bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal duration of antibiotic treatment for community-acquired pneumonia in adults: a systematic review and duration-effect meta-analysis
Authors: Furukawa Yuki , Luo Yan , Funada Satoshi , Onishi Akira , Ostinelli Edoardo G , Hamza Tasnim , Furukawa Toshi A , Kataoka Yuki 
Published: December 2021

ABSTRACTImportanceCommunity-acquired pneumonia (CAP) is a leading cause of morbidity and mortality globally. The optimal duration of antimicrobial therapy remains unclear and controversial.ObjectiveTo find the optimal treatment duration with antibiotics for CAP in adults.Data SourcesMEDLINE, Embase and CENTRAL from inception to present (25 August, 2021).Study SelectionAll randomized controlled trials comparing the same antibiotics used at the same daily dosage but for different durations for CAP in adults. We included any antibiotics, administered orally or intravenously. We included both outpatients and inpatients but not those admitted to intensive care unit.Data Extraction and SynthesisTwo review authors independently screened and extracted data. We conducted random-effects, one-stage duration-effect meta-analysis with restricted cubic splines. We tested the non-inferiority with the pre-specified non-inferiority margin of 10% examined against 10 days using intention-to-treat dataset.Main Outcomes and MeasuresThe primary outcome was clinical improvement at day 15 (range 7-45 days). Secondary outcomes were all-cause mortality, serious adverse events, and clinical improvement at day 30 (15-60 days). We calculated odds ratios.ResultsWe included 9 trials (2399 patients with a mean [SD] age of 61.2 [22.1]; 39% women). The duration-effect curve was monotonic with longer duration leading to lower probability of improvement, and the lower 95%CI curve was constantly above the prespecified non-inferiority margin throughout the examined duration. Harmful outcome curves indicated no association. The average percentage of clinical improvement rate at day 15 in the 10-day treatment arms was 68%. Using that average, we computed the absolute clinical improvement rates at the following durations: a 3-day treatment 75% (95%CI: 68 to 81%), 5-day treatment 72% (66 to 78%), and 7-day treatment 69% (61 to 76%).Conclusions and RelevanceShorter treatment duration probably achieves the optimal balance between efficacy and treatment burden for treating CAP in adults. However, the small number of included studies and the overall moderate to high risk of bias may compromise the certainty of the results. Further research focusing on the shorter duration range is required.RegistrationPROSPERO (CRD 42021273357).KEY POINTSQuestionWhat is the optimal treatment duration of antibiotics for community-acquired pneumonia (CAP) in adults.?FindingsThis systematic review and duration-effect meta-analysis of 9 trials with 2399 patients found that the shorter treatment duration (3-9 days) was likely to be non-inferior to the standard treatment duration (10 days) for CAP in adults if they achieved clinical stability.MeaningShorter antibiotic treatment duration probably achieves the optimal balance between efficacy and treatment burden for CAP in adults.
Neural networks for classification and image generation of aging in genetic syndromes
Authors: Duong Dat , Hu Ping , Tekendo-Ngongang Cedrik , Hanchard Suzanna Ledgister , Liu Simon , Solomon Benjamin D. , Waikel Rebekah L. 
Published: December 2021

AbstractIn medical genetics, one application of neural networks is the diagnosis of genetic diseases based on images of patient faces. While these applications have been validated in the literature with primarily pediatric subjects, it is not known whether these applications can accurately diagnose patients across a lifespan. We aimed to extend previous works to determine whether age plays a factor in facial diagnosis, as well as to explore other factors that may contribute to the overall diagnosis accuracy. To investigate this, we chose two relatively common conditions, Williams syndrome and 22q11.2 deletion syndrome. We built a neural network classifier trained on images of affected and unaffected individuals of different ages. Our classifier outperformed clinical geneticists at recognizing face images of these two conditions within each of the age groups (the performance varied between the age groups): (1) under 2 years old, (2) 2-9 years old, (3) 10-19 years old, (4) 20-34 years old, and (5) ≥35 years old. The overall accuracy improvement by our classifier over the clinical geneticists was 15.5% and 22.7% for Williams syndrome and 22q11.2 deletion syndrome, respectively. Additionally, comparison of saliency maps revealed that key facial features learned by the neural network differed slightly with respect to age. Finally, joint training real images with multiple different types of fake images created by a generative adversarial network showed up to 3.25% accuracy gain in classification accuracy.
Neutralizing Antibody Activity Against SARS-CoV-2 Variants in Gestational Age-Matched Mother-Infant Dyads
Authors: Matsui Yusuke , Li Lin , Prahl Mary , Cassidy Arianna G. , Ozarslan Nida , Golan Yarden , Gonzalez Veronica J. , Lin Christine Y. , Jigmeddagva Unurzul , Chidboy Megan A. , Montano Mauricio , Taha Taha Y. , Khalid Mir M. , Sreekumar Bharath , Hayashi Jennifer M. , Chen Pei-Yi , Kumar G. Renuka , Warrier Lakshmi , Wu Alan H.B. , Song Dongli , Jegatheesan Priya , Rai Daljeet S. , Govindaswami Balaji , Needens Jordan , Rincon Monica , Myatt Leslie , Asiodu Ifeyinwa V. , Flaherman Valerie J. , Afshar Yalda , Jacoby Vanessa L. , Murtha Amy P. , Robinson Joshua F. , Ott Melanie , Greene Warner C. , Gaw Stephanie L. 
Published: December 2021

