bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphangioleiomyomatosis in patients with tuberous sclerosis: a national centre audit
Authors: Johnson Jan , Somerfield Wendy , Johnson Simon R. 
Published: March 2024

Abstract
Background
Lymphangioleiomyomatosis (LAM) is common in tuberous sclerosis complex (TSC) yet under recognised with management mostly based upon evidence obtained from patients with sporadic LAM. We performed a prospective audit of patients with TSC-LAM attending a national referral centre to inform management guidelines.

Methods
The UK LAM Centre was established in 2011 and conducts a prospective audit of pre-defined quality outcomes for all subjects. Audit data are reported on all patients with TSC-LAM and a comparator population of patients with sporadic LAM.

Results
Between 2011 and 2022, 73 patients were seen with TSC-LAM. All were women with a mean (SD) age of 39 (12) years. Referral rates were similar over the study period including after the introduction of CT screening. Median age of diagnosis with TSC was 11 years (range 0–70) with one third diagnosed with TSC as adults. Compared with all TSC patients in the ‘TOSCA’ registry, TSC-LAM patients tended to have been diagnosed with TSC at an older age, had fewer neuro-cognitive manifestations and were more likely to have angiomyolipoma. The most common presentations of TSC-LAM were following workup for angiomyolipoma, pneumothorax or dyspnoea with only one fifth detected after CT screening. Baseline FEV1 and DLCO at first assessment were reduced to 77 and 63% predicted respectively and were similar to patients with sporadic LAM. During follow-up, FEV1 fell by a mean of 81 ml/year and DLCO fell by 0.309 mmol/ml/kPa/year in patients not being treated with an mTOR inhibitor. 55% required treatment with either sirolimus or Everolimus for LAM or angiomyolipoma respectively. For those treated with an mTOR inhibitor, mean FEV1 fell by 3 ml/year and DLCO increased by 0.032 mmol/ml/kPa/year and was similar to sporadic LAM. Risk of death due to LAM or need for lung transplant in patients with TSC-LAM was 0.67%/year.

Conclusions
Despite screening recommendations, LAM is often diagnosed in TSC after symptoms develop which may delay treatment. Complications including pneumothorax and loss of lung function are significant and similar to sporadic LAM. Work is needed to implement the recommended CT screening for LAM and improve respiratory care for TSC-LAM.
Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents + BCL2 inhibitor venetoclax
Authors: Li Danyang , Yuan Yigang , Meng Chen , Lin Zihan , Zhao Min , Shi Liuzhi , Li Min , Ye Daijiao , Cai Yue , He Xiaofei , Ye Haige , Zhou Shujuan , Zhou Haixia , Gao Shenmeng 
Published: March 2024

Abstract
Background
miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells have high miR-182 promoter methylation has not been determined.

Methods
To assess the methylation status of the miR-182 promoter, methylation and unmethylation-specific PCR analysis, bisulfite-sequencing analysis, and MethylTarget™ assays were performed to measure the frequency of methylation at the miR-182 promoter. Bone marrow cells were isolated from miR-182 knockout (182KO) and 182 wild type (182WT) mice to construct BCR-ABL (P190) and Notch-induced murine B-ALL and T-ALL models, respectively. Primary ALL samples were performed to investigate synergistic effects of the hypomethylation agents (HMAs) and the BCL2 inhibitor venetoclax (Ven) in vitro.

Results
miR-182 (miR-182-5P) expression was substantially lower in ALL blasts than in normal controls (NCs) because of DNA hypermethylation at the miR-182 promoter in ALL blasts but not in normal controls (NCs). Knockout of miR-182 (182KO) markedly accelerated ALL development, facilitated the infiltration, and shortened the OS in a BCR-ABL (P190)-induced murine B-ALL model. Furthermore, the 182KO ALL cell population was enriched with more leukemia-initiating cells (CD43+B220+ cells, LICs) and presented higher leukemogenic activity than the 182WT ALL population. Furthermore, depletion of miR-182 reduced the OS in a Notch-induced murine T-ALL model, suggesting that miR-182 knockout accelerates ALL development. Mechanistically, overexpression of miR-182 inhibited proliferation and induced apoptosis by directly targeting PBX3 and BCL2, two well-known oncogenes, that are key targets of miR-182. Most importantly, DAC in combination with Ven had synergistic effects on ALL cells with miR-182 promoter hypermethylation, but not on ALL cells with miR-182 promoter hypomethylation.

