bluuebunny/crossref_metadata_2025_split huggingface dataset:
Timing of anti–PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma
Authors: Hirayama Alexandre V. , Kimble Erik L. , Wright Jocelyn H. , Fiorenza Salvatore , Gauthier Jordan , Voutsinas Jenna M. , Wu Qian , Yeung Cecilia C. S. , Gazeau Nicolas , Pender Barbara S. , Kirchmeier Delaney R. , Torkelson Aiko , Chutnik Abigail N. , Cassaday Ryan D. , Chapuis Aude G. , Green Damian J. , Kiem Hans-Peter , Milano Filippo , Shadman Mazyar , Till Brian G. , Riddell Stanley R. , Maloney David G. , Turtle Cameron J. 
Published: October 2023

Abstract
More than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly due to PD-1/PD-L1–associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti–PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell–associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome and inferior efficacy, which was associated with slower accumulation of CAR T cells and lower concentrations of inflammatory cytokines in the blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR T-cell accumulation in the blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR T-cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR T-cell kinetics early after infusion, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR T cells in the blood, late regression of CD19+ and CD19– tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR T-cell immunotherapy for adults with LBCL.
Prevalence and factors associated with immunization coverage among children under five years in Mohamed Mooge health center, Hargeisa, Somaliland: a cross-sectional study
Authors: Abdilahi Mohamed Mussa , Mohamed Ahmed Ismail , Jonah Kiruja M. , Ismail Abdisamad Shukri 
Published: October 2023

Abstract
Background
Routine immunization contributes greatly to reduction in mortality from vaccine preventable diseases among children. The Somaliland Demographic and Health survey, 2020 revealed that only 13.7% of children in Marodijeh (Hargeisa) region had received all recommended vaccines, which is far below the World Health Organization (WHO) target of 80%. We therefore, assessed factors associated with immunization coverage among children under five years at Mohamed Mooge Health Center in Hargeisa, Somaliland.

Methods
Institutional based cross-sectional study was conducted on 174 systematically sampled, consented mothers that visited Mohamed Mooge Health Center for antenatal care during December 2022 to May 2023. Data was collected using a structured questionnaire. Data was analysed using SPSS and the relationship between dependent and independent variables was checked chi-square test at p ≤ 0.05. Finally, candidate variables were tested by using multivariate logistic regression in order to control potential confounders and the result was presented using AOR and 95% confidence interval. Model fitness was checked using Hosmer-Lemeshaw goodness of fit test with P > 0.05 for fitness. Multicollinearity between variables was checked using correlation coefficients at 0.80 or higher.

Result
Among 174 study participants, the prevalence of overall vaccine completion in this study was 55.3%. Women who had being aware about childhood immunization on BCG vaccination (AOR = 3.887; 95% CI: 1.275, 6.844), pentavalent (AOR = 11.385; 95% CI: 5.424–14.464), and measles (AOR = 3.074; 95% CI: 1.822–6.130) had higher odds of having immunized their children. Mothers who had employment had higher odds of having their children immunized against measles (AOR = 4.069; 95% CI: 1.822–6.130) compared to those who had not.

Conclusions
Full immunization coverage was lower than the target set by the World Health Organization in this study area. The current study revealed that, the mother’s awareness of childhood vaccinations on BCG, pentavalent, measles and employment status of mothers were positively associated with immunization coverage. To promote vaccination coverage, the government should implement a national awareness campaign on childhood immunization and increase the number of outreach services.
Neurobiological mechanisms of ECT and TMS treatment in depression: study protocol of a multimodal magnetic resonance investigation
Authors: Frid Leila Marie , Kessler Ute , Ousdal Olga Therese , Hammar Åsa , Haavik Jan , Riemer Frank , Hirnstein Marco , Ersland Lars , Erchinger Vera Jane , Ronold Eivind Haga , Nygaard Gyrid , Jakobsen Petter , Craven Alexander R. , Osnes Berge , Alisauskiene Renata , Bartsch Hauke , Le Hellard Stephanie , Stavrum Anne-Kristin , Oedegaard Ketil J. , Oltedal Leif 
Published: October 2023

Abstract
Background
Noninvasive neurostimulation treatments are increasingly being used to treat major depression, which is a common cause of disability worldwide. While electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are both effective in treating depressive episodes, their mechanisms of action are, however, not completely understood. ECT is given under general anesthesia, where an electrical pulse is administered through electrodes placed on the patient’s head to trigger a seizure. ECT is used for the most severe cases of depression and is usually not prescribed before other options have failed. With TMS, brain stimulation is achieved through rapidly changing magnetic fields that induce electric currents underneath a ferromagnetic coil. Its efficacy in depressive episodes has been well documented. This project aims to identify the neurobiological underpinnings of both the effects and side effects of the neurostimulation techniques ECT and TMS.

