bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE MAJOR ROLE OF JUNCTIONAL DIVERSITY IN THE HORSE ANTIBODY REPERTOIRE
Authors: Navas Carlena , Manso Taciana , Martins Fabio , Minto Lucas , Moreira Rennan , Minozzo João , Antunes Bruno , Vale André , McDaniel Jonathan R. , Ippolito Gregory C. , Felicori Liza F. 
Published: June 2022

AbstractThe sequencing of the antibody repertoire (Rep-seq) revolutionized the diversity of antigen B cell receptor studies, allowing deep and quantitative analysis to decipher the role of adaptive immunity in health and disease. Particularly, horse (Equus caballus) polyclonal antibodies have been produced and used since the century XIX to treat and prophylaxis of diphtheria, tuberculosis, tetanus, pneumonia, and, more recently, COVID-19. However, our knowledge about the horse B cell receptors repertories is minimal. We present a deep horse antibody heavy chain repertoire (IGH) characterization of non-immunized horses using HTS technology. In this study, we obtained a mean of 248,169 unique IgM clones and 66,141 unique IgG clones from four domestic adult horses. Rarefaction analysis showed sequence coverage was between 52 and 82% in IgM and IgG isotypes. We observed that besides horses antibody can use all of the functional IGHV genes, around 80% of their antibodies use only three IGHV gene segments, and around 55% use only one IGHJ gene segment. This limited VJ diversity seems to be compensated by the junctional diversity of these antibodies. We observed that the junctional diversity in horses antibodies is highly frequent, present in more than 90% of horse antibodies. Besides this, the length of this region seems to be higher in horse antibodies than in other species. N1 and N2 nucleotides addition range from 0 to 111 nucleotides. In addition, around 45% of the antibody clones have more than ten nucleotides in both N1 and N2 junction regions. This diversity mechanism may be one of the most important in providing variability to the equine antibody repertoire. This study provides new insights regarding horse antibody composition, diversity generation, and particularities compared to other species, such as the frequency and length of N nucleotide addition. This study also points out the urgent need to better characterize TdT in horses and in other species to better understand antibody repertoire characteristics.
Spatial Atlas of the Mouse Central Nervous System at Molecular Resolution
Authors: Shi Hailing , He Yichun , Zhou Yiming , Huang Jiahao , Wang Brandon , Tang Zefang , Tan Peng , Wu Morgan , Lin Zuwan , Ren Jingyi , Thapa Yaman , Tang Xin , Liu Albert , Liu Jia , Wang Xiao 
Published: June 2022

AbstractSpatially charting molecular cell types at single-cell resolution across the three-dimensional (3D) volume of the brain is critical for illustrating the molecular basis of the brain anatomy and functions. Single-cell RNA sequencing (scRNA-seq) has profiled molecular cell types in the mouse brain1, 2, but cannot capture their spatial organization. Here, we employed an in situ sequencing technique, STARmap PLUS3, 4, to map more than one million high-quality cells across the whole adult mouse brain and the spinal cord, profiling 1,022 genes at subcellular resolution with a voxel size of 194 X 194 X 345 nm in 3D. We developed computational pipelines to segment, cluster, and annotate 231 molecularly defined cell types and 64 tissue regions with single-cell resolution. To create a transcriptome-wide spatial atlas, we further integrated the STARmap PLUS measurements with a published scRNA-seq atlas1, imputing 11,844 genes at the single-cell level. Finally, we engineered a highly expressed RNA barcoding system to delineate the tropism of a brain-wide transgene delivery tool, AAV-PHP.eB5, 6, revealing its single-cell resolved transduction efficiency across the molecular cell types and tissue regions of the whole mouse brain. Together, our datasets and annotations provide a comprehensive, high-resolution single-cell resource that integrates a spatial molecular atlas, cell taxonomy, brain anatomy, and genetic manipulation accessibility of the mammalian central nervous system (CNS).
Pre-Omicron vaccine breakthrough infection induces superior cross-neutralization against SARS-CoV-2 Omicron BA.1 than primo infection
Authors: Santos da Silva Eveline , Kohnen Michel , Gilson Georges , Staub Therese , Arendt Victor , Hilger Christiane , Servais Jean-Yves , Charpentier Emilie , Domingues Olivia , Snoeck Chantal J. , Ollert Markus , Seguin-Devaux Carole , Perez-Bercoff Danielle 
Published: June 2022