Conclusions
Collectively, we identified miR-182 as a tumor suppressor gene in ALL cells and low expression of miR-182 because of hypermethylation facilitates the malignant phenotype of ALL cells. DAC + Ven cotreatment might has been applied in the clinical try for ALL patients with miR-182 promoter hypermethylation. Furthermore, the methylation frequency at the miR-182 promoter should be a potential biomarker for DAC + Ven treatment in ALL patients.
Real-world association between systemic corticosteroid exposure and complications in US patients with severe asthma
Authors: Casale Thomas B , Corbridge Thomas , Germain Guillaume , Laliberté François , MacKnight Sean D , Boudreau Julien , Duh Mei S , Deb Arijita 
Published: March 2024

Abstract
Background
Systemic corticosteroid (SCS) use remains widespread among patients with severe asthma, despite associated complications.

Objective
Evaluate the association between cumulative SCS exposure and SCS-related complications in severe asthma.

Methods
This retrospective, longitudinal study used claims data from the Optum Clinformatics Data Mart database (GSK ID: 214469). Eligible patients (≥ 12 years old) had an asthma diagnosis and were divided into two cohorts: SCS use and non/burst-SCS use. Patients in the SCS use cohort had a claim for a daily prednisone-equivalent dose ≥ 5 mg SCS following ≥ 6 months of continuous SCS use; those in the non/burst-SCS cohort had no evidence of continuous SCS use and had a non-SCS controller/rescue medication initiation claim. For each cohort, the date of the qualifying claim was the index date. SCS users were further stratified by SCS use during each quarter of follow-up: low (≤ 6 mg/day), medium (> 6–12 mg/day), high (> 12 mg/day), and continuous high (≥ 20 mg/day for 90 days). SCS-related complications were evaluated in the quarter following SCS exposure. The adjusted odds ratios (OR) of experiencing SCS-related complications during follow-up in each of the SCS use groups versus the non/burst SCS cohort were calculated using generalized estimating equations models.

Results
SCS and non/burst-SCS use cohorts included 7473 and 89,281 patients (mean follow-up: 24.6 and 24.2 months), respectively. Compared with the non/burst-SCS use cohort, medium, high, and continuous high SCS use was associated with greater odds of any SCS-related complication (adjusted OR [95% confidence interval]: 1.30 [1.21, 1.39], 1.49 [1.35, 1.64] and 1.63 [1.40, 1.89], respectively) including increased acute gastrointestinal, cardiovascular, and immune system-related complications, and chronic cardiovascular, metabolic/endocrine, central nervous system, bone-/muscle-related, ophthalmologic, and hematologic/oncologic complications. Low-dose SCS use was also associated with significantly increased odds of acute gastrointestinal and immune system-related complications, and chronic bone-/muscle-related and hematologic/oncologic complications versus the non/burst-SCS use cohort.

Conclusion
SCS use, even at low doses, is associated with increased risk of SCS-related complications among patients with severe asthma.
Menarche, pubertal timing and the brain: female-specific patterns of brain maturation beyond age-related development
Authors: Gottschewsky Nina , Kraft Dominik , Kaufmann Tobias 
Published: March 2024

Abstract
Background
Puberty depicts a period of profound and multifactorial changes ranging from social to biological factors. While brain development in youths has been studied mostly from an age perspective, recent evidence suggests that pubertal measures may be more sensitive to study adolescent neurodevelopment, however, studies on pubertal timing in relation to brain development are still scarce.

Methods
We investigated if pre- vs. post-menarche status can be classified using machine learning on cortical and subcortical structural magnetic resonance imaging (MRI) data from strictly age-matched adolescent females from the Adolescent Brain Cognitive Development (ABCD) cohort. For comparison of the identified menarche-related patterns to age-related patterns of neurodevelopment, we trained a brain age prediction model on data from the Philadelphia Neurodevelopmental Cohort and applied it to the same ABCD data, yielding differences between predicted and chronological age referred to as brain age gaps. We tested the sensitivity of both these frameworks to measures of pubertal maturation, specifically age at menarche and puberty status.

