across the decade following implementation of CMAM.MethodsThis research involved a retrospective analysis of existing data routinely collected across Malawi by the Ministry of Health between 2011 and 2019.ResultsThese data showed an increase in outpatient therapeutic feeding (OTP) admissions from 30323 children in 2011 to 37655 in 2019 (p=0.045). However, a significant decrease in nutritional rehabilitation unit (NRU) admissions was observed, from 11389 annual admissions in 2011 to 6271 in 2019 (p=0.006). In children identified with SAM, the percentage with oedema decreased in OTPs with an average annual rate of reduction (AARR) of 5.6% (p=0.001) and by 26.2% in NRUs in this timeframe with an AARR of 8.5% (p<0.001). There was a decrease in the percentage of children with SAM who had HIV over time in OTPs with an AARR of 16.1% (p=0.001). HIV rates also decreased in NRUs with an AARR of 7.2% (p=0.4), but this difference was not significant. Death rates decreased in OTPs with an AARR of 6.0% (p=0.01). Mortality rates did not change in NRUs over time with an AARR of 0.9% (p=0.5) with the NRU mortality rate in 2019 being 11.0%.ConclusionsThese trends indicate that there has been an increase in OTP admissions and a corresponding decrease in NRU admissions. There have been decreases in the percentage of children with oedematous SAM in OTPs and in NRUs and with HIV in OTPs. Children remain at high risk of mortality in NRUs.Competing interestsnone to declare
Change in Effectiveness of Sotrovimab for Preventing Hospitalization and Mortality in COVID-19 Outpatients During the Omicron Phase
Authors: Aggarwal Neil R. , Beaty Laurel E. , Bennett Tellen D. , Carlson Nichole E. , Ginde Adit A. 
Published: June 2022

ABSTRACTBackgroundSotrovimab, a neutralizing monoclonal antibody (mAb) treatment authorized for early symptomatic COVID-19 patients, was effective in preventing the progression of severe disease and mortality following SARS-CoV-2 Delta variant infection. It is not known whether sotrovimab is similarly effective for SARS-CoV-2 Omicron variant infection.MethodsObservational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from December 26, 2021 to March 10, 2022 (>96% Omicron BA.1 variant), using electronic health records from a statewide health system linked to state-level vaccine and mortality data. We used propensity matching to select up to 3 patients not receiving mAbs or other authorized antivirals for each patient who received outpatient sotrovimab treatment. The primary outcome was 28-day hospitalization; secondary outcomes included mortality. To evaluate change in sotrovimab effectiveness during the Omicron phase, we propensity matched sotrovimab-treated patients from Omicron to Delta (October 1-December 11, 2021) phases to each other and then to untreated controls with a treatment-variant interaction added to the logistic regression model.ResultsOf 30,247 patients with SARS-CoV-2 infection, we matched 1,542 receiving sotrovimab to 3,663 not receiving treatment. Compared to untreated patients, sotrovimab treatment was not associated with reduced odds of all-cause 28-day hospitalization (raw rate 2.5% versus 3.2%; adjusted OR 0.82, 95% CI 0.55, 1.19) or mortality (raw rate 0.1% versus 0.2%; adjusted OR 0.62, 95% CI 0.07, 2.78). In the combined analysis across Omicron and Delta phases, the observed treatment OR was higher during Omicron than during Delta (OR 0.85 vs. 0.39, respectively; interaction p=0.053)ConclusionReal-world evidence demonstrated sotrovimab was not associated with reduced hospitalization and all-cause 28-day mortality among COVID-19 outpatients during the Omicron BA.1 phase and attenuated compared to the Delta phaseSummaryReal-world evidence demonstrates that the neutralizing monoclonal antibody sotrovimab was not associated with lower 28-day hospitalization and mortality rates when administered to high-risk outpatients recently infected with SARS-CoV-2 during the Omicron variant phase, compared to a propensity-matched cohort of untreated outpatients.
How do Urban Factors Control the Severity of COVID-19?
Authors: Roxon Jacob , Dumont Marie-Sophie , Vilain Eric , Pellenq Roland J.M. 
Published: June 2022

