bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excess mortality associated with the COVID-19 pandemic (2020-2021) in an urban community of Bangladesh
Authors: Hossain Mohammad Sorowar , Khan Jahidur Rahman , Al Mamun SM Abdullah , Islam Mohammad Tariqul , Raheem Enayetur 
Published: November 2022

AbstractMeasurement of COVID-19-attributed mortality is vital for public health policy decisions. Unlike high-income countries, the magnitude of COVID-19-related mortality is largely unknown in many low- and middle-income countries due to inadequate COVID-19 testing capacity and a lack of robust civil registration and vital statistics systems. COVID-19-associated excess mortality was investigated in an urban setting in Bangladesh using a cemetery-based death registration dataset. A total of 6,271 deaths (3,790 male and 2,481 female) recorded between January 2015 and December 2021 were analyzed by using the Bayesian structural time series model (BSTS). During the pre-COVID-19 period, the average monthly number of deaths was 69, whereas, during the COVID-19 period, this number significantly increased to 92. Overall, according to model-based results, during COVID-19 period, the number of deaths increased on average by 17% (95% CrI: -18%, 57%): males 29% (95 % CrI: -15%, 75%) and 2.9% for females (95% CrI: -61%, 70%). This first-of-its-kind study in Bangladesh has revealed the excess mortality due to the COVID-19 pandemic (2020-2021) in an urban community. It appears that cemetery-based death registration could help track various crises (e.g., COVID-19), especially when collecting data on the ground is challenging for resource-limited countries.
Diagnosing early-onset neonatal sepsis in low-resource settings: development of a multivariable prediction model
Authors: Neal Samuel R. , Fitzgerald Felicity , Chimhuya Simbarashe , Heys Michelle , Cortina-Borja Mario , Chimhini Gwendoline 
Published: November 2022

ABSTRACTObjectiveTo develop a clinical prediction model to diagnose neonatal sepsis in low-resource settings.DesignSecondary analysis of data collected by the Neotree digital health system from 01/02/2019 to 31/03/2020. We used multivariable logistic regression with candidate predictors identified from expert opinion and literature review. Missing data were imputed using multivariate imputation and model performance was evaluated in the derivation cohort.SettingA tertiary neonatal unit at Sally Mugabe Central Hospital, Zimbabwe.PatientsWe included 2628 neonates aged <72 hours, gestation ≥ 32+0weeks and birth weight ≥ 1500 grams.InterventionsParticipants received standard care as no specific interventions were dictated by the study protocol.Main outcome measuresClinical early-onset neonatal sepsis (within the first 72 hours of life), defined by the treating consultant neonatologist.ResultsClinical early-onset sepsis was diagnosed in 297 neonates (11.3%). The optimal model included eight predictors: maternal fever, offensive liquor, prolonged rupture of membranes, neonatal temperature, respiratory rate, activity, chest retractions and grunting. Receiver operating characteristic analysis gave an area under the curve of 0.736 (95% confidence interval 0.701-0.772). For a sensitivity of 95% (92-97%), corresponding specificity was 11% (10-13%), positive predictive value 12% (11-13%), negative predictive value 95% (92-97%), positive likelihood ratio 1.1 (95% CI 1.0-1.1), and negative likelihood ratio 0.4 (95% CI 0.3-0.6).ConclusionsOur clinical prediction model achieved high sensitivity with modest specificity, suggesting it may be suited to excluding early-onset sepsis. Future work will validate and refine this model before considering it for clinical use within the Neotree.What is already known on this topicVarious clinical prediction models exist to diagnose neonatal sepsis. However, there is a paucity of literature on models in low-resource settings, particularly sub-Saharan Africa.What this study addsWe developed a clinical prediction model to diagnose clinical early-onset neonatal sepsis with over 2,500 neonates in a lower middle-income, low-resource neonatal unit. Our model is easy to implement, does not require laboratory tests and achieved high sensitivity with modest specificity in the derivation cohort.How this study might affect research, practice or policyOur model could support less experienced healthcare professionals avoid unnecessary antibiotic therapy in the absence of immediate local senior support. Before implementation, this model must be externally validated and its impact on sepsis-related neonatal morbidity and mortality must be assessed in future studies.
Quantifying the causal impact of biological risk factors on healthcare costs
Authors: Lee Jiwoo , Jukarainen Sakari , Dixon Padraig , Davies Neil M , Smith George Davey , Natarajan Pradeep , Ganna Andrea 
Published: November 2022