Results
The machine learning model achieved moderate but statistically significant accuracy in the menarche classification task, yielding for each subject a class probability ranging from 0 (pre-) to 1 (post- menarche). Comparison to brain age predictions revealed shared and distinct patterns of neurodevelopment captured by both approaches. Continuous menarche class probabilities were positively associated with brain age gaps, but only the menarche class probabilities—not the brain age gaps—were associated with age at menarche.

Conclusions
This study demonstrates the use of a machine learning model to classify menarche status from structural MRI data while accounting for age-related neurodevelopment. Given its sensitivity towards measures of puberty timing, our work suggests that menarche class probabilities may be developed toward an objective brain-based marker of pubertal development.
Non-specific effects of inactivated Mycobacterium bovis oral and parenteral treatment in a rabbit scabies model
Authors: Casais Rosa , Iglesias Natalia , Sevilla Iker A. , Garrido Joseba M. , Balseiro Ana , Dominguez Mercedes , Juste Ramon A. 
Published: March 2024

AbstractTuberculosis BCG vaccination induced non-specific protective effects in humans led to postulate the concept of trained immunity (TRAIM) as an innate type of immune mechanism that triggered by a pathogen, protects against others. Killed vaccines have been considered not to be effective. However, field efficacy of a commercial vaccine against paratuberculosis, as well as of a recently developed M. bovis heat-inactivated vaccine (HIMB) prompted to test whether it could also induce TRAIM. To this, we used a sarcoptic mange rabbit model. Twenty-four weaned rabbits were treated orally or subcutaneously with a suspension of either HIMB (107 UFC) or placebo. Eighty-four days later the animals were challenged with approximately 5000 S. scabiei mites on the left hind limb. Skin lesion extension was measured every 2 weeks until 92 days post-infection (dpi). Two animals were killed at 77 dpi because of extensive skin damage. The rest were euthanized and necropsied and the lesion area and the mite burden per squared cm were estimated. Specific humoral immune responses to S. scabiei and to M. bovis were investigated with the corresponding specific ELISA tests. Subcutaneously and orally HIMB vaccinated animals compared with placebo showed reduced lesion scores (up to 74% and 62%, respectively) and mite counts (−170% and 39%, respectively). This, together with a significant positive correlation (r = 0.6276, p = 0.0031) between tuberculosis-specific antibodies and mite count at 92 dpi supported the hypothesis of non-specific effects of killed mycobacterial vaccination. Further research is needed to better understand this mechanism to maximize cross protection.
Unveiling the functional heterogeneity of cytokine-primed human umbilical cord mesenchymal stem cells through single-cell RNA sequencing
Authors: Hu Zhiwei , Li Duanduan , Wu Shiduo , Pei Ke , Fu Zeqin , Yang Yulin , Huang Yinfu , Yang Jian , Liu Chuntao , Hu Junyuan , Cai Cheguo , Liao Yan 
Published: March 2024

Abstract
Background
Mesenchymal stem cells (MSCs) hold immense promise for use in immunomodulation and regenerative medicine. However, their inherent heterogeneity makes it difficult to achieve optimal therapeutic outcomes for a specific clinical disease. Primed MSCs containing a certain cytokine can enhance their particular functions, thereby increasing their therapeutic potential for related diseases. Therefore, understanding the characteristic changes and underlying mechanisms of MSCs primed by various cytokines is highly important.