Methods
The study will utilize a pre-post case control longitudinal design. The sample will consist of 150 subjects: 100 patients (bipolar and major depressive disorder) who are treated with either ECT (N = 50) or TMS (N = 50) and matched healthy controls (N = 50) not receiving any treatment. All participants will undergo multimodal magnetic resonance imaging (MRI) as well as neuropsychological and clinical assessments at multiple time points before, during and after treatment. Arterial spin labeling MRI at baseline will be used to test whether brain perfusion can predict outcomes. Signs of brain disruption, potentiation and rewiring will be explored with resting-state functional MRI, magnetic resonance spectroscopy and multishell diffusion weighted imaging (DWI). Clinical outcome will be measured by clinician assessed and patient reported outcome measures. Memory-related side effects will be investigated, and specific tests of spatial navigation to test hippocampal function will be administered both before and after treatment. Blood samples will be stored in a biobank for future analyses. The observation time is 6 months. Data will be explored in light of the recently proposed disrupt, potentiate and rewire (DPR) hypothesis.

Discussion
The study will contribute data and novel analyses important for our understanding of neurostimulation as well as for the development of enhanced and more personalized treatment.

Trial registration
ClinicalTrials.gov Identifier: NCT05135897.
Prevalence and significance of clonal hematopoiesis of indeterminate potential in lung transplant recipients
Authors: Swaminathan Aparna C. , Barfield Richard , Zhang Mengqi , Povysil Gundula , Chen Cliburn , Frankel Courtney , Kelly Francine , McKinney Matthew , Todd Jamie L. , Allen Andrew , Palmer Scott M. 
Published: October 2023

Abstract
Background
Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition of somatic mutations that leads to an expanded blood cell clone, has been associated with development of a pro-inflammatory state. An enhanced or dysregulated inflammatory response may contribute to rejection after lung transplantation, however the prevalence of CHIP in lung recipients and influence of CHIP on allograft outcomes is unknown.

Methods
We analyzed whole-exome sequencing data in 279 lung recipients to detect CHIP, defined by pre-specified somatic mutations in 74 genes known to promote clonal expansion of hematopoietic stem cells. We compared the burden of acute rejection (AR) over the first post-transplant year in lung recipients with vs. without CHIP using multivariable ordinal regression. Multivariate Cox proportional hazards models were used to assess the association between CHIP and CLAD-free survival. An exploratory analysis evaluated the association between the number of CHIP-associated variants and chronic lung allograft dysfunction (CLAD)-free survival.

Results
We detected 64 CHIP-associated mutations in 45 individuals (15.7%), most commonly in TET2 (10.8%), DNMT3A (9.2%), and U2AF1 (9.2%). Patients with CHIP tended to be older but did not significantly differ from patients without CHIP in terms of race or native lung disease. Patients with CHIP did not have a higher incidence of AR over the first post-transplant year (p = 0.45) or a significantly increased risk of death or CLAD (adjusted HR 1.25, 95% CI 0.88–1.78). We did observe a significant association between the number of CHIP variants and CLAD-free survival, specifically patients with 2 or more CHIP-associated variants had an increased risk for death or CLAD (adjusted HR 3.79, 95% CI 1.98–7.27).

Conclusions
Lung recipients have a higher prevalence of CHIP and a larger variety of genes with CHIP-associated mutations compared with previous reports for the general population. CHIP did not increase the risk of AR, CLAD, or death in lung recipients.
Pharmacokinetics and metabolism of lidocaine HCl 2% with epinephrine in horses following a palmar digital nerve block
Authors: Knych Heather K. , Katzman Scott , McKemie Daniel S. , Arthur Rick M. , Blea Jeff 
Published: October 2023

Abstract
Background
Lidocaine is a local anesthetic that is sometimes administered in combination with epinephrine. The addition of epinephrine increases the time lidocaine remains at the site of administration, thus prolonging the duration of effect. Due to their potential to prevent the visual detection of lameness, the administration of local anesthetics is strictly regulated in performance and racehorses. Recent reports of positive regulatory findings for lidocaine in racehorses suggests a better understanding of the behavior of this drug is warranted. The objective of the current study was to describe serum and urine concentrations and the pharmacokinetics of lidocaine and its primary metabolites following administration in combination with epinephrine, as a palmar digital nerve block in horses. Twelve horses received a single administration of 1 mL of 2% lidocaine HCl (20 mg/horse) with epinephrine 1:100,000, over the palmar digital nerve. Blood samples were collected up to 30 h and urine samples up to 48 h post administration. Lidocaine and metabolite concentrations were determined by liquid chromatography- mass spectrometry and pharmacokinetic (non-compartmental and compartmental) analysis was performed.

