bluuebunny/crossref_metadata_2025 huggingface dataset:
Using the International Alcohol Control (IAC) policy index to assess effects of legislative change in Aotearoa New Zealand
Authors: Casswell Sally , Randerson Steve , Parker Karl , Huckle Taisia
Published: June 2024

Background

The IAC Policy Index was developed to allow comparison in alcohol policy between countries and within countries over time including in low resource settings. It measures four effective alcohol policies and takes into account stringency of regulation and the actual impact on the alcohol environment, such as trading hours and prices paid. This framework was used to assess policy in Aotearoa New Zealand in a time period covering two relevant legislative changes. This is the first study to use an alcohol policy index to assess and describe legislative change within country.

Methods

Data to calculate the IAC Policy Index was collected for 2013 and 2022. Stringency of policy was assessed from legislative statutes and impacts of policy on the alcohol environment from administrative data and specifically designed data collection.

Results

The overall IAC Policy Index score improved over the time period. The scores for the separate policy areas reflected the legislative changes as hypothesised, but also independent changes in impact, given ecological changes including reduced enforcement of drink driving countermeasures and increased exposure to marketing in digital channels. The IAC Policy index reflects the changes in policy status observed in Aotearoa, NZ.

Discussion

The IAC Policy Index provided a useful framework to assess and describe change in alcohol legislation contextualised by other influences on policy impact over time within a country. The results indicated the value of assessing stringency and impact separately as these moved independently.

Conclusions

The IAC Alcohol Policy Index, measuring both stringency and actual impact on the alcohol environment with a focus on only the most effective alcohol policies provides meaningful insights into within-country policy strength over time. The IAC Policy Index used over time can communicate to policy makers successes and gaps in alcohol policy.
Estimating the causal effects of income on health: how researchers’ definitions of “income” matter
Authors: Igelström Erik , Kopasker Daniel , Craig Peter , Lewsey Jim , Katikireddi Srinivasa Vittal
Published: June 2024

Background

There is a well-established cross-sectional association between income and health, but estimates of the causal effects of income vary substantially. Different definitions of income may lead to substantially different empirical results, yet research is often framed as investigating “the effect of income” as if it were a single, easily definable construct.

Methods/Results

The aim of this paper is to introduce a taxonomy for definitional and conceptual issues in studying individual- or household-level income for health research. We focus on (1) the definition of the income measure (earned and unearned; net, gross, and disposable; real and nominal; individual and household; relative and absolute income) and (2) the definition of the causal contrast (amount, functional form assumptions/transformations, direction, duration of change, and timing of exposure and follow-up). We illustrate the application of the taxonomy to four examples from the published literature.

Conclusions

Quantified estimates of causal effects of income on health and wellbeing have crucial relevance for policymakers to anticipate the consequences of policies targeting the social determinants of health. However, much prior evidence has been limited by lack of clarity in distinguishing between different causal questions. The present framework can help researchers explicitly and precisely articulate income-related exposures and causal questions.
Targeted analysis of Ubiquitin-Specific Peptidase (USP8) in a population of Iranian people with Cushing’s disease and a systematic review of the literature
Authors: Hashemi-Madani Nahid , Cheraghi Sara , Emami Zahra , Mehrjardi Ali Zare , Kaynama Mahmoud Reza , Khamseh Mohammad E.
Published: June 2024

Objective

Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs.

Methods

Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases.

Results

In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas.

Conclusion

Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.
Transforming the delivery of care from “I” to “We” by developing the crisis resource management skills in pediatric interprofessional teams to handle common emergencies through simulation
Authors: Saeed Sana , Hegazy Nagwa Nashat , Malik Marib Ghulam Rasool , Abbas Qalab , Atiq Huba , Ali Muhammad Maisam , Aslam Aashir , Hashwani Yasmin , Ahmed Farzana Bashir
Published: June 2024

Background

The healthcare system is highly complex, and adverse events often result from a combination of human factors and system failures, especially in crisis situations. Crisis resource management skills are crucial to optimize team performance and patient outcomes in such situations. Simulation-based training offers a promising approach to developing such skills in a controlled and realistic environment.