Results
In this study, we aimed to reveal the cellular heterogeneity, functional subpopulations, and molecular mechanisms of MSCs primed with IFN-γ, TNF-α, IL-4, IL-6, IL-15, and IL-17 using single-cell RNA sequencing (scRNA-seq). Our results demonstrated that cytokine priming minimized the heterogeneity of the MSC transcriptome, while the expression of MSC surface markers exhibited only slight changes. Notably, compared to IL-6, IL-15, and IL-17; IFN-γ, TNF-α, and IL-4 priming, which stimulated a significantly greater number of differentially expressed genes (DEGs). Functional analysis, which included Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, indicated that IFN-γ, TNF-α, and IL-4-primed hUC-MSCs are involved in interferon-mediated immune-related processes, leukocyte migration, chemotaxis potential, and extracellular matrix and cell adhesion, respectively. Moreover, an investigation of various biological function scores demonstrated that IFN-γ-primed hUC-MSCs exhibit strong immunomodulatory ability, TNF-α-primed hUC-MSCs exhibit high chemotaxis potential, and IL-4-primed hUC-MSCs express elevated amounts of collagen. Finally, we observed that cytokine priming alters the distribution of functional subpopulations of MSCs, and these subpopulations exhibit various potential biological functions. Taken together, our study revealed the distinct regulatory effects of cytokine priming on MSC heterogeneity, biological function, and functional subpopulations at the single-cell level.

Conclusions
These findings contribute to a comprehensive understanding of the inflammatory priming of MSCs, paving the way for their precise treatment in clinical applications.
The ENJOY Seniors Exercise Park IMP-ACT project: IMProving older people’s health through physical ACTivity: a hybrid II implementation design study protocol
Authors: Levinger Pazit , Fearn Marcia , Dreher Bronwyn , Bauman Adrian , Brusco Natasha K. , Gilbert Andrew , Soh Sze-Ee , Burton Elissa , James Lisa , Hill Keith D. 
Published: March 2024

Abstract
Introduction
The health benefits of physical activity are well established; however, most older people are not sufficiently physically active. Despite the availability of various physical activity interventions and programs, implementation of effective prevention strategies to reduce older people’s physical inactivity are lacking. The ENJOY IMP-ACT project is an implementation research project, based on a previous evidence-based physical and social activity program utilising specialised outdoor exercise equipment (the Seniors Exercise Park) for older people. The ENJOY IMP-ACT aims to increase participation in physical activity to improve health outcomes for older people in Victoria, Australia.

Method
The ENJOY IMP-ACT is a hybrid II implementation-effectiveness pre-post mixed method study design. Five local governments (6 public sites/parks) will undergo a 3-month control period followed by 9-months implementation intervention (TERM framework intervention: Training, Engagement, Resources development, Marketing and promotion), and a maintenance phase (3 months). Various methodologies will be employed throughout the project at each site and will include direct observations of park users, intercept surveys with park users, online access monitor platform (using an online app), interviews with stakeholders and exercise program leaders, a process evaluation of physical activity programs, a social return-on-investment analysis, and other related activities.

Discussion
Through the implementation framework design, the ENJOY IMP-ACT is uniquely placed to translate an evidenced-based physical and social activity program into real world settings and increase physical activity among older people. If successful, this program will inform scale up across Australia with the goal of improving the health and wellbeing of older people.

Trial registration
This registration trial is prospectively registered with the Australian New Zealand Clinical Trials Registry. Trial number ACTRN12622001256763. Date registered 20/09/2022.
Sex-dependent resilience to extreme drought events: implications for climate change adaptation of a South American endangered tree species
Authors: Piraino Sergio , Hadad Martín Ariel , Ribas‑Fernández Yanina Antonia , Roig Fidel Alejandro 
Published: March 2024

Abstract
Background
Recent changes in climatic trends are resulting in an increased frequency and intensity of extreme events, with unknown effect on ecosystem dynamics in the near future. Extreme drought episodes are recognized as disturbance factors capable of modifying forest dynamics and tree growth. Within this context, dioecious tree species may be impacted by climatic extremes, affecting male/female proportions and, consequently, reproductive processes and species persistence. Therefore, there is an urgent need for species-specific assessments of growth tolerance to extreme dry spells in dioecious tree species, to establish effective conservation strategies for these particular natural resources. Araucaria araucana (araucaria), an endangered dioecious Patagonian tree species, has recently undergone decay and mortality episodes in response to increasing dry climatic conditions. While sex-dependent tolerance to extreme drought episodes has been assessed in the species’ humid distribution range, there is still a lack of information on the gender-based resilience of trees growing in the drier environments of the species’ distribution.

Methods
We reconstructed, through dendrochronological methods, the sex-dependent response of 105 araucaria individuals (55 female and 50 male trees) to five regional extreme dry spells employing a set of different indices. Resistance, recovery period, and average growth reduction of standardized tree-ring growth were examined, analysing the effect of biotic (sex, pre-drought stem tree growth) and abiotic (local climatic conditions before, during, and after extreme climatic episodes) factors on tree resilience.

