bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of biallelic mutations in MCM3AP and comprehensive literature analysis
Authors: Liu Chan , Xie Qingfeng , Hu Quan , Xiang Bingwu , Zhao Kaiyi , Chen Xiang , Zheng Feixia 
Published: August 2024

BackgroundMinichromosome maintenance complex component 3 associated protein (MCM3AP) is a gene in which mutations can result in autosomal recessive peripheral neuropathy with or without impaired intellectual development. The MCM3AP genotype-phenotype correlation and prognosis remain unclear. The aim of this study was to explore the genotype–phenotype correlations pertaining to MCM3AP.MethodsWhole-exome sequencing (WES) combined with copy number variation sequencing (CNV-seq) were performed on the genomic DNA isolated from a Chinese family, and Sanger sequencing, quantitative PCR and cDNA analyses were performed to examine the mutations. The retrospective study was conducted on 28 individuals with biallelic MCM3AP mutation-related diseases, including features such as mutations, motor development impairment, intellectual disability, weakness/atrophy, and cerebral magnetic resonance imaging abnormalities.ResultsSequencing identified novel compound heterozygous mutations in MCM3AP, namely, a paternal variant c.1_5426del (loss of exons 1–25) and a maternal splicing variant c.1858 + 3A&gt;G. Functional studies revealed that the variant c.1858 + 3A&gt;G resulted in the heterozygous deletion of exon 5, thereby affecting splicing functionality. Furthermore, the compound heterozygous mutation may affect the functionality of the protein domain. Retrospective analysis revealed different genotype–phenotype correlations for the pathogenic variants in biallelic MCM3AP: all individuals (100%) with mutations outside the Sac3 domain exhibited early-onset symptoms, motor developmental delays, and cognitive abnormalities, conversely, the proportions of individuals carrying mutations within the domain were 26.7% (motor delays) and 46.7% (cognitive abnormalities).ConclusionOur findings further expand the genetic mutation spectrum of biallelic MCM3AP and highlight the genotype-phenotype associations. Additionally, we elaborate on the importance of rehabilitation intervention.
Potential role of B- and NK-cells in the pathogenesis of pediatric aplastic anemia through deep phenotyping
Authors: Vissers Lotte T. W. , van Ostaijen-ten Dam Monique M. , Melsen Janine E. , van der Spek Yanna M. , Kemna Koen P. , Lankester Arjan C. , van der Burg Mirjam , Mohseny Alexander B. 
Published: August 2024

IntroductionPediatric patients with unexplained bone marrow failure (BMF) are often categorized as aplastic anemia (AA). Based on the accepted hypothesis of an auto-immune mechanism underlying AA, immune suppressive therapy (IST) might be effective. However, due to the lack of diagnostic tools to identify immune AA and prognostic markers to predict IST response together with the unequaled curative potential of hematopoietic stem cell transplantation (HSCT), most pediatric severe AA patients are momentarily treated by HSCT if available. Although several studies indicate oligoclonal T-cells with cytotoxic activities towards the hematopoietic stem cells, increasing evidence points towards defective inhibitory mechanisms failing to inhibit auto-reactive T-cells.MethodsWe aimed to investigate the role of NK- and B-cells in seven pediatric AA patients through a comprehensive analysis of paired bone marrow and peripheral blood samples with spectral flow cytometry in comparison to healthy age-matched bone marrow donors. ResultsWe observed a reduced absolute number of NK-cells in peripheral blood of AA patients with a skewed distribution towards CD56bright NK-cells in a subgroup of patients. The enriched CD56bright NK-cells had a lower expression of CD45RA and TIGIT and a higher expression of CD16, compared to healthy donors. Functional analysis revealed no differences in degranulation. However, IFN-γ production and perforin expression of NK-cells were reduced in the CD56bright-enriched patient group. The diminished NK-cell function in this subgroup might underly the auto-immunity. Importantly, NK-function of AA patients with reduced CD56bright NK-cells was comparable to healthy donors. Also, B-cell counts were lower in AA patients. Subset analysis revealed a trend towards reduction of transitional B-cells in both absolute and relative numbers compared to healthy controls. As these cells were previously hypothesized as regulatory cells in AA, decreased numbers might be involved in defective inhibition of auto-reactive T-cells. Interestingly, even in patients with normal distribution of precursor B-cells, the transitional compartment was reduced, indicating partial differentiation failure from immature to transitional B-cells or a selective loss. DiscussionOur findings provide a base for future studies to unravel the role of transitional B-cells and CD56bright NK-cells in larger cohorts of pediatric AA patients as diagnostic markers for immune AA and targets for therapeutic interventions.
Genetically predicted circulating concentrations of micronutrients and risk of autoimmune thyroiditis: a Mendelian randomized study
Authors: Qiu Rongliang , Sha Xuemei , Kuang Penghao , Chen Fangsen , Fu Jinbo 
Published: August 2024