AbstractHuman health in urban environment has emerged as a primary focus of sustainable development during the time of global pandemic caused by a severe acute respiratory syndrome due to the SARS-CoV-2 coronavirus, COVID-19. It has reshaped the world with the way our communities interact, people work, commute, and spend their leisure time. While different mitigation solutions for controlling COVID-19 virus transmission have already been established, global models that would explain and predict the impact of urban environments on the case fatality ratio CFR of COVID-19 (defined as the number of deaths divided by the number of cases over a time window) are missing. Here, with readily available data from public sources, we study the CFR of the coronavirus for 118 locations (city zip-codes, city boroughs, and cities) worldwide to identify the links between the CFR and outdoor, indoor and personal urban factors. We show that a probabilistic model, optimized on the sample of 20 districts from 4 major US cities, provides an accurate predictive tool for the CFR of COVID-19 regardless of the geographical location. When adjusted for the population, our model can be used to evaluate risk and severity of the disease at multi-geospatial scales worldwide ranging from zip-codes and neighborhoods to cities and countries for different waves of the pandemic. Our results suggest that although disease screening and vaccination policies to containment and lockdowns remain critical in controlling the spread of airborne diseases, urban factors such as population density, humidity, or order of buildings, should all be taken into consideration when identifying resources and planning targeted responses to mitigate the impact and severity of the viruses transmitted through air. We advocate the study of urban factors as a path towards facilitating timely deployment of targeted countermeasures and confinement strategies where sharing of personal information and availability of tests may be restricted or limited.
RNA-Seq-Pop: Exploiting the sequence in RNA-Seq - a Snakemake workflow reveals patterns of insecticide resistance in the malaria vector Anopheles gambiae
Authors: Nagi Sanjay C , Oruni Ambrose , Weetman David , Donnelly Martin J 
Published: June 2022

AbstractBackgroundWe provide a reproducible and scalable Snakemake workflow, called RNA-Seq-Pop, which provides end-to- end analysis of RNA-Seq data sets. The workflow allows the user to perform quality control, differential expression analyses, call genomic variants and generate a range of summary statistics. Additional options include the calculation of allele frequencies of variants of interest, summaries of genetic variation and population structure (in measures such as nucleotide diversity, Watterson’s θ, and PCA), and genome wide selection scans (Fst, PBS), together with clear visualisations. We demonstrate the utility of the workflow by investigating pyrethroid-resistance in selected strains of the major malaria mosquito, Anopheles gambiae. The workflow provides additional modules specifically for An. gambiae, including estimating recent ancestry and determining the karyotype of common chromosomal inversions.ResultsThe Busia lab-colony used for selections was collected in Busia, Uganda, in November 2018. We performed a comparative analysis of three groups: a parental G24 Busia strain; its deltamethrin-selected G28 offspring; and the susceptible reference strain Kisumu. Measures of genetic diversity reveal patterns consistent with that of laboratory colonisation and selection, with the parental Busia strain exhibiting the highest nucleotide diversity of 1.04·10-3, followed by the selected Busia offspring (7.1·10-4), and finally, Kisumu (6.2·10-4). Differential expression and variant analyses reveal that the selected Busia colony exhibits a number of distinct mechanisms of pyrethroid resistance, including the Vgsc-995S target-site mutation, upregulation of SAP genes, P450s, and a cluster of carboxylesterases. During deltamethrin selections, the 2La chromosomal inversion rose in frequency (from 33% to 86%), suggesting a link with pyrethroid resistance, which was previously observed in field samples from the same region. RNA-Seq-Pop analysis also reveals that the most widely-used insecticide-susceptible An. gambiae strain, Kisumu, appears to be a hybrid strain of An. gambiae and its sibling species An. coluzzii, which should be taken into consideration in future research.RNA-Seq-Pop is designed for ease of use, does not require programming skills and integrates the package manager Conda to ensure that all dependencies are automatically installed for the user. We anticipate that the workflow will provide a useful tool to facilitate reproducible, transcriptomic studies in An. gambiae and other taxa.
Machine learning-based classification of binary dynamic fluorescence signals reveals muscle stem cell fate transitions in response to pro-regenerative niche factors
Authors: Togninalli Matteo , Ho Andrew T.V. , Madl Christopher M. , Holbrook Colin A. , Wang Yu Xin , Magnusson Klas E.G. , Kirillova Anna , Chang Andrew , Blau Helen M. 
Published: June 2022