AbstractBackgroundA critical step in evaluating healthcare interventions is to understand their impact on healthcare costs. However, there is a limited understanding of the causal impact that biomarkers and risk factors for disease have on healthcare-related costs. Previous studies based on observational data have major limitations including residual confounding and reverse causation. Here, we used a genetically-informed design, Mendelian Randomization (MR), to infer the causal impact of 15 routinely measured and clinically relevant risk factors on annual total healthcare costs.MethodsWe considered 373,160 participants from the FinnGen Study, which were linked to detailed healthcare costs covering inpatient, outpatient, and medication costs. Several MR approaches were used to assess the causal effects of 15 risk factors (e.g., waist circumference (WC), HDL cholesterol, vitamin D), with strong genetic bases on annual total healthcare costs, as well as stratified by service type, age, and sex. We further assessed the generalizability and robustness of our results by accounting for selection bias and by leveraging additional data from 323,774 individuals from the United Kingdom and Netherlands.ResultsRobust causal effects were observed for waist circumference (WC), adult body mass index, and systolic blood pressure, in which a one standard deviation increase in the risk factors corresponded to 22.78% [95% CI: 18.75, 26.95], 13.64% [10.26, 17.12], and 13.08% [8.84, 17.48] increased annual total healthcare costs, respectively. The relative effect of WC on annual total healthcare costs was consistent across age and sex and was not attenuated when accounting for increased risk of five major diseases: back pain, chronic ischemic heart disease, type 2 diabetes, chronic obstructive pulmonary disease, and stroke. A lack of causal effects was observed for some clinically relevant biomarkers, such as albumin, C-reactive protein, and vitamin D.ConclusionOur results indicated that increased WC is a major contributor to annual total healthcare costs and more attention should be given to WC screening, surveillance, and mitigation. On the contrary, several biomarkers relevant in clinical settings did not have a direct impact on annual total healthcare costs.
Catch-up Routine Immunization to Restore Childhood Immunization Coverage following COVID-induced Declines in Zamboanga Peninsula, Philippines
Authors: Punzalan Mary Germeyn D. 
Published: November 2022

AbstractDue to numerous waves of COVID-19 surge and a more focused government initiative to jump-start the COVID-19 vaccination in 2021, routine immunization was neglected in Zamboanga Peninsula, Philippines, ending the year with a fully-immunized coverage of only 59%. To address this, an intensified catch-up immunization campaign was conducted in April-June 2022 among children 0-23 months of age who missed their routine immunizations. A program case study is utilized to describe the catch-up immunization campaign conducted. The target for the catch-up immunization campaign was to vaccinate at least 80% of infants ages 0-23 months who missed any of their routine immunizations schedule. Online microplanning workshops and consultative meetings were conducted in preparation for the campaign. A record review was conducted from data from municipal and provincial health offices and then consolidated at the regional level. The coverage for all antigens at the regional level (all cities, and municipalities combined), was 49-60%, except for inactivated polio vaccine 2 (32%). In other words, approximately half of those children under 23 months who had missed doses got vaccinated during the catch-up vaccination activities. This was a relatively fair turnout of the campaign considering that the local government units are still transitioning to non-COVID health services. To address the immunization gap, the catch-up immunization campaign will continue to be conducted wherein local government unit health workers have already allotted one day every month to conduct house-to-house vaccination activity to track and vaccinate missed children.
Elevated circulating monocytes and monocyte activation in pulmonary post-acute sequelae of SARS-CoV-2 infection
Authors: Park Juwon , Dean Logan S , Jiyarom Boonyanudh , Gangcuangco Louie Mar , Shah Parthav , Awamura Thomas , Ching Lauren L. , Nerurkar Vivek R. , Chow Dominic C. , Igno Fritzie , Shikuma Cecilia M , Devendra Gehan 
Published: November 2022