BackgroundMicronutrients play pivotal roles in modulating various aspects of the immune response. However, the existing literature on the association between micronutrients and autoimmune thyroiditis (AIT) remains limited and contentious. To address this gap, we conducted Mendelian randomization (MR) to investigate potential links between genetically predicted concentrations of six micronutrients (Copper (Cu), Iron (Ir), Calcium (Ca), Vitamin D (VD), Vitamin C (VC), Zinc (Zn)) and the risk of AIT.MethodUtilizing summary statistics from genome-wide association studies (GWAS) in individuals of European descent, we employed MR methodologies to elucidate the interplay between micronutrients and AIT. Three distinct MR techniques were employed: Inverse Variance Weighted (IVW), MR-Egger regression, and Weighted Median Estimator (WME). Additionally, we evaluated outcome heterogeneity using Cochran’s Q statistic and assessed pleiotropy using the MR-Egger intercept.ResultIVW analysis revealed no substantial evidence supporting a significant impact of genetically predicted micronutrient concentrations on AIT risk (Cu: OR = 0.918, P = 0.875; Ir: OR = 0.653, P = 0.264; Ca: OR = 0.964, P = 0.906; VD: OR = 0.717, P = 0.378; VC: OR = 0.986, P = 0.875; Zn: OR = 0.789, P = 0.539). Cochran’s Q test for IVW indicated no notable heterogeneity. Moreover, the MR-Egger intercept method suggested the presence of horizontal pleiotropy between serum VC levels and AIT (MR-Egger intercept = −0.037, p = 0.026), while no such pleiotropy was observed for other micronutrients.ConclusionOur MR analysis does not support a causal relationship between genetically predicted concentrations of six micronutrients (Cu, Ir, Ca, VD, VC, and Zn) and the risk of AIT.
Immunogenicity and safety of different combinations involving a third booster dose of SARS-CoV-2 inactivated vaccine, inactivated quadrivalent influenza vaccine, and 23-valent pneumococcal polysaccharide vaccine in adults aged ≥60 years: a phase 4, randomized, open-label study
Authors: Bai Shuang , Zhou Shanshan , Zhang Junnan , Chen Weixin , Lv Min , Wang Jian , Zhang Ao , Wu Jiang , Zhao Wei 
Published: August 2024

BackgroundConcomitant administration of COVID-19, influenza, and pneumococcal vaccines could reduce the burden on healthcare systems. However, the immunogenicity and safety of various combinations of a third booster dose of SARS-CoV-2 inactivated vaccine (CoronaVac), inactivated quadrivalent influenza vaccine (IIV4), and 23-valent pneumococcal polysaccharide vaccine (PPV23), particularly in different age groups, is still unknown.MethodsA phase 4, randomized, open-label, controlled trial was conducted in Beijing, China. 636 healthy adults were divided into two age groups (18-59 and ≥60 years) and randomized equally into three groups: CoronaVac and IIV4 followed by PPV23; CoronaVac and PPV23 followed by IIV4; or CoronaVac followed by IIV4 and PPV23, with a 28-day interval between vaccinations. Immunogenicity was evaluated by measuring antibody titers, and safety was monitored. ClinicalTrials.gov Identifier: NCT05298800.ResultsCo-administration of a third dose of CoronaVac, IIV4, and PPV23 in any combination was safe. Among adults aged 18-59, co-administration with PPV23 maintained non-inferiority of antibody levels for CoronaVac and IIV4, despite a slight reduction in antibody responses. This reduction was not observed in participants ≥60 years. Furthermore, co-administration of IIV4 and PPV23 affected seroconversion rates for both vaccines.ConclusionsCo-administration of the third dose of SARS-CoV-2 inactivated vaccine with the influenza vaccine, followed by PPV23, may be optimal for adults aged 18-59. In adults ≥60, all vaccine combinations were immunogenic, suggesting a flexible vaccination approach. Since antibody measurements were taken 28 days post-vaccination, ongoing surveillance is essential to assess the longevity of the immune responses.
Comprehensive landscapes of the causal network between immunity and sarcopenia
Authors: Liu Mingchong , Wang Jiaming , Han Yi , Fu Xiao , Pan Yutao , Yang Chensong , Sun Guixin 
Published: August 2024

