bluuebunny/crossref_metadata_2025_split huggingface dataset:
Medical, Psychiatric, and Sociodemographic Predictors of Clozapine Initiation at an Academic Medical Center
Authors: Shangraw Kathleen , Schmutz Christian , Dowdle Tom , Kelley Ryan , Porter Caleb , Reynolds Merrick , Schwartz Zachary , Sutton Olivia , Kious Brent 
Published: June 2024

Background and HypothesisClozapine is an effective yet underutilized treatment for treatment‐resistant schizophrenia spectrum disorders. This study aimed to identify factors affecting clozapine prescribing patterns among patients with treatment‐resistant schizophrenia and schizoaffective disorder at an academic medical center.Study DesignThis retrospective combined cohort and case‐control study examined demographic, socioeconomic, medical and psychiatric characteristics to determine predictors of clozapine initiation. Eligible patients had a diagnosis of schizophrenia or schizoaffective disorder with at least two prior antipsychotic trials and were admitted to a University of Utah inpatient psychiatric facility (1/2014–3/2021). Patients who did and did not receive clozapine during the index hospitalization were compared in cohort and case‐control study arms.Study ResultsTwelve percent (59/477) of the cohort received clozapine during the index admission. Among the cohort (n = 477), Black patients were twice as likely to receive clozapine than White and Hispanic patients (OR 2.18, 95% CI 1.20–3.97, p = 0.008). In the case‐control analysis, patients with a greater number of previous psychiatric admissions (OR 1.14, p = 0.079) and antipsychotic trials (OR 1.40, p = 0.038) had greater odds of receiving clozapine. Homelessness was identified as a predictor against clozapine use (OR 2.77, p = 0.014).ConclusionsThis is the first study to identify homelessness as a predictor against clozapine use, which raises important clinical and ethical considerations. Our findings also add to the literature on clozapine prescribing discrepancies among ethnic‐minority patients. Overall, clozapine remains underutilized as the gold‐standard treatment for treatment‐resistant schizophrenia‐spectrum disorders, reinforcing a need to improve evidence‐based prescribing.
IL-9 secreted by leukemia stem cells induces Th1-skewed CD4+ T cells, which promote their expansion
Authors: Radpour Ramin , Simillion Cedric , Wang Bofei , Abbas Hussein A. , Riether Carsten , Ochsenbein Adrian F. 
Published: June 2024

Abstract
In acute myeloid leukemia (AML), leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating their expansion and differentiation. To study the interaction of CD4+ and CD8+ T cells in the BM with LSCs and LPCs, we analyzed their transcriptome and predicted cell-cell interactions by unbiased high-throughput correlation network analysis. We found that CD4+ T cells in the BM of patients with AML were activated and skewed toward T-helper (Th)1 polarization, whereas interleukin-9 (IL-9)–producing (Th9) CD4+ T cells were absent. In contrast to normal hematopoietic stem cells, LSCs produced IL-9, and the correlation modeling predicted IL9 in LSCs as a main hub gene that activates CD4+ T cells in AML. Functional validation revealed that IL-9 receptor signaling in CD4+ T cells leads to activation of the JAK-STAT pathway that induces the upregulation of KMT2A and KMT2C genes, resulting in methylation on histone H3 at lysine 4 to promote genome accessibility and transcriptional activation. This induced Th1-skewing, proliferation, and effector cytokine secretion, including interferon gamma (IFN-γ) and tumor necrosis factor α (TNF-α). IFN-γ and, to a lesser extent, TNF-α produced by activated CD4+ T cells induced the expansion of LSCs. In accordance with our findings, high IL9 expression in LSCs and high IL9R, TNF, and IFNG expression in BM–infiltrating CD4+ T cells correlated with worse overall survival in AML. Thus, IL-9 secreted by AML LSCs shapes a Th1-skewed immune environment that promotes their expansion by secreting IFN-γ and TNF-α.
Inflammasome activation in patients with Kaposi sarcoma herpesvirus–associated diseases
Authors: Lage Silvia Lucena , Ramaswami Ramya , Rocco Joseph M. , Rupert Adam , Davis David A. , Lurain Kathryn , Manion Maura , Whitby Denise , Yarchoan Robert , Sereti Irini 
Published: June 2024