AbstractPregnancy confers unique immune responses to infection and vaccination across gestation. To date, there is limited data comparing vaccine versus infection-induced nAb to COVID-19 variants in mothers during pregnancy. We analyzed paired maternal and cord plasma samples from 60 pregnant individuals. Thirty women vaccinated with mRNA vaccines were matched with 30 naturally infected women by gestational age of exposure. Neutralization activity against the five SARS-CoV-2 Spike sequences was measured by a SARS-CoV-2 pseudotyped Spike virion assay. Effective nAbs against SARS-CoV-2 were present in maternal and cord plasma after both infection and vaccination. Compared to wild type or Alpha variant Spike, these nAbs were less effective against the Kappa, Delta, and Mu Spike variants. Vaccination during the third trimester induced higher nAb levels at delivery than infection during the third trimester. In contrast, vaccine-induced nAb levels were lower at the time of delivery compared to infection during the first trimester. The transfer ratio (cord nAb level/maternal nAb level) was greatest in mothers vaccinated in the second trimester. SARS-CoV-2 vaccination or infection in pregnancy elicit effective nAbs with differing neutralization kinetics that is impacted by gestational time of exposure. Vaccine induced neutralizing activity was reduced against the Delta, Mu, and Kappa variants.Graphic abstract
SUMMIT: An integrative approach for better transcriptomic data imputation improves causal gene identification
Authors: Zhang Zichen , Bae Ye Eun , Bradley Jonathan R. , Wu Lang , Wu Chong 
Published: December 2021

AbstractGenes with moderate to low expression heritability may explain a large proportion of complex trait heritability, but these genes are insufficiently captured in transcriptome-wide association studies (TWAS) partly due to the relatively small available reference datasets for developing expression genetic prediction models to capture the moderate to low genetically regulated components of gene expression. Here, we introduce a new method, Summary-level Unified Method for Modeling Integrated Transcriptome (SUMMIT), to improve the expression prediction model accuracy and the power of TWAS by using a large expression quantitative trait loci (eQTL) summary-level dataset. We applied SUMMIT to the eQTL summary-level data provided by the eQTLGen consortium, which involve 31,684 blood samples from 37 cohorts. Through simulation studies and analyses of GWAS summary statistics for 24 complex traits, we show that SUMMIT substantially improves the accuracy of expression prediction in blood, successfully builds expression prediction models for genes with low expression heritability, and achieves higher statistical power than several benchmark methods. In the end, we conducted a case study of COVID-19 severity with SUMMIT and identified 11 likely causal genes associated with COVID-19 severity.
The minor spliceosome offers a therapeutically viable target for the treatment of a broad spectrum of cancers
Authors: Doggett Karen , Morgan Kimberly J , Mieruszynski Stephen , Williams Benjamin B , Olthof Anouk M , Garnham Alexandra L , Milevskiy Michael J G , Whitehead Lachlan , Coates Janine , Buchert Michael , O’Donoghue Robert JJ , Hall Thomas E , Gong Zhiyuan , Putoczki Tracy L , Ernst Matthias , Sutherland Kate D , Kanadia Rahul N , Heath Joan K 
Published: December 2021