BackgroundInflammaging, an immune status characterized by a sustained increase in pro-inflammatory markers and a decline in anti-inflammatory mechanisms, is a critical risk factor in the development of sarcopenia. Landscapes of the causal relationships between immunity and sarcopenia are needed to understand the mechanism of sarcopenia and provide novel treatments comprehensively.MethodsWe used Mendelian Randomization (MR) as the basic method in this study. By setting immune proteins, immune cells, and sarcopenia as exposures and outcomes alternatively, and then combining them in different directions, we potentially estimated their causal relationships and directions and subsequently mapped the comprehensive causal landscape based on this information efficiently. To further understand the network, we developed a method based on rank-sums to integrate multiple algorithms and identify the key immune cells and proteins.ResultsMore than 1,000 causal relationships were identified between immune cell phenotypes, proteins, and sarcopenia traits (p &lt; 0.05), and the causal maps of these linkages were established. In the threshold of FDR &lt; 0.05, hundreds of causal linkages were still significant. The final comprehensive map included 13 immune cell phenotypes and 8 immune proteins. The star factors in the final map included EM CD8br %CD8br, EM DN (CD4- CD8-) %DN, SIRT2, and so on.ConclusionBy reading the landscapes in this study, we may not only find the factors and the pathways that have been reported and proven but also identify multiple novel immunity cell phenotypes and proteins with enriched upstream and downstream pathways.
Apramycin kills replicating and non-replicating Mycobacterium tuberculosis
Authors: Kaur Parvinder , V. K. Ramya , C. N. Naveenkumar , K. Bharathkumar , Singh Mayas , Hobbie Sven N. , Shandil Radha Krishan , Narayanan Shridhar 
Published: August 2024

IntroductionMycobacterium tuberculosis (Mtb) has the capability to dodge the immune system by escaping into alternate physiological forms by forming drug tolerant populations under the immune pressure in the host. New drugs are urgently needed to treat these non-replicating persisters. In the past, aminoglycoside antibiotics have played a pivotal role in TB chemotherapy.MethodsHere, we explored the therapeutic potential of a monosubstituted deoxystreptamine aminoglycoside, apramycin (APR) which is different in its chemical structure from the other clinically relevant aminoglycoside antibiotics that are all disubstituted, e.g., amikacin (AMI). We determined the APR MIC as 0.25-1 µg/ml for sensitive and multidrug-resistant Mtb (MDRTB), including amikacin (AMI) resistant strains.ResultsIn standard time-kill kinetic assays, the bactericidal activity of APR was similar to that of AMI demonstrating dose-dependent killing of planktonic Mtb. However, in biofilm and macrophage intracellular killing assays, APR appeared significantly more potent than AMI. Further, APR monotherapy was efficacious in a mouse chronic TB lung infection model (~0.92 log10 CFU/lung reduction). APR combination therapy with the current 1st line standard of care (SoC) antibiotic combination of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z) was found to be additive (HREZ=1.88 vs. HREZ-APR=2.78 log10CFU/lung reduction).DiscussionThe results indicate the potential of apramycin-based combinations for the treatment of human tuberculosis.
Degradation and life prediction of mechanical equipment based on multivariate stochastic process
Authors: Lin Chengwang 
Published: August 2024

IntroductionAccurately predicting the remaining mechanical equipment is of great significance for ensuring the safe operation of the equipment and improving economic efficiency.MethodsTo accurately assess the mechanical equipment degradation, predict its remaining useful life, and ensure efficient, stable, and safe operation, a degradation and life prediction model for mechanical equipment based on multivariate stochastic processes is studied. The study innovatively predicts the remaining life of mechanical equipment using multivariate stochastic processes, and facilitates the correlation analysis between performance indicators based on the characteristics of Copula functions.Results and discussionThe results showed that the Root Mean Squared Error value of the prediction results based on the trivariate Wiener process was 2.58, which decreased by 46.91% and 35.82% compared with the univariate and bivariate Wiener processes, respectively. The prediction value based on the trivariate gamma process was 3.49, which decreased by 44.95% and 40.54% compared with the univariate and bivariate gamma processes, respectively. In conclusion, the degradation and life prediction model with multivariate stochastic processes can effectively assess the mechanical equipment degradation and predict its remaining useful life. This provides an important reference for the maintenance and management of mechanical equipment, improving equipment efficiency and extend its service life.
Trends of drug expenditure in Taiwan National Health Insurance before and during COVID-19 pandemic
Authors: Wu Shu-I , Lee An-Sheng , Chung Ching-Hu 
Published: August 2024