AbstractThe proper regulation of muscle stem cell (MuSC) fate by cues from the niche is essential for regeneration of skeletal muscle. How pro-regenerative niche factors control the dynamics of MuSC fate decisions remains unknown due to limitations of population-level endpoint assays. To address this knowledge gap, we developed a novel binary dynamic fluorescence time lapse imaging analysis (BDFA) approach that leverages machine learning classification strategies to track single cell fate decisions with high temporal resolution. Using two fluorescent reporters that read out maintenance of stemness and myogenic commitment, we constructed detailed lineage trees for individual MuSCs and their progeny, classifying each division event as symmetric self-renewing, asymmetric, or symmetric committed. Our analysis reveals that treatment with the lipid metabolite, prostaglandin E2 (PGE2), accelerates the rate of MuSC proliferation over time, while biasing division events toward symmetric self-renewal. In contrast, the IL6 family member, Oncostatin M (OSM) decreases the proliferation rate after the first generation, while blocking myogenic commitment. These insights into the dynamics of MuSC regulation by niche cues were uniquely enabled by our BDFA approach. We anticipate that similar binary live cell readouts derived from BDFA will markedly expand our understanding of how niche factors control tissue regeneration in real time.
A beary good genome: Haplotype-resolved, chromosome-level assembly of the brown bear (Ursus arctos)
Authors: Armstrong Ellie E. , Perry Blair W. , Huang Yongqing , Garimella Kiran V. , Jansen Heiko T. , Robbins Charles T. , Tucker Nathan R. , Kelley Joanna L. 
Published: June 2022

AbstractThe brown bear (Ursus arctos) is the second largest and most widespread extant terrestrial carnivore on Earth and has recently emerged as a medical model for human metabolic diseases. Here, we report a fully-phased chromosome-level assembly of a male North American brown bear built by combining Pacific Biosciences (PacBio) HiFi data and publicly available Hi-C data. The final genome size is 2.47 Gigabases (Gb) with a scaffold and contig N50 length of 70.08 and 43.94 Mb, respectively. BUSCO analysis revealed that 94.5% of single-copy orthologs from mammalia were present in the genome (the highest of any ursid genome to date). Repetitive elements accounted for 44.48% of the genome and a total of 20,480 protein coding genes were identified. Based on whole genome alignment, the brown bear is highly syntenic with the polar bear, and our phylogenetic analysis of 7,246 single-copy BUSCOs supports the currently proposed species tree for Ursidae. This highly contiguous genome assembly will support future research on both the evolutionary history of the bear family and the physiological mechanisms behind hibernation, the latter of which has broad medical implications.SignificanceBrown bears (Ursus arctos) are the most widespread, large terrestrial carnivore on the planet and represent an interesting example of speciation through hybridization, as well as a medical model for sedentary lifestyle-related disease. Although a previous genome for a brown bear has been published, the reported contig N50 was low (only ∼530 kb), despite being scaffolded into putative chromosomes. Genomes of this quality limit the accuracy of analyses which rely on long contiguous stretches of the genome to be assembled (such as with many demographic analyses) as well as attempts at connecting genotype to phenotype (such as in association analyses). In order to support studies on both the complex hybridization history of the brown bear and investigations into medically-relevant phenotypes, we generated a fully-phased, chromosome-level assembly from a male grizzly bear. The genome has a total size of 2.47 Gb and 90% of the genome is contained in 36 scaffolds, roughly corresponding to one autosome per scaffold. This high-quality genome will enable studies across a variety of disciplines, including conservation, evolution, and medicine.
Rapid, scalable, combinatorial genome engineering by Marker-less Enrichment and Recombination of Genetically Engineered loci (MERGE)
Authors: Abdullah Mudabir , Greco Brittany M. , Laurent Jon M. , Vandeloo Michelle , Marcotte Edward M. , Kachroo Aashiq H. 
Published: June 2022