AbstractMinor splicing is a second splicing system required for the correct expression of ∼700 human minor intron-containing genes (MIGs). Many MIGs are expressed in vigorously proliferating cells and are frequently dysregulated in cancer includingBRAF, ERK, JNKandp38. Minor splicing is carried out by the minor spliceosome which comprises several unique components, including a 65kDa protein encoded byRNPC3. We show thatRnpc3heterozygosity reduces tumour burden in a broad spectrum ofin vivocancer settings, without harming normal tissues. Using the collective power of zebrafish, mouse and human cancer models, we reveal a sequence of events connectingRnpc3deficiency and impaired splicing of MIGs to DNA damage and activation of a Tp53-dependent transcriptional program that restricts tumour burden by inducing cell cycle arrest and apoptosis. Interrogation of human liver and lung cancer transcriptomes curated in TCGA revealed that the expression of many of the genes encoding protein components of the minor spliceosome is upregulated in these cancers. This is accompanied by upregulation of the expression of MIGs that are enriched in cell cycle and DNA damage pathways. These findings suggest that cancer cells can invoke mechanisms to increase the efficiency of minor splicing to support their high proliferation rates. Finally, Kaplan Meier survival analysis shows that highly expressed MIGs are frequently associated with poor patient survival. Taken together, these results indicate that the minor spliceosome offers a therapeutically viable target for the treatment of a broad spectrum of cancers.
No evidence of paralogous loci or new bona fide microRNAs in telomere to telomere (T2T) genomic data
Authors: Patil Arun H. , Halushka Marc K. , Fromm Bastian 
Published: December 2021

AbstractThe telomere to telomere (T2T) genome project discovered and mapped ∼240 million additional base pairs of primarily telomeric and centromeric reads. Much of this sequence was comprised of satellite sequences and large segmental duplications. We evaluated the extent to which human bona fide microRNAs (miRNAs) may be found in additional paralogous genomic loci or if previously undescribed microRNAs are present in these newly sequenced regions of the human genome. New genomic regions of the T2T project spanning ∼240 million bp of sequence were obtained and evaluated by blastn for the human miRNAs contained in MirGeneDB2.0 (N=556) and miRBase (N = 1917) along with all species of MirGeneDB2.0 miRNAs (N=10,899). Additionally, bowtie was used to compare unmapped reads from >4,000 primary cell samples to the new T2T sequence. Based on sequence and structure, no bona fide miRNAs were identified. Ninety-seven miRNAs of questionable authenticity (frequently known repeat elements) were identified from the miRBase dataset across the newly described regions of the human genome. These 97 represent only 51 miRNA families due to paralogy of highly similar miRNAs such as 24 members of the hsa-mir-548 family. Altogether, this data strongly supports our having identified widely expressed bona fide miRNAs in the human genome and move us further toward the completion of human miRNA discovery.
Using ultraconserved elements to reconstruct the termite tree of life
Authors: Hellemans Simon , Wang Menglin , Hasegawa Nonno , Šobotník Jan , Scheffrahn Rudolf H. , Bourguignon Thomas 
Published: December 2021

AbstractThe phylogenetic history of termites has been investigated using mitochondrial genomes and transcriptomes. However, both sets of markers have specific limitations. Mitochondrial genomes represent a single genetic marker likely to yield phylogenetic trees presenting incongruences with species trees, and transcriptomes can only be obtained from well-preserved samples. In contrast, ultraconserved elements (UCEs) include a great many independent markers that can be retrieved from poorly preserved samples. Here, we designed termite-specific baits targeting 50,616 UCE loci. We tested our UCE bait set on 42 samples of termites and three samples of Cryptocercus, for which we generated low-coverage highly-fragmented genome assemblies and successfully extracted in silico between 3,426 to 42,860 non-duplicated UCEs per sample. Our maximum likelihood phylogenetic tree, reconstructed using the 5,934 UCE loci retrieved from upward of 75% of samples, was congruent with transcriptome-based phylogenies, demonstrating that our UCE bait set is reliable and phylogenetically informative. Combined with non-destructive DNA extraction protocols, our UCE bait set provides the tool needed to carry out a global taxonomic revision of termites based on poorly preserved specimens such as old museum samples. The Termite UCE database is maintained at: https://github.com/oist/TER-UCE-DB/.
Exploring selection bias in COVID-19 research: Simulations and prospective analyses of two UK cohort studies
Authors: Millard Louise AC , Fernández-Sanlés Alba , Carter Alice R , Hughes Rachael , Tilling Kate , Morris Tim P , Major-Smith Daniel , Griffith Gareth J , Clayton Gemma L , Kawabata Emily , Smith George Davey , Lawlor Deborah A , Borges Maria Carolina 
Published: December 2021