AbstractSARS-CoV-2 variants raise concern because of their high transmissibility and their ability to evade neutralizing antibodies elicited by prior infection or by vaccination. Here we compared the ability of sera from 70 unvaccinated COVID-19 patients infected before the emergence of variants of concern (VOCs) and from 16 vaccine breakthrough infection (BTI) cases infected with Gamma or Delta to neutralize the ancestral B.1 strain, and the Gamma, Delta and Omicron BA.1 variants using live virus. We further determined antibody levels against the Spike protein, the Receptor Binding Domain (RBD) and the N-terminal domain (NTD) of Spike. Convalescent sera featured considerable variability in neutralization of B.1 and in cross-neutralization of different strains, and neutralizing capacity moderately correlated with antibody levels against Spike and the RBD. All but one convalescent serum failed to neutralize Omicron BA.1. Overall, convalescent sera from patients with moderate disease had higher antibody levels and displayed higher neutralizing ability against all strains than patients with mild or severe forms of disease. Sera from BTI cases fell into one of two categories: half the sera had high neutralizing activity against the ancestral B.1 strain as well as against the infecting strain, while the other half had no or very low neutralizing activity against all strains. Although antibody levels against Spike and the RBD were lower in BTI cases than in unvaccinated convalescent sera, most neutralizing sera also retained partial neutralizing activity against Omicron BA.1, indicative of cross-neutralization between B.1, Delta and Omicron and suggestive of higher affinity, as confirmed by the IC50:Ab level ratios. Neutralizing activity of BTI sera was strongly correlated with antibodies against Spike and the RBD. Together, these findings highlight qualitative differences in antibody responses elicited by infection in vaccinated and unvaccinated individuals. They further suggest that breakthrough infection with a pre-Omicron variant boosts immunity and induces cross neutralizing antibodies against different strains, including Omicron BA.1.
Financial Incentives for Quitting Smoking in Pregnancy: Are they cost-effective?
Authors: McMeekin Nicola , Sinclair Lesley , Robinson-Smith Lyn , Mitchell Alex , Bauld Linda , Tappin David M , Boyd Kathleen A 
Published: June 2022

ABSTRACTAimsTo evaluate whether adding financial incentives to usual care is cost-effective in encouraging pregnant women to quit tobacco smoking, compared to usual care alone.DesignCost-effectiveness analysis (CEA) and cost-utility analysis (CUA) from a healthcare provider’s perspective, embedded in the Smoking Cessation in Pregnancy Incentives Trial (CPIT III). Long-term analyses were conducted from the same perspective, using an existing Markov model over a lifetime horizon.SettingSeven maternity smoking cessation sites in Scotland, England and Northern Ireland in the United Kingdom.ParticipantsIn the short-term analysis CPIT III participants were assessed: women 16 years or older, self-reporting as smokers, less than 24 weeks pregnant and English speaking (n=944). The same population was used for the lifetime analysis, plus their infants.MeasurementsCosts include financial incentive vouchers and postage, cessation support and nicotine replacement therapy and neonatal stays. The outcome measure was biochemically verified quit rate for the CEA and quality adjusted life-years (QALY) for CUA. Costs are presented in 2020 GBP sterling (£).Data for the lifetime analysis came from the trial and was combined with data from published literature embedded in the model, reporting incremental cost per quitter and QALY. A 3.5% discount rate was applied.FindingsThe short-term incremental cost per quitter was £4,400, uncertainty in QALY gains resulted in a cost per QALY of £150,000. Results of sensitivity analyses confirm these results. The long-term analysis combined costs and outcomes for mother and infants, results show a cost saving of £37 (-£35 to £106) and increase in QALYs of 0.171 (0.124 to 0.229). These findings indicate that, over a lifetime, financial incentives are cost saving and improve health outcomes.ConclusionsOffering up to £400 financial incentives, in addition to usual care, to support pregnant women to stop smoking is cost-effective over a lifetime for mother and infants.EthicsEthics approval received from NHS West of Scotland Research Ethics Committee-2, August 2017.Registration detailsTrial registration number: ISRCTN15236311, date registered 09/10/2017 https://doi.org/10.1186/ISRCTN15236311
Brain aerobic glycolysis and resilience in Alzheimer disease
Authors: Goyal Manu S. , Blazey Tyler , Metcalf Nicholas V. , McAvoy Mark P. , Strain Jeremy , Rahmani Maryam , Durbin Tony J. , Xiong Chengjie , Benzinger Tammie L.-S. , Morris John C. , Raichle Marcus E. , Vlassenko Andrei G. 
Published: June 2022