Abstract
Kaposi sarcoma herpesvirus (KSHV)–associated diseases include Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated multicentric Castleman disease (MCD), and KS inflammatory cytokine syndrome (KICS). PEL, MCD, and KICS are associated with elevated circulating inflammatory cytokines. However, activation of the inflammasome, which generates interleukin-1β (IL-1β) and IL-18 via active caspase-1/4/5, has not been evaluated in patients with KSHV-associated diseases (KADs). Herein we report that patients with HIV and ≥1 KAD present with higher plasma levels of IL-18 and increased caspase-1/4/5 activity in circulating monocytes compared with HIV-negative healthy volunteers (HVs) or people with HIV (PWH) without KAD. Within KAD subtypes, KICS and MCD shared enhanced caspase-1/4/5 activity and IL-18 production compared with HVs and PWH, whereas patients with PEL showed remarkably high levels of inflammasome complex formation (known as apoptosis–associated speck-like protein containing a caspase recruitment domain). Moreover, caspase-1/4/5 activity and IL-18 plasma levels correlated with KSHV viral load, indicating KSHV-driven inflammasome activation in KAD. Accordingly, factors released by cells latently infected with KSHV triggered inflammasome activation and cytokine production in bystander monocytes in vitro. Finally, both supervised and unsupervised analyses with inflammasome measurements and other inflammatory biomarkers demonstrate a unique inflammatory profile in patients with PEL, MCD, and KICS as compared with KS. Our data indicate that detrimental inflammation in patients with KAD is at least partially driven by KSHV-induced inflammasome activation in monocytes, thus offering novel approaches to diagnose and treat these complex disorders. These trials were registered at www.ClinicalTrials.gov as #NCT01419561, NCT00092222, NCT00006518, and NCT02147405.
Serglycin controls megakaryocyte retention of platelet factor 4 and influences megakaryocyte fate in bone marrow
Authors: Lykins Joshua , Becker Isabelle C. , Camacho Virginia , Alfar Hammodah R. , Park JoonWoo , Italiano Joseph , Whiteheart Sidney W. 
Published: June 2024

Abstract
Megakaryocytes (MKs) produce platelets, and similar to other hematopoietic progenitors, they are involved in homeostatic aspects of their bone marrow niche. MKs release and endocytose various factors, such as platelet factor 4 (PF4)/CXCL4. Here, we show that the intra-α-granular proteoglycan, serglycin (SRGN), plays a key role in this process by retaining PF4, and perhaps other factors, during MK maturation. Immature, SRGN–/– MKs released ∼80% of their PF4, and conditioned media from these cells negatively affected wild-type MK differentiation in vitro. This was replicated in wild-type MKs by treatment with the polycation surfen, a known inhibitor of glycosaminoglycan (GAG)/protein interactions. In vivo, SRGN–/– mice had an interstitial accumulation of PF4, transforming growth factor β1, interleukin-1β, and tumor necrosis factor α in their bone marrow and increased numbers of immature MKs, consistent with their mild thrombocytopenia. SRGN–/– mice also had reduced numbers of hematopoietic stem cells and multipotent progenitors, reduced laminin, and increased collagen I deposition. These findings demonstrate that MKs depend on SRGN and its charged GAGs to balance the distribution of PF4 and perhaps other factors between their α-granules and their adjacent extracellular spaces. Disrupting this balance negatively affects MK development and bone marrow microenvironment homeostasis.
Genes divided according to the relative position of the longest intron show increased representation in different KEGG pathways
Authors: Dvorak Pavel , Hlavac Viktor , Hanicinec Vojtech , Rao Bhavana Hemantha , Soucek Pavel 
Published: June 2024