ABSTRACTBackgroundNon-random selection into analytic subsamples could introduce selection bias in observational studies of SARS-CoV-2 infection and COVID-19 severity (e.g. including only those have had a COVID-19 PCR test). We explored the potential presence and impact of selection in such studies using data from self-report questionnaires and national registries.MethodsUsing pre-pandemic data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (mean age=27.6 (standard deviation [SD]=0.5); 49% female) and UK Biobank (UKB) (mean age=56 (SD=8.1); 55% female) with data on SARS-CoV-2 infection and death-with-COVID-19 (UKB only), we investigated predictors of selection into COVID-19 analytic subsamples. We then conducted empirical analyses and simulations to explore the potential presence, direction, and magnitude of bias due to selection when estimating the association of body mass index (BMI) with SARS-CoV-2 infection and death-with-COVID-19.ResultsIn both ALSPAC and UKB a broad range of characteristics related to selection, sometimes in opposite directions. For example, more educated participants were more likely to have data on SARS-CoV-2 infection in ALSPAC, but less likely in UKB. We found bias in many simulated scenarios. For example, in one scenario based on UKB, we observed an expected odds ratio of 2.56 compared to a simulated true odds ratio of 3, per standard deviation higher BMI.ConclusionAnalyses using COVID-19 self-reported or national registry data may be biased due to selection. The magnitude and direction of this bias depends on the outcome definition, the true effect of the risk factor, and the assumed selection mechanism.Key messagesObservational studies assessing the association of risk factors with SARS-CoV-2 infection and COVID-19 severity may be biased due to non-random selection into the analytic sample.Researchers should carefully consider the extent that their results may be biased due to selection, and conduct sensitivity analyses and simulations to explore the robustness of their results. We provide code for these analyses that is applicable beyond COVID-19 research.
Functional brain network and trail making test changes after major surgery and delirium
Authors: van Montfort Simone JT , Ditzel Fienke L , Kant Ilse MJ , Aarts Ellen , Vernooij Lisette M , Spies Claudia D , Hendrikse Jeroen , Slooter Arjen JC , van Dellen Edwin 
Published: December 2021

AbstractBackgroundDelirium is a frequent complication of elective surgery in elderly patients, associated with an increased risk of long-term cognitive impairment and dementia. Disturbances in the functional brain network were previously reported during delirium. We hypothesized persisting alterations in functional brain networks three months after elective surgery in patients with postoperative delirium, and hypothesized that postoperative brain connectivity changes (irrespective of delirium) are related to cognitive decline.MethodsElderly patients (N=554) undergoing elective surgery underwent clinical assessments (including Trail Making Test B (TMT-B) and resting-state functional magnetic resonance imaging (rs-fMRI) before and three months after surgery. Delirium was assessed on the first seven postoperative days. After strict motion correction, rs-fMRI connectivity strength and network characteristics were calculated in 246 patients (130 patients underwent scans at both timepoints), of whom 38 (16%) developed postoperative delirium.ResultsRs-fMRI functional connectivity strength increased after surgery in the total study population (β=0.006, 95%CI=0.000–0.012, p=0.021), but decreased after postoperative delirium (β=-0.014, 95%CI=0.000–0.012, p=0.026). No difference in TMT-B scores was found at follow-up between patients with and without postoperative delirium. Patients who decreased in functional connectivity strength declined in TMT-B scores compared to the group that did not (β=11.04, 95%CI=0.85-21.2, p=0.034).ConclusionsDelirium was associated with decreased functional connectivity strength three months after the syndrome was clinically resolved, which implies that delirium has lasting impact on brain networks. Decreased connectivity strength was associated with statistically significant (but not necessarily clinically relevant) cognitive deterioration after major surgery, which was not specifically related to delirium.Summary statementDelirium was associated with decreased resting-state fMRI functional connectivity strength three months after the syndrome was clinically resolved. Irrespective of delirium, decreased connectivity strength after major surgery was associated with a statistically significant cognitive deterioration.
Increased risk of fungal infection detection in women using menstrual cups vs. tampons: a cross-sectional study
Authors: Tessandier Nicolas , Uysal Ilkay Başak , Elie Baptiste , Selinger Christian , Bernat Claire , Boué Vanina , Grasset Sophie , Groc Soraya , Kamiya Tsukushi , Rahmoun Massilva , Reyné Bastien , Bender Noemi , Bonneau Marine , Graf Christelle , Tribout Vincent , Foulongne Vincent , Ravel Jacques , Waterboer Tim , Hirtz Christophe , Bravo Ignacio G , Reynes Jacques , Segondy Michel , Murall Carmen Lia , Boulle Nathalie , Alizon Samuel 
Published: December 2021