AbstractBackgroundMonocytes and macrophages play a pivotal role in inflammation during acute SARS-CoV-2 infection. However, their contribution to the development of post-acute sequelae of SARS-CoV-2 infection (PASC) are not fully elucidated.MethodsA cross sectional study was conducted comparing plasma cytokine and monocyte levels among three groups: participants with pulmonary PASC (PPASC) with a reduced predicted diffusing capacity for carbon monoxide [DLCOc, <80%; (PG)]; fully recovered from SARS-CoV-2 with no residual symptoms (recovered group, RG); and negative for SARS-CoV-2 (negative group, NG). The expressions of cytokines were measured in plasma of study cohort by Luminex assay. The percentages and numbers of monocyte subsets (classical, intermediate, and non-classical monocytes) and monocyte activation (defined by CD169 expression) were analyzed using flow cytometry analysis of peripheral blood mononuclear cells.ResultsPlasma IL-1Ra levels were elevated but FGF levels were reduced in PG compared to NG. Circulating monocytes and three subsets were significantly higher in PG and RG compared to NG. PG and RG exhibited higher levels of CD169+monocyte counts and higher CD169 expression was detected in intermediate and non-classical monocytes from RG and PG than that found in NG. Further correlation analysis with CD169+monocyte subsets revealed that CD169+intermediate monocytes negatively correlated with DLCOc%, and CD169+non-classical monocytes positively correlated with IL-1α, IL-1β, MIP-1α, Eotaxin, and IFNγ.ConclusionThis study present evidence that COVID convalescents exhibit monocyte alteration beyond the acute COVID-19 infection period even in convalescents with no residual symptoms. These data provide further rational for determining the role of monocyte subsets in PPASC pathogenesis.
Oligosymptomatic long-term carriers of SARS-CoV-2 display impaired innate resistance and high Spike-specific neutralizing antibodies
Authors: Montes-Cobos Elena , Bastos Victoria C , Monteiro Clarice , de Freitas João CR , Fernandes Heiny DP , Constancio Clarice S , Rodrigues Danielle AS , Gama Andreza MDS , Vidal Vinicius M , Alves Leticia S , Zalcberg-Renault Laura , de Lira Guilherme S , Ota Victor A , Caloba Carolina , Conde Luciana , Leitão Isabela C , Tanuri Amilcar , Ferreira Orlando DC , Pereira Renata M , Vale André M , Castiñeiras Terezinha M , Kaiserlian Dominique , Echevarria-Lima Juliana , Bozza Marcelo T 
Published: November 2022

SummaryThe vast spectrum of clinical features of COVID-19 keeps challenging scientists and clinicians. Control of pathogen load (host resistance) and prevention of tissue damage (disease tolerance) are essential for the outcome of infectious diseases. Both low resistance and high disease tolerance might result in long-term viral persistence, but the underlying mechanisms remain unclear. Here, we studied the immune response of immunocompetent COVID-19 patients with prolonged SARS-CoV-2 infection by immunophenotyping, cytokine and serological analysis. Despite viral loads and symptoms comparable to regular mildly-symptomatic patients, long-term carriers displayed weaker systemic IFN-I responses and fewer circulating pDCs and NK cells at disease onset. Type 1 cytokines remained low, while type-3 cytokines were in turn enhanced. Interestingly, the plasma of these patients showed a higher spike-specific neutralization capacity. The identification of very early distinct immune responses in long-term carriers adds up to our understanding on essential host protective mechanisms to ensure tissue damage control despite prolonged viral infection.
The Neogene-Quaternary diversification trend in the shaping of modern Caribbean mangroves
Authors: Rull Valentí 
Published: November 2022

AbstractThis paper analyzes the diversification of the Neotropical mangrove flora from the Miocene to the present, using a fairly comprehensive database of 110 pollen records distributed across the whole Caribbean region. A Neogene-Quaternary diversification trend (NQDT) has been identified, characterized by an increase of 25 genera (~78%) with respect to the 7 already existing Paleogene representatives. Only two genera appeared during the Miocene and the maximum increases were observed in the Pliocene-Quaternary transition and the modernliving record. Half of the true-mangrove genera (Rhizophora, Pelliciera, Acrostichum) were already present before the Neogene and the others appeared gradually in the Oligo-Miocene (Crenea), the Early-Middle Miocene (Avicennia) and the Mio-Pliocene (Laguncularia). None of the extant associate mangrove genera were present during the Paleogene and all appeared in the Miocene (23 genera) or the Oligo-Miocene transition (3 genera), being the main responsible for the NQDT, in absolute numbers. No regional extinctions were recorded since the Miocene in the Caribbean mangroves, at the generic level. These observations should be complemented with further high-resolution quantitative studies aimed at finding potential causal relationships with climatic, eustatic and paleogeographical shifts.
Free Energy Differences from Molecular Simulations: Exact Confidence Intervals from Transition Counts
Authors: Kříž Pavel , Beránek Jan , Spiwok Vojtěch 
Published: November 2022