AbstractDespite the fact that introns mean an energy and time burden for eukaryotic cells, they play an irreplaceable role in the diversification and regulation of protein production. As a common feature of eukaryotic genomes, it has been reported that in protein-coding genes, the longest intron is usually one of the first introns. The goal of our work was to find a possible difference in the biological function of genes that fulfill this common feature compared to genes that do not. Data on the lengths of all introns in genes were extracted from the genomes of six vertebrates (human, mouse, koala, chicken, zebrafish and fugu) and two other model organisms (nematode worm and arabidopsis). We showed that more than 40% of protein-coding genes have the relative position of the longest intron located in the second or third tertile of all introns. Genes divided according to the relative position of the longest intron were found to be significantly increased in different KEGG pathways. Genes with the longest intron in the first tertile predominate in a range of pathways for amino acid and lipid metabolism, various signaling, cell junctions or ABC transporters. Genes with the longest intron in the second or third tertile show increased representation in pathways associated with the formation and function of the spliceosome and ribosomes. In the two groups of genes defined in this way, we further demonstrated the difference in the length of the longest introns and the distribution of their absolute positions. We also pointed out other characteristics, namely the positive correlation between the length of the longest intron and the sum of the lengths of all other introns in the gene and the preservation of the exact same absolute and relative position of the longest intron between orthologous genes.
The effects of killer cell immunoglobulin-like receptor (KIR) genes on susceptibility to severe COVID-19 in the Iranian population
Authors: Karami Narges , Barani Shaghik , Fani Mona , Meri Seppo , Shafiei Reza , Kalantar Kurosh 
Published: June 2024

Abstract
Background
Variations in the innate and adaptive immune response systems are linked to variations in the severity of COVID-19. Natural killer cell (NK) function is regulated by sophisticated receptor system including Killer-cell immunoglobulin-like receptor (KIR) family. We aimed to investigate the impact of possessing certain KIR genes and genotypes on COVID19 severity in Iranians. KIR genotyping was performed on 394 age/sex matched Iranians with no underlying conditions who developed mild and severe COVID- 19. The presence and/or absence of 11 KIR genes were determined using the PCR with sequence specific primers (PCR-SSP).

Results
Patients with mild symptoms had higher frequency ofKIR2DS1 (p = 0.004) and KIR2DS2 (p = 0.017) genes compared to those with severe disease. While KIR3DL3 and deleted variant of KIR2DS4 occurred more frequently in patients who developed a severe form of the disease. In this study, a significant increase of and B haplotype was observed in the Mild group compared to the Severe group (respectively, p = 0.002 and p = 0.02). Also, the prevalence of haplotype A was significantly higher in the Severe group than in the Mild group (p = 0.02).

Conclusions
These results suggest that the KIR2DS1, KIR2DS, and B haplotype maybe have a protective effect against COVID-19 severity. The results also suggest the inhibitory gene KIR2DL3 and haplotype A are risk factors for the severity of COVID-19.
OsAlR3 regulates aluminum tolerance through promoting the secretion of organic acids and the expression of antioxidant genes in rice
Authors: Su Chang , Wang Jingbo , Feng Jing , Jiang Sixu , Man Fuyuan , Jiang Linlin , Zhao Minghui 
Published: June 2024

AbstractIn acidic soils, aluminum (Al) toxicity inhibits the growth and development of plant roots and affects nutrient and water absorption, leading to reduced yield and quality. Therefore, it is crucial to investigate and identify candidate genes for Al tolerance and elucidate their physiological and molecular mechanisms under Al stress. In this study, we identified a new gene OsAlR3 regulating Al tolerance, and analyzed its mechanism from physiological, transcriptional and metabolic levels. Compared with the WT, malondialdehyde (MDA) and hydrogen peroxide (H2O2) content were significantly increased, superoxide dismutase (SOD) activity and citric acid (CA) content were significantly decreased in the osalr3 mutant lines when exposed to Al stress. Under Al stress, the osalr3 exhibited decreased expression of antioxidant-related genes and lower organic acid content compared with WT. Integrated transcriptome and metabolome analysis showed the phenylpropanoid biosynthetic pathway plays an important role in OsAlR3-mediated Al tolerance. Exogenous CA and oxalic acid (OA) could increase total root length and enhance the antioxidant capacity in the mutant lines under Al stress. Conclusively, we found a new gene OsAlR3 that positively regulates Al tolerance by promoting the chelation of Al ions through the secretion of organic acids, and increasing the expression of antioxidant genes.
Seasonal distribution and upsurge of respiratory viruses among indigenous tribes with ILI and SARI in a far-flung Car Nicobar Island
Authors: Muruganandam Nagarajan , Vipat Veena , Jadhav Sheetal , Vins Alwin , Beniwal Nisha , Kaur Harpreet , Renuka Remya Rajan , Parvez Rehnuma , Potdar Varsha 
Published: June 2024