Results
Sex influences only the species resistance to climatic disturbance, with male individuals showing lower tolerance to extreme drought events. Pre-drought radial growth rates and local meteorological conditions preceding, during, and following extreme dry spells strongly modulated araucaria radial growth resilience regardless of tree sex, influencing the species resistance, recovery period, and average growth reduction.

Conclusions
We provide novel and crucial information for the species conservation and management in the current climate change scenario, and contribute to the debate regarding the role of tree sex as a factor influencing woody species growth under particularly adverse climatic conditions. In the face of climate change, an increase in extreme drought events is expected in the easternmost araucaria xeric end distribution area, which will likely decrease the species resilience.
Regional climate models and bias correction methods for rainfall-runoff modeling in Katar watershed, Ethiopia
Authors: Yersaw Babur Tesfaye , Chane Mulusew Bezabih 
Published: March 2024

AbstractSystematic errors in regional climate models (RCMs) hinder their implementation and lead to uncertainties in regional hydrological climate change studies. As a result, checking the accuracy of climate model simulations and applying bias correction are preliminary methods for achieving consistent findings. Therefore, identifying suitable RCM models for bias correction is important for providing reliable inputs for evaluating climate change impacts. The impacts of bias correction methods on streamflow were assessed on the Katar catchment within the Lake Ziway subbasin using coordinated regional climate downscaling experiments with a spatial resolution of 50 km (CORDEX-44) RCMs through the Integrated Hydrological Modelling System (IHMS) version 6.3. This study evaluated fourteen RCM models under five precipitation and three temperature bias correction methods for the Katar catchment. Statistical approaches, such as bias (PBIAS), the root mean square error (RMSE), the mean absolute error (MAE), the coefficient of variation (CV), the coefficient of determination (R2), and the relative volume error (RVE), are used for performance analysis. GERICS-MPI, RAC4-NOAA-2G, and CCLM4-NCCR-AFR-22 have better performances for both rainfall and temprature. The empirical cumulative distribution function (ECDF) method performed best in removing bias from the frequency-based statistics of rainfall and streamflow, followed by the power transformation (PT), distribution mapping (DM), local intensity scaling (LOCI), and linear scaling (LS) methods. Specifically, for temperature, the VARI and DM methods perform better in frequency-based statistics than the LS method. The performance of hydrological modeling is strongly affected by the selection of rainfall bias correction methods. In addition, the effect of the temperature bias correction method was not significant. The adequacy of the BCM depends on the RCM models and regional context. Therefore, the BCM implementation procedure can be adapted from region to region. This study revealed that the performance of the RCM models differed and that the errors in the RCM model outputs were reduced by the use of bias correction methods.
Profile and burden of the family caregiver: the caring experience in multiple sclerosis. An observational study
Authors: Ponzio Michela , Tacchino Andrea , Verri Anna , Battaglia Mario Alberto , Brichetto Giampaolo , Podda Jessica 
Published: March 2024

Abstract
Background
The broad implications of caring for a family member with a chronic medical condition, such as MS, can lead caregivers to experience a high burden of care. The aim of the study was to describe profile of MS caregivers and their burden and to explore potential factors influencing this burden.

Methods
200 family caregivers of a person with MS completed survey questionnaires across a cross-sectional study. Many information were collected: caregiver socio-demographic and health-related data, caregiving activities, knowledge of MS, coping strategies, mood, social support received and care recipient information. Caregiving burden was measured by the ZBI (Zarit Burden Interview). The extent to which the variables explained caregiver burden was analyzed using a hierarchical approach.

Results
68% of the caregivers reported a perceived burden of care (ZBI score > 20). Our results show that physical and mental related-health variables are important predictive factors of the care burden, explaining much of the observed variance (40.9%).

Conclusion
Family caregivers in MS continue to make up the shortfall produce by national health and welfare systems. We highlighted the importance of good physical and mental health in decreasing perceived burden. Working to alleviate psychological distress through mechanisms focus on reducing worries and perceived burden may be a valid approach.