AbstractHere we demonstrate a method to estimate the errors of free energy differences calculated by molecular simulations. The widths of the confidence intervals can be calculated solely from temperature and the number of transitions between states. Accuracy better than ± 4.184 kJ/mol (1 kcal/mol) can be achieved by a simulation at 300 K with four forward and four reverse transitions. Markovianity of the process is a pre-requisite. For a two-state Markovian system, the confidence interval suggested below is exact (not only asymptotic or approximative), regardless the number of transitions.TOC Graphic
Novel mRNA vaccines encoding Monkeypox virus M1R and A35R protect mice from a lethal virus challenge
Authors: Hou Fujun , Zhang Yuntao , Liu Xiaohu , Murad Yanal , Xu Jiang , Yu Zhibin , Hua Xianwu , Song Yingying , Ding Jun , Huang Hongwei , Zhao Ronghua , Jia William , Yang Xiaoming 
Published: November 2022

AbstractThe outbreak of Monkeypox virus infection urgently need effective vaccines. However, the vaccines so far approved are all based on whole-virus, which raises safety concerns. MRNA vaccines has demonstrated its high efficacy and safety against SARS-Cov-2 infection. Here, we developed three mRNA vaccines encoding Monkeypox proteins M1R and A35R, including A35R-M1R fusions (VGPox1 and VGPox 2) and a combination of encapsulated full-length mRNAs for A35R and M1R (VGPox 3). All three vaccines induced anti-A35R total IgGs as early as day 7 following a single vaccination. However, only VGPox 1 and 2 produced anti-M1R total IgGs at early dates following vaccination while VGPox 3 did not show significant anti-M1R antibody till day 35. Similar results were also found in neutralizing antibodies and T cell immune response. However, all mRNA vaccine groups completely protected mice from a lethal dose virus challenge and effectively cleared virus in lungs. Collectively, our results indicate that the novel mRNA vaccines coding for a fusion protein of A35R and M1R had a better anti-virus immunity than co-expression of the two individual proteins. The mRNA vaccines are highly effective and can be an alternative to the current whole-virus vaccines to defend Monkeypox virus infection.
Split selectable marker mediated gene stacking in plants
Authors: Yuan Guoliang , Lu Haiwei , De Kuntal , Hassan Md Mahmudul , Muchero Wellington , Tuskan Gerald A. , Yang Xiaohan 
Published: November 2022

AbstractPlant synthetic biology and genetic engineering depend on the controlled expression of transgenes of interest, which relies heavily on the use ofAgrobacterium-mediated transformation. Here we establish a novel split selectable marker system using protein splicing elements called “inteins” forAgrobacterium-mediated co-transformation in plants. This method enables robust co-transformation inArabidopsisand poplar, providing a novel strategy for the simultaneous insertion of multiple genes into both herbaceous and woody plants.
Comparative Study of High-resolution LysB29(Nε-myristoyl) des(B30) Insulin Structures Display Novel Dynamic Causal Interrelations in Monomeric-Dimeric Motions
Authors: Ayan Esra , Destan Ebru , Kepceoğlu Abdullah , Ciftci Halilibrahim , Katı Ahmet , DeMirci Hasan 
Published: November 2022