Abstract
Background
Respiratory viral illnesses among children are a prominent cause of morbidity and mortality in the developing world. The aim of this study is to understand the seasonal pattern and surge of respiratory viruses among the Nicobarese tribe.

Methods
Respiratory specimens were collected from both ARI and SARI cases attended the BJR district hospital in Car Nicobar Island, India, between 2021 and 2022. Respiratory viruses were identified from the specimens by using the qRT-PCR assay. Meteorological parameters were collected and evaluated using Microsoft Excel and SPSS 21. The significant association between the surge of respiratory viruses and each climatic parameter was evaluated.

Results
In this hospital-based cross-sectional study, 471 ILI cases were enrolled, and 209 of these were positive for respiratory viral infections. Of these respiratory virus infections, 201 (96.2%) were infected with a single respiratory virus infection, and 8 (3.8%) had mixed viral infections. Fever, cough, and chills were the most common symptoms of respiratory illness among this indigenous population. There was a significant link between respiratory viruses and influenza-like illness in children (below 5 years and 6 to 15 years).

Conclusion
This prevalence study revealed that viral respiratory infections were more common in children than adults. Among these respiratory viruses, respiratory syncytial virus A (RSV) and influenza B virus were predominantly reported among tribal children up to age five years. In the year 2021, these viruses were recorded frequently during the winter season. Climate factors such as high humidity, high precipitation, moderate temperature, and moderate rainfall are found to be correlated with respiratory viral infections. This study implicates important information for preventing a further outbreak of respiratory viral infections in Car Nicobar Island.
Protocol for the MS-CEBA study: an observational, prospective cohort study identifying Cognitive, Energetic, Behavioural and Affective (CEBA) profiles in Multiple Sclerosis to guide neuropsychological treatment choice
Authors: Reinhardt Anniek , Rakers Sandra E. , Heersema Dorothea J. , Beenakker Ernesto A. C. , Meilof Jan F. , Timmerman Marieke E. , Spikman Jacoba M. 
Published: June 2024

Abstract
Background
Neuropsychological symptoms in the Cognitive, Energetic, Behavioural, and Affective (CEBA) domains are common in people with multiple sclerosis (PwMS) and can negatively affect societal participation. The current study aims to investigate whether there are combinations of symptoms in the different CEBA domains that consistently occur together, that is, if there are CEBA profiles that can be identified. If so, this study aims to develop a screening instrument identifying CEBA profiles in PwMS to select the most suitable neuropsychological rehabilitation treatment for a given CEBA profile and consequently improve the societal participation of PwMS.

Methods
This study is an observational, prospective cohort study consisting of 3 phases. Phase 1 focuses on the identification of CEBA profiles in a large sample of PwMS (n = 300). Phase 2 focuses on validating these CEBA profiles through replication of results in a new sample (n = 100) and on the development of the screening instrument. Phase 3 focuses on qualitatively evaluating in a small group of PwMS whether the selected treatment is suitable for the given CEBA profile or whether existing neuropsychological treatments should be adapted to meet the needs of PwMS suffering from symptoms in multiple CEBA domains simultaneously. Primary outcome is the CEBA profile, which will be derived from performance on neuropsychological assessment consisting of tests and questionnaires regarding the CEBA domains using a latent profile analysis. Inclusion criteria include MS diagnosis, sufficient ability in the Dutch language, and an age between 18 and 70 years.