BackgroundThe Taiwanese government adopted the National Health Insurance (NHI) system in March 1995. This study aimed to understand the difference in medication costs before (year 2019) and during the COVID-19 pandemic (2020–2021) among different hospitals for treating their patients.MethodsThe NHI claims database consisting of claims of prescription drugs for inpatients (IPD) and outpatients (OPD) in Taiwan was used to determine drug expenditure in different hospitals, particularly the top 10 prescription Anatomical Therapeutic Chemical (ATC) categories.ResultsIn medical centers, L01X (other antineoplastic agents) showed the highest drug expenditure, followed by L04A (immunosuppressants) and J05A (direct-acting antivirals). The drug expenditure pattern in regional hospitals was similar to that in medical centers, with L01X (other antineoplastic agents) showing the highest drug expenditure. L01X (other antineoplastic agents) also showed the highest drug expenditure in district hospitals, followed by N05A (antipsychotics) and A10B (blood glucose-lowering drugs, excluding insulin). In clinics, A10B (blood glucose-lowering drugs, excluding insulin) showed the highest drug expenditure. The total medication costs in 2021 were lower or similar to those in 2019. The use of systemic use anti-infectives decreased over time in OPDs among all hospita1 levels but increased in IPDs in medical centers and district hospitals. Furthermore, our analysis revealed that the trend in drug expenditure closely mirrored the trend in drug prescription volume for the highest annual sum cost item among the top 10 drug subgroups across different hospital levels.ConclusionOur analysis found that annual drug expenditures in 2021 were lower or similar to those in 2019, suggesting that the COVID-19 pandemic has contributed to this reduction in drug expenditure.
Quality improvement in neonatal care through enhanced patient safety and clinical risk management: a before-and-after study about neonatal sepsis
Authors: Ferorelli Davide , Goffredo Vito Maria , Graziano Elena , Mastrapasqua Maurizio , Telegrafo Michele , Vinci Annachiara , Visci Paolo , Benevento Marcello , Zotti Fiorenza , Foglianese Alessandra , Panza Raffaella , Solarino Biagio , Dell’Erba Alessandro , Laforgia Nicola 
Published: August 2024

IntroductionNeonatal sepsis, classified into early-onset and late-onset based on symptom timing, poses significant risks of morbidity and mortality, especially in low birth weight infants. Effective clinical risk management protocols are crucial in reducing these risks.MethodsThis before-and-after study evaluated the impact of a newly implemented clinical risk management protocol in the Neonatology and Neonatal Intensive Care Unit (NICU) at Policlinico Hospital-University of Bari. The study included 399 neonates over three years, comparing pre- and post-protocol outcomes. Data collection focused on maternal and neonatal demographics, infection rates, and hospital stay lengths. Statistical analysis included t-tests, Wilcoxon-Mann–Whitney tests, and logistic regression models.ResultsThe study found no significant differences in neonatal pathologies or demographics between pre- and post-protocol groups. However, post-protocol implementation showed a notable reduction in umbilical venous catheter (UVC) infections (p = 0.018) and improved hospital stay lengths. Blood and urine cultures did not show significant changes in microbial patterns post-protocol.DiscussionThe findings underscore the effectiveness of structured clinical risk management protocols in enhancing neonatal outcomes, particularly in reducing specific infection risks. Despite the study’s limitations, including its observational nature and sample size, the results advocate for broader adoption and further research on these protocols in diverse healthcare settings. The positive outcomes highlight the importance of continuous clinical risk management efforts in high-risk neonatal environments.
From intra- to extra-uterine: early phase design of a transfer to extra-uterine life support through medical simulation
Authors: van Haren J. S. , Delbressine F. L. M. , Monincx M. , Hoveling T. , Meijer N. , Bangaru C. , Sterk J. , van der Woude D. A. A. , Oei S. G. , van der Hout-van der Jagt M. B. 
Published: August 2024