AbstractObjectiveTo determine if the use of menstrual cups rather than tampons is associated with more or less health risk.DesignAnalysing biological, demographic, and behavioural data in a cohort of women who reported using mostly tampons (n = 81) or menstrual cups (n = 22).SettingA cross-sectional analysis using the inclusion data of a single centre longitudinal study.Population149 women from 18 to 25 years old living in the area of Montpellier (France) who reported having at least one new sexual partner over the last year.MethodsStatistical modelling (mainly binomial regression models and factor analyses of mixed data).Main Outcome MeasuresSelf-reported data from questionnaires (fungal infection, urinary tract infection, stress level) and biological data (HPV screening, vaginal microbiota profiling, circulating antibodies titration, and local cytokine concentrations).ResultsWe identify an increased risk of reporting fungal infections for women using menstrual cups over tampons. We do not detect significant differences in terms of vaginal microbiota composition or local cytokines expression profile but find that women fall into two different clusters in a factor analysis of mixed data depending on the type of menstrual product they use more (cups or tampons).ConclusionsThese results point to potential health risks in the use of menstrual cups and differences in local vaginal environments. In-depth studies are needed to better understand potential associations between menstrual product use and women’s health.FundingEuropean Research Council (EVOLPROOF, grant 648963)EthicsThe PAPCLEAR study ClinicalTrials.gov identifier is NCT02946346.Tweetable abstractA cross-sectional study finds a significant association between menstrual cup use and fungal infection risk.
Cerebrospinal fluid formation is controlled by membrane transporters to modulate intracranial pressure
Authors: Oernbo Eva K. , Steffensen Annette B. , Khamesi Pooya Razzaghi , Toft-Bertelsen Trine L. , Barbuskaite Dagne , Vilhardt Frederik , Gerkau Niklas J. , Tritsaris Katerina , Simonsen Anja H. , Lolansen Sara D. , Andreassen Søren N. , Hasselbalch Steen G. , Zeuthen Thomas , Rose Christine R. , Kurtcuoglu Vartan , MacAulay Nanna 
Published: December 2021

AbstractDisturbances in the brain fluid balance can lead to life-threatening elevation in the intracranial pressure (ICP), which represents a vast clinical challenge. Nevertheless, the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP. Here, we employed experimental rats to demonstrate low osmotic water permeability of the choroid plexus, lack of an osmotic gradient across this tissue, and robust CSF secretion against osmotic gradients. Together, these results illustrate that CSF secretion occurs independently of conventional osmosis, which challenges the existing assumption that CSF production is driven entirely by bulk osmotic forces across the CSF-secreting choroid plexus. Instead, we reveal that the choroidal Na+/K+/Cl− cotransporter NKCC1, Na+/HCO3− cotransporter NBCe2, and Na+/K+-ATPase are actively involved in CSF production and propose a molecular mode of water transport supporting CSF production in this secretory tissue. Further, we demonstrate that inhibition of NKCC1 directly reduces the ICP, illustrating that altered CSF secretion may be employed as a strategy to modulate ICP. These insights identify new promising therapeutic targets against brain pathologies associated with elevated ICP.
Generation of bright autobioluminescent bacteria by chromosomal integration of the improved lux operon ilux2
Authors: Gregor Carola 
Published: December 2021

AbstractThe bacterial bioluminescence system enables light production in living cells without an external luciferin. Due to its relatively low levels of light emission, many applications of bioluminescence imaging would benefit from an increase in brightness of this system. In this report a new approach of mutagenesis and screening of the involved proteins is described that is based on the identification of mutants with improved properties under rate-limiting reaction conditions. Multiple rounds of screening in Escherichia coli resulted in the operon ilux2 that contains 26 new mutations in the fatty acid reductase complex which provides the aldehyde substrate for the bioluminescence reaction. Chromosomal integration of ilux2 yielded an autonomously bioluminescent E. coli strain with 7-fold increased brightness compared to the previously described ilux operon. The ilux2 strain produces sufficient signal for the robust detection of individual cells and enables highly sensitive long-term imaging of bacterial propagation without a selection marker.