AbstractLarge-scale genome engineering in yeast is feasible primarily due to prodigious homology-directed DNA repair (HDR), a plethora of genetic tools, and simple conversion between haploid and diploid forms. However, a major challenge to rationally building multi-gene processes in yeast arises due to the combinatorics of combining all of the individual edits into the same strain. Here, we present an approach for scalable, precise, multi-site genome editing that combines all edits into a single strain without the need for selection markers by using CRISPR-Cas9 and gene drives. First, we show that engineered loci become resistant to the corresponding CRISPR reagent, allowing the enrichment of distinct genotypes. Next, we demonstrate a highly efficient gene drive that selectively eliminates specific loci by integrating CRISPR-Cas9 mediated Double-Strand Break (DSB) generation and homology-directed recombination with yeast sexual assortment. The method enables Marker-less Enrichment and Recombination of Genetically Engineered loci (MERGE) in yeast. We show that MERGE converts single heterologous yeast loci to homozygous loci at ∼100% efficiency, independent of chromosomal location. Furthermore, MERGE is equally efficient at converting and combining loci, thus identifying viable intermediate genotypes. Finally, we establish the feasibility of MERGE by engineering a fungal carotenoid biosynthesis pathway and most of the human α proteasome core into yeast. MERGE, therefore, lays the foundation for marker-less, highly efficient, and scalable combinatorial genome editing in yeast.
Discovery of a broadly-neutralizing human antibody that can rescue mice challenged with neurotoxin-rich snake venoms
Authors: Ledsgaard Line , Wade Jack , Boddum Kim , Oganesyan Irina , Harrison Julian , Jenkins Timothy P. , Villar Pedro , Leah Rachael A. , Zenobi Renato , McCafferty John , Lomonte Bruno , Gutiérrez José M. , Laustsen Andreas H. , Karatt-Vellatt Aneesh 
Published: June 2022

AbstractSnakebite envenoming continues to claim many lives across the globe, necessitating the development of improved therapies. To this end, human monoclonal antibodies may possess advantages over current plasma-derived antivenoms by offering superior safety and improved neutralization capacity. However, as new antivenom products may need to be polyvalent, i.e., target multiple different snake species, without dramatically increasing dose or cost of manufacture, such monoclonal antibodies need to be broadly-neutralizing. Here, we report the establishment of a pipeline for the discovery of high affinity broadly-neutralizing human monoclonal antibodies. We further demonstrate its utility by discovering an antibody that can prevent lethality induced by N. kaouthia whole venom at an unprecedented low molar ratio of one antibody per toxin, and which also prolongs survival of mice injected with Dendroaspis polylepis or Ophiophagus hannah whole venoms.
ReachingBot: an automated and scalable benchtop device for highly parallel Single Pellet Reach-and-Grasp training and assessment in mice
Authors: Kakanos Sotiris G. , Gadiagellan Dhireshan , Kim Eugene , Cash Diana , Moon Lawrence D. F. 
Published: June 2022