Methods

This study employed a mixed-methods (quantitative-qualitative) design and aimed to assess the effectiveness of a simulation-based training workshop in developing crisis resource management skills in pediatric interprofessional teams at a tertiary care hospital. The effectiveness of the intervention was evaluated using Kirkpatrick’s Model, focusing on reaction and learning levels, employing the Collaboration and Satisfaction about Care Decisions scale, Clinical Teamwork Scale, and Ottawa Global Rating Scale for pre- and post-intervention assessments. Focused group discussions were conducted with the participants to explore their experiences and perceptions of the training.

Results

Thirty-nine participants, including medical students, nurses, and residents, participated in the study. Compared to the participants’ pre-workshop performance, significant improvements were observed across all measured teamwork and performance components after the workshop, including improvement in scores in team communication (3.16 ± 1.20 to 7.61 ± 1.0, p < 0.001), decision-making (3.50 ± 1.54 to 7.16 ± 1.42, p < 0.001), leadership skills (2.50 ± 1.04 to 5.44 ± 0.6, p < 0.001), and situation awareness (2.61 ± 1.13 to 5.22 ± 0.80, p < 0.001). No significant variations were observed post-intervention among the different teams. Additionally, participants reported high levels of satisfaction, perceived the training to be highly valuable in improving their crisis resource management skills, and emphasized the importance of role allocation and debriefing.

Conclusions

The study underscores the effectiveness of simulation-based training in developing crisis resource management skills in pediatric interprofessional teams. The findings suggest that such training can impact learning transfer to the workplace and ultimately improve patient outcomes. The insights from our study offer additional valuable considerations for the ongoing refinement of simulation-based training programs. There is a need to develop more comprehensive clinical skills evaluation methods to better assess the transferability of these skills in real-world settings. The potential challenges unveiled in our study, such as physical exhaustion during training, must be considered when refining and designing such interventions.
Perception of enhanced learning in medicine through integrating of virtual patients: an exploratory study on knowledge acquisition and transfer
Authors: Li Zhien , Asoodar Maryam , de Jong Nynke , Keulers Tom , Liu Xian , Dolmans Diana
Published: June 2024

Introduction

Virtual Patients (VPs) have been shown to improve various aspects of medical learning, however, research has scarcely delved into the specific factors that facilitate the knowledge gain and transfer of knowledge from the classroom to real-world applications. This exploratory study aims to understand the impact of integrating VPs into classroom learning on students’ perceptions of knowledge acquisition and transfer.

Methods

The study was integrated into an elective course on “Personalized Medicine in Cancer Treatment and Care,” employing a qualitative and quantitative approach. Twenty-two second-year medical undergraduates engaged in a VP session, which included role modeling, practice with various authentic cases, group discussion on feedback, and a plenary session. Student perceptions of their learning were measured through surveys and focus group interviews and analyzed using descriptive statistics and thematic analysis.

Results

Quantitative data shows that students highly valued the role modeling introduction, scoring it 4.42 out of 5, and acknowledged the practice with VPs in enhancing their subject matter understanding, with an average score of 4.0 out of 5. However, students’ reflections on peer dialogue on feedback received mixed reviews, averaging a score of 3.24 out of 5. Qualitative analysis (of focus-group interviews) unearthed the following four themes: ‘Which steps to take in clinical reasoning’, ‘Challenging their reasoning to enhance deeper understanding’, ‘Transfer of knowledge ‘, and ' Enhance Reasoning through Reflections’. Quantitative and qualitative data are cohered.

Conclusion

The study demonstrates evidence for the improvement of learning by incorporating VPs with learning activities. This integration enhances students’ perceptions of knowledge acquisition and transfer, thereby potentially elevating students’ preparedness for real-world clinical settings. Key facets like expert role modeling and various authentic case exposures were valued for fostering a deeper understanding and active engagement, though with some mixed responses towards peer feedback discussions. While the preliminary findings are encouraging, the necessity for further research to refine feedback mechanisms and explore a broader spectrum of medical disciplines with larger sample sizes is underscored. This exploration lays a groundwork for future endeavors aimed at optimizing VP-based learning experiences in medical education.
Gender sensitivity in nursing practice: assessing the impact of childhood experiences of domestic violence and perceptions of sexism among healthcare providers on their gender sensitivity
Authors: Yun Sun Jeong , Kim Hye Young
Published: June 2024