ABSTRACTThe distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aβ) deposition in individuals with dementia of the Alzheimer type (DAT) and asymptomatic individuals with brain amyloid deposition. Brain AG decreases with age but the functional significance of this decrease with regard to the development of DAT symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption and glucose utilization—from which we derive AG—we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in typical, cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results implicate preserved AG as a factor in brain resilience to amyloid pathology and suggest that white matter disease may be a cause and/or consequence of this impaired resilience.
Enhancement of mitochondrial function fosters B cell immune memory
Authors: Shukla Ashima , Tiwari Ashutosh , Saulnier Olivier , Hendrikse Liam , Hall Bryan , Rickert Robert , Taylor Michael D , Shukla Vipul , Bagchi Anindya 
Published: June 2022

AbstractDifferentiation of T and B cells to effector and memory cell fates are associated with extensive metabolic changes which are accompanied by altered mitochondrial dynamics. However, whether alterations in mitochondrial structure and function plays an active role in regulating effector versus memory cell fate decisions during immune responses remains unclear. Our studies here characterize changes in mitochondrial dynamics in activated B cells and show that increased mitochondrial mass and activity is a distinct feature of memory B cell lineage commitment in vivo. Using a directed screen of mitochondrial modulators, we identify mitochondrial fission inhibitor, Mdivi-1 as an agent that could enhance mitochondrial mass and function leading to augmented memory B cell differentiation. The enhanced memory B cell responses mediated by Mdivi-1, translated to more robust recall responses upon secondary antigen exposures. Moreover, Mdivi-1 when used in combination with subunit (SARS-CoV2) and inactivated (H1N1 influenza) vaccines led to remarkably improved vaccine efficacies and protection from lethal viral (H1N1) challenge. Single-cell transcriptomics revealed enhanced commitment to memory lineage differentiation in B cells following Mdivi-1 treatment. We propose that mitochondrial modulators such as Mdivi-1 are a novel class of “immune enhancers” that specifically reinforces immunological memory and could be broadly applied to improve the fidelity of immune responses and vaccine efficacies.
Rare genetic variants impact muscle strength
Authors: Huang Yunfeng , Bodnar Dora , Chen Chia-Yen , Gurria Gabi , Sanderson Mark ,   Biogen Biobank Team, Shi Jun , Meilleur Katherine G , Hurles Matthew E. , Gerety Sebastian S. , Tsai Ellen A. , Runz Heiko 
Published: June 2022

AbstractMuscle strength is highly heritable and predictive for multiple adverse health outcomes including mortality. Here, we present a rare protein-coding variant association study in 340,319 individuals for hand grip strength, a proxy measure of muscle strength. We identify six significant genes (KDM5B, OBSCN, GIGYF1, TTN, RB1CC1, EIF3J), propose shared mechanisms between brain and muscle function and demonstrate additive effects between rare and common genetic variation on muscle strength.
Neural Correlates of Remotely versus In-person Administered Symbol Digit Modalities Test in Multiple Sclerosis
Authors: Buyukturkoglu Korhan , Dworkin Jordan D. , Leiva Victor , Provenzano Frank A. , Guevara Pamela , De Jager Philip L. , Leavitt Victoria M. , Riley Claire S. 
Published: June 2022