AbstractThe treatment of insulin-dependent diabetes mellitus is characterized by artificial supplementation of pancreatic β-cell ability to regulate sugar levels in the blood. Even though various insulin analogs are crucial for reasonable glycemic control, understanding the dynamic mechanism of the insulin analogs may help to improve the best-protracted insulin analog to assist people with Type 1 Diabetes (T1D) to live comfortably while maintaining tight glycemic control. Here we present the high-resolution crystal structure of NN304, known as insulin detemir, to 1.7 Å resolution at cryogenic temperature. We computationally further investigated our crystal structure’s monomeric-dimeric conformation and dynamic profile by comparing it with a previously available detemir structure (PDB ID: 1XDA). Our structure (PDB ID: 8HGZ) obtained at elevated pH provides electrostatically triggered minor movements in the equilibrium between alternate conformational substates compared to the previous structure, suggesting it might induce an intermediate state in the dissociation pathway of the insulin detemir’s hexamer:dihexamer equilibrium. Supplemented with orientational cross-correlation analysis by Gaussian Network Model (GNM), this alternate oligomeric conformation offers the distinct cooperative motions originated by loose coupling of distant conformational substates of a protracted insulin analog that has not been previously observed.
Characterizing adjuvants’ effects at the murine immunoglobulin repertoire level
Authors: Feng Feng , Yuen Rachel , Wang Yumei , Hua Axin , Kepler Thomas B. , Wetzler Lee 
Published: November 2022

ABSTRACTHigh-throughput immunoglobulin sequencing (IgSeq) has been developed and applied to study the adaptive immune response extensively for more than a decade. However, generating large-scale, high-fidelity sequencing data is still challenging, and furthermore, not much has been done to characterize adjuvants’ effects at the repertoire level. Thus, we developed an improved library prep protocol and standardized the data analysis pipeline for accurate repertoire profiling. In addition, two metrics were implemented to assess repertoire clone properties. We then studied systemically the effects of two adjuvants, CpG and Alum, on the Ig heavy chain repertoire using the ovalbumin (OVA) challenged mouse model. Ig repertoires of different tissues (spleen and bone marrow) and isotypes (IgG and IgM) were examined and compared in terms of sequence mutation frequency, IGHV gene usage, CDR3 length, rescaled Hill numbers for clonal diversity, and clone selection strength. As a result, Ig repertoires of different tissues or isotypes exhibited distinguishable profiles at the non-immunized steady state. Adjuvanted immunizations further resulted in statistically significant alterations in Ig repertoire compared with PBS or OVA alone immunized groups. Lastly, we applied unsupervised machine learning techniques – multiple factor analysis and clustering – to identify Ig repertoire signatures in different compartments and under varying immunizations. We found that the IGH repertoires of distinct tissue-isotype compartments or under varying immunizations differed in unique sets of properties. Notably, Alum and CpG effects on the Ig repertoire exhibited different tissue and isotype preferences. The former led to increased diversity of abundant clones of both isotypes in BM only, and the latter promoted the selection of IgG clones only but in both tissues. The patterns of Ig repertoire changes likely reflected possible action mechanisms of these two adjuvants.
Large scale functional screen identifies genetic variants with splicing effects in modern and archaic humans
Authors: Rong Stephen , Neil Christopher R. , Maguire Samantha , Meremikwu Ijeoma C. , Meyerson Malcolm , Evans Ben J. , Fairbrother William G. 
Published: November 2022

AbstractHumans co-existed and interbred with other hominins which later became extinct. These archaic hominins are known to us only through fossil records and for two cases, genome sequences. Here we engineer Neanderthal and Denisovan sequences into thousands of artificial genes to reconstruct the pre-mRNA processing patterns of these extinct populations. Of the 5,224 alleles tested in this massively parallel splicing reporter assay (MaPSy), we report 969 exonic splicing mutations (ESMs) that correspond to differences in exon recognition between extant and extinct hominins. Using MaPSy splicing variants, predicted splicing variants, and splicing quantitative trait loci, we show that splice-disrupting variants experienced greater purifying selection in anatomically modern humans than in Neanderthals. Adaptively introgressed variants were enriched for moderate effect splicing variants, consistent with positive selection for alternative spliced alleles following introgression. As particularly compelling examples, we characterized a novel tissue-specific alternative splicing variant at the adaptively introgressed innate immunity geneTLR1, as well as a novel Neanderthal introgressed alternative splicing variant in the geneHSPG2that encodes perlecan. We further identified potentially pathogenic splicing variants found only in Neanderthals and Denisovans in genes related to sperm maturation and immunity. Finally, we found splicing variants that may contribute to variation among modern humans in total bilirubin, balding, hemoglobin levels, and lung capacity. Our findings provide novel insights into natural selection acting on splicing in human evolution and demonstrate how functional assays can be used to identify candidate causal variants underlying differences in gene regulation and phenotype.