Results
Serum concentrations of lidocaine and 3-hydroxylidocaine were above the LOQ of the assay at 30 h post administration and monoethylglycinexylidide (MEGX) and glycinexylidide (GX) were below detectable levels by 24 and 48 h, respectively. In urine, lidocaine, MEGX and GX were all non-detectable by 48 h post administration while 3-hydroxylidocaine was above LOQ at 48 h post administration. The time of maximal concentration for lidocaine was 0.26 h (median) and the terminal half-life was 3.78 h (mean). The rate of absorption (Ka) was 1.92 1/h and the rate of elimination (Kel) was 2.21 1/h.

Conclusions
Compared to previous reports, the terminal half-life and subsequent detection time observed following administration of lidocaine in combination with epinephrine is prolonged. This is likely due to a decrease in systemic uptake of lidocaine because of epinephrine induced vasoconstriction. Results of the current study suggest it is prudent to use an extended withdrawal time when administering local anesthetics in combination with epinephrine to performance horses.
Association between high sensitivity cardiac troponin and mortality risk in the non-diabetic population: findings from the National Health and Nutrition Examination Survey
Authors: Liu Lin , Cheng Yuen Ting , Xu Aimin , Cheung Bernard M. Y. 
Published: October 2023

Abstract
Objective
We investigated the association of high-sensitivity cardiac troponin (Hs-cTn) with all-cause and cardiovascular mortality in non-diabetic individuals.

Methods
This study included 10,393 participants without known diabetes and cardiovascular disease from the US National Health and Nutrition Examination Survey (NHANES). Serum Hs-cTnI and Hs-cTnT concentrations were measured. Prediabetes was defined as fasting blood glucose between 100 and 125 mg/dL or HbA1c between 5.7 and 6.4%. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality risk. Time-dependent receiver operating characteristics (tROC) curves were utilized to measure the predictive performance of the biomarkers. Net Reclassification Improvement (NRI) were calculated to estimate the improvement in risk classification for adding Hs-cTnT or Hs-cTnI to the standard models based on Framingham risk factors.

Results
The mean age of the participants was 48.1 ± 19.1 years, with 53.3% being female and 25.8% being prediabetic. After multivariable adjustment, compared to those with Hs-cTnI concentration less than the limit of detection, the HRs (95% CIs) of the participants with Hs-cTnI concentration higher than the 99th upper reference limit were 1.74 (1.35, 2.24) for all-cause mortality and 2.10 (1.36, 3.24) for cardiovascular mortality. The corresponding HRs (95% CIs) for Hs-cTnT were 2.07 (1.53, 2.81) and 2.92 (1.47, 5.80) for all-cause and cardiovascular mortality. There was a significant interaction between prediabetes and Hs-cTnI on the mortality risk; a positive relationship was only observed in prediabetic individuals. No interaction was observed between prediabetes and Hs-cTnT on mortality risk. The Areas Under tROC indicated both Hs-cTnT and Hs-cTnI show better predictive performance in cardiovascular mortality than in all-cause mortality. NRI (95% CI) for adding Hs-cTnT to the standard model were 0.25 (0.21, 0.27) and 0.33 (0.26, 0.39) for all-cause and cardiovascular mortality. The corresponding NRI (95% CI) for Hs-cTnI were 0.04 (0, 0.06) and 0.07 (0.01, 0.13).

Conclusions
Elevated blood levels of Hs-cTnI and Hs-cTnT are associated with increased mortality. Measurement of Hs-cTnT in non-diabetic subjects, particularly those with prediabetes, may help identify individuals at an increased risk of cardiovascular disease and provide early and more intensive risk factor modification.
The effect of long-term care insurance on healthcare utilization of middle-aged and older adults: evidence from China health and retirement longitudinal study
Authors: Yang Songhao , Guo Dandan , Bi Shengxian , Chen Yingchun 
Published: October 2023

Abstract
Background
As global ageing continues to increase and many countries face challenges from the growing demand for long-term care. Drawing on the experiences of developed countries, developing countries have explored their own suitable long-term care insurance and have shown strong potential for development and research prospects. However, due to their late start, relevant research is underrepresented in the global research network and still needs to be supplemented. The present study hopes to examine the effect of long-term care insurance on healthcare utilization among the middle-aged and elderly from an empirical perspective, using China as an example.

Methods
Panel data from wave 3 (2015) and wave 4 (2018) of the nationally-representative China health and retirement longitudinal study were selected to obtain a sample of 661 processing participants and 16,065 control participants after matching the policy implementation time in the first pilot cities, and quantitative analysis was conducted using difference-in-differences propensity score matching estimator method to assess the net effect of long-term care insurance on health care utilization among the middle-aged and elderly adults.