AbstractBackgroundPrior studies in multiple sclerosis (MS) support reliability of telehealth-delivered cognitive batteries, although, to date, none have reported predictive external validity, i.e., relationships of cognitive test performance to neural correlates across administration modalities. In this study we aimed to compare brain-behavior relationships, using the Symbol Digit Modalities Test (SDMT), the most reliable and sensitive cognitive measure in MS, measured from patients seen via telehealth versus in-person.MethodsSDMT was administered to individuals with MS either in-person (N=60, mean age=39.7) or remotely via video conference (N=51, mean age=47.4). Magnetic resonance imaging (MRI) data was collected in 3-Tesla scanners. Using 3D-T1 images cerebral, cortical, deep gray, cerebral white matter and thalamic nuclei volumes were calculated. Using a meta-analysis approach with an interaction term for participant group, individual regression models were run for each MRI measure having SDMT as the outcome variable in each model. In addition, the correlation and average difference between In-person and Remote group effect sizes across the MRI measures were calculated. Finally, for each MRI variable I2score was quantified to test the heterogeneity between the groups.ResultsAdministration modality did not affect the association of SDMT with MRI measures. Brain tissue volumes showing high associations with the SDMT in one group also showed high associations in the other (r= 0.83; 95% CI = [0.07, 0.86]). The average difference between the In-person and the Remote group effect sizes was not significant (βRemote- βIn-person= 0.14, 95% CI = [-0.04, 0.34]). Across MRI measures, the average I2value was 14%, reflecting very little heterogeneity in the relationship of SDMT to brain volume.ConclusionWe found consistent relationships to neural correlates across in-person and remote SDMT administration modalities. Hence, our study can be considered a step towards providing predictive external validity to remote administration of the SDMT in MS.HighlightsSymbol Digit Modalities Test (SDMT) was administered to individuals with MS either in-person or remotely via video conference.Administration modality did not affect the association of SDMT with MRI measures.Brain tissue volumes showing high associations with the SDMT in one group also showed high associations in the other.The average difference between the In-person and the Remote group effect sizes was not significant.This study can be considered a step towards providing predictive external validity to remote administration of the SDMT in MS.
A novel workflow for the safe and effective integration of AI as supporting reader in double reading breast cancer screening: A large-scale retrospective evaluation
Authors: Ng Annie Y. , Glocker Ben , Oberije Cary , Fox Georgia , Nash Jonathan , Karpati Edith , Kerruish Sarah , Kecskemethy Peter D. 
Published: June 2022

AbstractObjectivesTo evaluate the effectiveness of a novel strategy for using AI as a supporting reader for the detection of breast cancer in mammography-based double reading screening practice. Instead of replacing a human reader, here AI serves as the second reader only if it agrees with the recall/no-recall decision of the first human reader. Otherwise, a second human reader makes an assessment, enacting standard human double reading.DesignRetrospective large-scale, multi-site, multi-device, evaluation study.Participants280,594 cases from 180,542 female participants who were screened for breast cancer with digital mammography between 2009 and 2019 at seven screening sites in two countries (UK and Hungary).Main outcome measuresPrimary outcome measures were cancer detection rate, recall rate, sensitivity, specificity, and positive predictive value. Secondary outcome was reduction in workload measured as arbitration rate and number of cases requiring second human reading.ResultsThe novel workflow was found to be superior or non-inferior on all screening metrics, almost halving arbitration and reducing the number of cases requiring second human reading by up to 87.50% compared to human double reading.ConclusionsAI as a supporting reader adds a safety net in case of AI discordance compared to alternative workflows where AI replaces the second human reader. In the simulation using large-scale historical data, the proposed workflow retains screening performance of the standard of care of human double reading while drastically reducing the workload. Further research should study the impact of the change in case mix for the second human reader as they would only assess cases where the AI and first human reader disagree.
Availability and readiness of healthcare facilities and their effects on under-five mortality in Bangladesh: Analysis of linked data
Authors: Khan Md. Nuruzzaman , Trisha Nahidha Islam , Rashid Md. Mamunur 
Published: June 2022