IntroductionExtra-uterine life support technology could provide a more physiologic alternative for the treatment of extremely premature infants, as it allows further fetal growth and development ex utero. Animal studies have been carried out which involved placing fetuses in a liquid-filled incubator, with oxygen supplied through an oxygenator connected to the umbilical vessels. Hence, by delaying lung exposure to air, further lung development and maturation can take place. This medical intervention requires adjustments to current obstetric procedures to maintain liquid-filled lungs through a so-called transfer procedure.MethodsOur objective was to develop obstetric device prototypes that allow clinicians to simulate this birth procedure to safely transfer the infant from the mother's uterus to an extra-uterine life support system. To facilitate a user-centered design, implementation of medical simulation during early phase design of the prototype development was used. First, the requirements for the procedure and devices were established, by reviewing the literature and through interviewing direct stakeholders. The initial transfer device prototypes were tested on maternal and fetal manikins in participatory simulations with clinicians.Results &amp; discussionThrough analysis of recordings of the simulations, the prototypes were evaluated on effectiveness, safety and usability with latent conditions being identified and improved. This medical simulation-based design process resulted in the development of a set of surgical prototypes and allowed for knowledge building on obstetric care in an extra-uterine life support context.
Genetic prediction of blood metabolites mediating the relationship between gut microbiota and Alzheimer’s disease: a Mendelian randomization study
Authors: Chen Guanglei , Jin Yaxian , Chu Cancan , Zheng Yuhao , Chen Yunzhi , Zhu Xing 
Published: August 2024

BackgroundObservational studies have suggested an association between gut microbiota and Alzheimer’s disease (AD); however, the causal relationship remains unclear, and the role of blood metabolites in this association remains elusive.PurposeTo elucidate the causal relationship between gut microbiota and AD and to investigate whether blood metabolites serve as potential mediators.Materials and methodsUnivariable Mendelian randomization (UVMR) analysis was employed to assess the causal relationship between gut microbiota and AD, while multivariable MR (MVMR) was utilized to mitigate confounding factors. Subsequently, a two-step mediation MR approach was employed to explore the role of blood metabolites as potential mediators. We primarily utilized the inverse variance-weighted method to evaluate the causal relationship between exposure and outcome, and sensitivity analyses including Contamination mixture, Maximum-likelihood, Debiased inverse-variance weighted, MR-Egger, Bayesian Weighted Mendelian randomization, and MR pleiotropy residual sum and outlier were conducted to address pleiotropy.ResultsAfter adjustment for reverse causality and MVMR correction, class Actinobacteria (OR: 1.03, 95% CI: 1.01–1.06, p = 0.006), family Lactobacillaceae (OR: 1.03, 95% CI: 1.00–1.05, p = 0.017), genus Lachnoclostridium (OR: 1.03, 95% CI: 1.00–1.06, p = 0.019), genus Ruminiclostridium9 (OR: 0.97, 95% CI: 0.94–1.00, p = 0.027) and genus Ruminiclostridium6 (OR: 1.03, 95% CI: 1.01–1.05, p = 0.009) exhibited causal effects on AD. Moreover, 1-ribosyl-imidazoleacetate levels (−6.62%), Metabolonic lactone sulfate levels (2.90%), and Nonadecanoate (19:0) levels (−12.17%) mediated the total genetic predictive effects of class Actinobacteria on AD risk. Similarly, 2-stearoyl-GPE (18:0) levels (−9.87%), Octadecanedioylcarnitine (C18-DC) levels (4.44%), 1-(1-enyl-stearoyl)-2-oleoyl-GPE (p-18:0/18:1) levels (38.66%), and X-23639 levels (13.28%) respectively mediated the total genetic predictive effects of family Lactobacillaceae on AD risk. Furthermore, Hexadecanedioate (C16-DC) levels (5.45%) mediated the total genetic predictive effects of genus Ruminiclostridium 6 on AD risk; Indole-3-carboxylate levels (13.91%), X-13431 levels (7.08%), Alpha-ketoglutarate to succinate ratio (−13.91%), 3-phosphoglycerate to glycerate ratio (15.27%), and Succinate to proline ratio (−14.64%) respectively mediated the total genetic predictive effects of genus Ruminiclostridium 9 on AD risk.ConclusionOur mediation MR analysis provides genetic evidence suggesting the potential mediating role of blood metabolites in the causal relationship between gut microbiota and AD. Further large-scale randomized controlled trials are warranted to validate the role of blood metabolites in the specific mechanisms by which gut microbiota influence AD.