Discussion
The results of the current study will contribute to a more comprehensive understanding of the entire spectrum of neuropsychological symptoms in PwMS. Identification of possible CEBA profiles, and accordingly, the development of a screening instrument determining the CEBA profile of PwMS in clinical practice, contributes to the timely referral of PwMS to the most suitable neuropsychological rehabilitation treatment. If necessary, adjustments to existing treatments will be suggested in order to sufficiently meet the needs of PwMS. All of this with the ultimate aim to improve societal participation, and thereby quality of life, of PwMS.

Trial registration
Dutch Central Committee on Research Involving Human Subjects (CCMO) NL83954.042.23; ClinicalTrials.gov NCT06016309.
Research on segmentation model of optic disc and optic cup in fundus
Authors: Chen Naigong , Lv Xiujuan 
Published: June 2024

Abstract
Background
Glaucoma is a worldwide eye disease that can cause irreversible vision loss. Early detection of glaucoma is important to reduce vision loss, and retinal fundus image examination is one of the most commonly used solutions for glaucoma diagnosis due to its low cost. Clinically, the cup-disc ratio of fundus images is an important indicator for glaucoma diagnosis. In recent years, there have been an increasing number of algorithms for segmentation and recognition of the optic disc (OD) and optic cup (OC), but these algorithms generally have poor universality, segmentation performance, and segmentation accuracy.

Methods
By improving the YOLOv8 algorithm for segmentation of OD and OC. Firstly, a set of algorithms was designed to adapt the REFUGE dataset’s result images to the input format of the YOLOv8 algorithm. Secondly, in order to improve segmentation performance, the network structure of YOLOv8 was improved, including adding a ROI (Region of Interest) module, modifying the bounding box regression loss function from CIOU to Focal-EIoU. Finally, by training and testing the REFUGE dataset, the improved YOLOv8 algorithm was evaluated.

Results
The experimental results show that the improved YOLOv8 algorithm achieves good segmentation performance on the REFUGE dataset. In the OD and OC segmentation tests, the F1 score is 0.999.

Conclusions
We improved the YOLOv8 algorithm and applied the improved model to the segmentation task of OD and OC in fundus images. The results show that our improved model is far superior to the mainstream U-Net model in terms of training speed, segmentation performance, and segmentation accuracy.
The impact of family factors and communication on recreational sedentary screen time among primary school-aged children: a cross-sectional study
Authors: Ding Xueting , Ji Ying , Dong Yuan , Li Zhijing , Zhang Yan 
Published: June 2024

Abstract
Background
Childhood obesity is increasingly recognized as a major public health challenge worldwide, and excessive sedentary screen time is emerging as a key risk factor. This study aimed to assess the recreational screen sedentary time of Chinese primary school-aged children and investigate the relationship between screen-related family factors and the outcome variable.

Methods
Our study used data from a cross-sectional survey collected from fifth-grade students and their parents in Beijing, China, from April to May 2018 (n = 2,373). The questions included basic demographic information, family socioeconomic status, students’ and parents’ sedentary and exercising habits, within-family communicational factors, and health belief patterns. The recreational screen sedentary time of the children was compared across demographic groups. The study employed multivariate linear regression models to examine associations between children’s screen time and various family factors, as well as the moderating effect of overall family communication.

Results
Our findings revealed an average daily recreational screen sedentary time of 2.4 h among participants. Screen time significantly varied across demographic categories, including children’s sex, age, residence, parents’ education, household income, family size, and primary family member. After adjustment, the proportion of child-owned digital devices (p < 0.01), child’s personal room (p < 0.05), family screen-viewing together (p < 0.01), and parental screen time (p < 0.01) were positively related to children’s recreational sedentary screen time. Parental restrictions on screen time (p < 0.001) and attitudes toward reducing sitting time (p < 0.01) were correlated with a decrease in children’s screen time. The overall family communication environment significantly moderated the effects of parental practice of restricting children’s screen time (p < 0.001), positive reinforcement by parents (p < 0.05), and parents’ recreational sedentary screen time (p < 0.001).

Conclusions
Our findings underscored the significance of family dynamics, parental practices, and communication in shaping children’s screen time behaviors, providing valuable insights for tailored interventions and strategies to reduce childhood obesity.