AbstractBackgroundUnder-five mortality is unacceptably high in Bangladesh instead of governmental level efforts to reduce its prevalence over the years. Increased availability and access to the healthcare services can play a significant role to reduce under-five mortality. We explored the associations of several forms of child mortality with health facility level factors adjusted for individual-, household-, and community level factors.MethodsThe 2017-18 Bangladesh Demographic and Health Survey data and 2017 Bangladesh Health Facility Survey data were linked and analysed. Our outcome variables were neonatal mortality, infant mortality, and under-five mortality. Health facility level factors were considered as major explanatory variables. They were the basic management and administrative system of the healthcare facility, availability of the child healthcare services at the nearest healthcare facility, readiness of the nearest healthcare facility to provide child healthcare services and the average distance of the nearest healthcare facility providing child healthcare services. The associations between the outcome variables and explanatory variables were determined using the multilevel mixed-effect logistic regression model.ResultsReported under-five, infant and neonatal mortality were 40, 27, and 22 per 10000 live births, respectively. The likelihood of neonatal mortality was found to be declined by 15% for every unit increase in the score of the basic management and administrative system of the mothers’ homes nearest healthcare facility where child healthcare services are available. Similarly, the availability and readiness of the mothers’ homes nearest healthcare facilities to provide child healthcare services were found to be linked with the 18-24% reduction in neonatal and infant mortality. On contrary, for every kilometre increased distance between mothers’ homes and their nearest healthcare facility was found to be associated with a 15-20% increase in the likelihoods of neonatal, infant and under-five mortality.ConclusionThe availability of health facilities providing child healthcare services close to residence and their improved management, infrastructure, and readiness to provide child healthcare services play a significant role in reducing under-five mortality in Bangladesh. Policies and programs should prioritize to increase the availability and accessibility of health facilities that provide child healthcare services.
COVID-19 vaccine booster strategies in light of emerging viral variants: Frequency, timing, and target groups
Authors: Kelly Sherrie L , Le Rutte Epke A , Richter Maximilian , Penny Melissa A , Shattock Andrew J 
Published: June 2022

AbstractBackgroundVaccinations have reduced severe burden of COVID-19 and allowed for lifting of non-pharmaceutical interventions. However, with immunity waning alongside emergence of more transmissible variants of concern, vaccination strategies must be examined.MethodsHere we apply a SARS-CoV-2 transmission model to identify preferred frequency, timing, and target groups for vaccine boosters to minimise public health burden and health systems risk. We estimated new infections and hospital admissions averted over two-years through annual or biannual boosting of those eligible (those who received doses one and two) who are 1) most vulnerable (60+ or persons with comorbidities) or 2) those 5+, at universal (98% of eligible) or lower coverage (85% of those 50+ or with comorbidities and 50% of 5−49-year-olds who are eligible) representing moderate vaccine fatigue and/or hesitancy. We simulated three emerging variant scenarios: 1) no new variants; 2) 25% more infectious and immune-evading, Omicron-level severity, variants emerge annually and become dominant; and 3) emerge biannually. We further explored the impact of varying seasonality, variant severity, timing, immune evasion, and infectivity, and vaccine infection blocking assumptions.ResultsTo minimise COVID-19-related hospitalisations over the next two years, boosters should be provided for all those eligible annually three-four months ahead of peak winter whether or not new variants of concern emerge. Only boosting those most vulnerable is unlikely to ensure reduced stress on health systems. Moreover, boosting all eligible protects those most vulnerable more than only boosting the vulnerable group. Conversely, more hospitalisations could be averted per booster dose through annual boosting of those most vulnerable versus all eligible, an indication of cost-effectiveness. Whereas increasing to biannual boosting showed diminishing returns. Results were robust when key model parameters were varied. However, we found that the more frequently variants emerge, the less the effect boosters will have, regardless of whether administered annually or biannually.ConclusionsWell-timed and targeted vaccine boosters preferencing vulnerable, and if possible, all those eligible to receive boosters, can minimise infections and hospital admissions. Findings provide model-based evidence for decision-makers to plan for administering COVID-19 boosters ahead of winter 2022−2023 to help mitigate the health burden and health system stress.