AbstractThe single pellet reaching and grasp (SPRG) task is a behavioural assay widely used to study motor learning, control and recovery after nervous system injury in animals. The manual training and assessment of the SPRG is labour intensive and time consuming and has led to the development of multiple devices which automate the SPRG task. Current state-of-the-art desktop methods either still require attendance, manual classification of trial outcome, or expensive locally-installed hardware such as graphical processing units (GPUs). Here, using robotics, computer vision, and machine learning analysis of videos, we describe a novel cost-effective benchtop device that can be left unattended, presents pellets to mice automatically, video records each trial, and, using two supervised learning algorithms, classifies the outcome of each trial automatically with an accuracy of greater than 94% without the use of GPUs. Finally, the device is simple in design with few components meaning manufacturing at scale is straightforward and, with few moving parts, reliable and robust. Our devices can also be operated using our cross-platform Graphical User Interface (GUI), meaning no knowledge of programming is required by its users.We show that these devices can train 30 mice with them collectively performing ~83,000 trials over 3 months, saving users an estimated 8 and half hours of labour per day. Over five weeks, most mice undertook more trials per session and retrieved more pellets successfully. 21 out of 30 mice retrieved at least 40% of pellets successfully in at least one session during the training period. Devices measured motor deficits induced in mice by a focal ischaemic stroke; some mice showed large persistent deficits whilst others showed only transient deficits. This highlights the heterogeneity in reaching outcomes following stroke. We conjecture that reach-and-grasp is represented in motor cortex bilaterally but with greater asymmetry in some mice than in others. We predict that bilateral lesions of motor cortex would cause long-lasting deficits in reach-and-grasp in mice.We propose a strategy for preclinical evaluation of novel therapeutics that improve reach-and-grasp by pre-screening a large cohort of mice automatically and excluding those that fail to achieve pre-specific success rates, which generates a cohort of mice trained with consistent performance levels, suitable for randomization to treatment arms in a preclinical study. Well-powered sample sizes are easily achievable. Highly parallel automated training and assessment should accelerate the development of new therapies for movement disorders.
Identification of essential modules regulating T cell migration to the central nervous system in multiple sclerosis
Authors: Kendirli Arek , de la Rosa Clara , Lämmle Katrin F. , Eglseer Klara , Bauer Isabel J. , Kavaka Vladyslav , Winklmeier Stephan , Wichmann Christian , Gerdes Lisa-Ann , Kümpfel Tania , Dornmair Klaus , Beltrán Eduardo , Kerschensteiner Martin , Kawakami Naoto 
Published: June 2022

SUMMARYMultiple sclerosis (MS) is a neuroinflammatory disease initiated by the infiltration of autoreactive T cells into the central nervous system (CNS). Several molecules that modulate T cell CNS infiltration in MS have been identified, but how the components of cell adhesion, migration and signalling pathways interact to execute this fundamental step in MS pathogenesis is unknown. We conducted a genome-wide in vivo CRISPR screen in an experimental autoimmune encephalomyelitis model of MS and identified 18 essential facilitators of T cell migration that include known targets of MS therapies. Combining in vitro studies with in vivo cell transfer and multiphoton microscopy enabled us to reveal three functional modules, centred around the adhesion molecule α4-integrin, the chemokine receptor CXCR3, and the GRK2 kinase, that are required for the migration of autoreactive CD4+ T cells into the CNS. Single-cell analysis of T cells from patients with MS confirmed that the expression of the essential regulators correlates with the propensity of CD4+ T cells to reach the CNS. Taken together, our data reveal the identity and functions of key modules that govern the critical step in the induction of MS lesions.
Fidelity of and biases in the developmental acquisition of song tempo in a songbird
Authors: James Logan S. , Wang Angela S. , Sakata Jon T. 
Published: June 2022

ABSTRACTThe temporal organization of sounds used in social contexts can provide information about signal function and evoke varying responses in listeners (receivers). For example, music is a universal and learned human behavior that is characterized by different rhythms and tempos that can evoke disparate responses in listeners. Similarly, birdsong is a ubiquitous social behavior in birds that is learned during critical periods in development and used to evoke physiological and behavioral responses in listeners. Recent investigations have begun to reveal the breadth of universal patterns in birdsong and their similarity to common patterns in speech and music, but relatively little is known about the degree to which biological predispositions and developmental experiences interact to shape the temporal patterning of birdsong. Here, we investigated how biological predispositions modulate the acquisition and production of an important temporal feature of birdsong, namely the duration of silent intervals (“gaps”) between vocal elements (“syllables”). Through analyses of semi-naturally raised and experimentally tutored zebra finches, we observed that juvenile zebra finches imitate the durations of the silent gaps in their tutor’s song with high fidelity and can “alter” the durations of gaps toward a central duration. When juveniles were experimentally tutored with stimuli containing a wide range of gap durations, we observed biases in the stereotypy but not in the central tendency of gap durations. Together, these studies demonstrate how biological predispositions and developmental experiences differently affect distinct temporal features of birdsong and highlight similarities in developmental plasticity across birdsong, speech, and music.