Results
In the matched frequency-weighted regression difference-in-differences estimator results, long-term care insurance had a negative effect on the number and costs of annual hospitalizations at the 5% significance level (key variable values of − 0.0568101 and − 1236.309, respectively) and a non-significant effect on outpatient service utilization (P > 0.05). Further exploration of the heterogeneous effect of it revealed that implementation had a more significant negative effect on hospitalization utilization for middle-aged and older people in the East and for those with higher levels of education or attended care.

Conclusion
Long-term care insurance has played a role in controlling hospitalization costs but has not yet achieved the expected effect in controlling outpatient costs. The policy effects in terms of regional distribution and education level and care situation have been variable. The treatment plan of long-term care insurance needs to be improved, the supply of resources for long-term care services should be increased, and the promotion of long-term care insurance and health science should be given attention.
Comparison of gene clustering criteria reveals intrinsic uncertainty in pangenome analyses
Authors: Manzano-Morales Saioa , Liu Yang , González-Bodí Sara , Huerta-Cepas Jaime , Iranzo Jaime 
Published: October 2023

AbstractBackgroundA key step for comparative genomics is to group open reading frames into functionally and evolutionarily meaningful gene clusters. Gene clustering is complicated by intraspecific duplications and horizontal gene transfers that are frequent in prokaryotes. In consequence, gene clustering methods must deal with a trade-off between identifying vertically transmitted representatives of multicopy gene families, which are recognizable by synteny conservation, and retrieving complete sets of species-level orthologs. We studied the implications of adopting homology, orthology, or synteny conservation as formal criteria for gene clustering by performing comparative analyses of 125 prokaryotic pangenomes.ResultsClustering criteria affect pangenome functional characterization, core genome inference, and reconstruction of ancestral gene content to different extents. Species-wise estimates of pangenome and core genome sizes change by the same factor when using different clustering criteria, allowing robust cross-species comparisons regardless of the clustering criterion. However, cross-species comparisons of genome plasticity and functional profiles are substantially affected by inconsistencies among clustering criteria. Such inconsistencies are driven not only by mobile genetic elements, but also by genes involved in defense, secondary metabolism, and other accessory functions. In some pangenome features, the variability attributed to methodological inconsistencies can even exceed the effect sizes of ecological and phylogenetic variables.ConclusionsChoosing an appropriate criterion for gene clustering is critical to conduct unbiased pangenome analyses. We provide practical guidelines to choose the right method depending on the research goals and the quality of genome assemblies, and a benchmarking dataset to assess the robustness and reproducibility of future comparative studies.
Developmental prediction modeling based on diffusion tensor imaging uncovering age-dependent heterogeneity in early childhood autistic brain
Authors: Huang Xinyue , Ming Yating , Zhao Weixing , Feng Rui , Zhou Yuanyue , Wu Lijie , Wang Jia , Xiao Jinming , Li Lei , Shan Xiaolong , Cao Jing , Kang Xiaodong , Chen Huafu , Duan Xujun 
Published: October 2023

Abstract
Objective
There has been increasing evidence for atypical white matter (WM) microstructure in autistic people, but findings have been divergent. The development of autistic people in early childhood is clouded by the concurrently rapid brain growth, which might lead to the inconsistent findings of atypical WM microstructure in autism. Here, we aimed to reveal the developmental nature of autistic children and delineate atypical WM microstructure throughout early childhood while taking developmental considerations into account.

Method
In this study, diffusion tensor imaging was acquired from two independent cohorts, containing 91 autistic children and 100 typically developing children (TDC), aged 4–7 years. Developmental prediction modeling using support vector regression based on TDC participants was conducted to estimate the WM atypical development index of autistic children. Then, subgroups of autistic children were identified by using the k-means clustering method and were compared to each other on the basis of demographic information, WM atypical development index, and autistic trait by using two-sample t-test. Relationship of the WM atypical development index with age was estimated by using partial correlation. Furthermore, we performed threshold-free cluster enhancement-based two-sample t-test for the group comparison in WM microstructures of each subgroup of autistic children with the rematched subsets of TDC.

Results
We clustered autistic children into two subgroups according to WM atypical development index. The two subgroups exhibited distinct developmental stages and age-dependent diversity. WM atypical development index was found negatively associated with age. Moreover, an inverse pattern of atypical WM microstructures and different clinical manifestations in the two stages, with subgroup 1 showing overgrowth with low level of autistic traits and subgroup 2 exhibiting delayed maturation with high level of autistic traits, were revealed.

Conclusion
This study illustrated age-dependent heterogeneity in early childhood autistic children and delineated developmental stage-specific difference that ranged from an overgrowth pattern to a delayed pattern.
Trial registration This study has been registered at ClinicalTrials.gov (Identifier: NCT02807766) on June 21, 2016 (https://clinicaltrials.gov/ct2/show/NCT02807766).