Background

Gender sensitivity, which is the capacity to recognize and address issues of gender discrimination and inequality, is initiated with an awareness of gender differences. This is particularly crucial in nursing, where care is tailored to the holistic needs of individuals. Given the sensitive nature of nursing to gender variances, it is essential that the influences of nurses’ own experiences and perceptions on their gender sensitivity are explored. This study is aimed at assessing the effects of childhood experiences of domestic violence and perceptions of sexism among healthcare providers on their gender sensitivity. Additionally, it seeks to provide empirical data to support the enhancement of gender-sensitive practices within nursing environments, thereby fostering a culture of gender equality, and helping to promote the practical application of gender equality within nursing organizations.

Methods

A cross-sectional survey was employed to gather data from 146 nurses aged 24 and above residing in Daegu. The general characteristics of these nurses, their childhood experiences of domestic violence, their perceptions of sexism, and their level of gender sensitivity were measured. The data were then subjected to a series of statistical analyses, including t-tests, one-way analysis of variance, Pearson’s correlation coefficients, and hierarchical regression analysis, to identify the factors influencing gender sensitivity.

Results

It was revealed by the analysis that nurses’ gender sensitivity was not significantly associated with their childhood experiences of domestic violence. However, a negative correlation was found between gender sensitivity and their perceptions of sexism (r = -0.46, p < 0.001). Additionally, age and perception of sexism were emerged as significant predictors of gender sensitivity, accounting for 42.7% of the variance in the regression model.

Conclusion

This study identifies age and sexism perceptions as key predictors of gender sensitivity among nurses, accounting for 42.7% of the variance. It highlights the importance of recognizing generational cultural differences and implementing flexible practices in nursing organizations. Leaders should enhance cultural awareness and address sexism. Further research is needed on the role of societal and cultural norms in recognizing domestic violence. These findings emphasize the need for targeted interventions to improve gender sensitivity and support high-quality nursing care.
Protein truncating variants in mitochondrial-related nuclear genes and the risk of chronic liver disease
Authors: Yuan Huangbo , Liu Zhenqiu , Chen Mingyang , Xu Qiaoyi , Jiang Yanfeng , Zhang Tiejun , Suo Chen , Chen Xingdong
Published: June 2024

Background

Mitochondrial (MT) dysfunction is a hallmark of liver diseases. However, the effects of functional variants such as protein truncating variants (PTVs) in MT-related genes on the risk of liver diseases have not been extensively explored.

Methods

We extracted 60,928 PTVs across 2466 MT-related nucleus genes using whole-exome sequencing data obtained from 442,603 participants in the UK Biobank. We examined their associations with liver dysfunction that represented by the liver-related biomarkers and the risks of chronic liver diseases and liver-related mortality.

Results

96.10% of the total participants carried at least one PTV. We identified 866 PTVs that were positively associated with liver dysfunction at the threshold of P value < 8.21e − 07. The coding genes of these PTVs were mainly enriched in pathways related to lipid, fatty acid, amino acid, and carbohydrate metabolisms. The 866 PTVs were presented in 1.07% (4721) of participants. Compared with participants who did not carry any of the PTVs, the carriers had a 5.33-fold (95% CI 4.15–6.85), 2.82-fold (1.69–4.72), and 4.41-fold (3.04–6.41) increased risk for fibrosis and cirrhosis of liver, liver cancer, and liver disease-related mortality, respectively. These adverse effects were consistent across subgroups based on age, sex, body mass index, smoking status, and presence of hypertension, diabetes, dyslipidemia, and metabolic syndrome.

Conclusions

Our findings revealed a significant impact of PTVs in MT-related genes on liver disease risk, highlighting the importance of these variants in identifying populations at risk of liver diseases and facilitating early clinical interventions.
Utility of shaking chills as a diagnostic sign for bacteremia in adults: a systematic review and meta-analysis
Authors: Aita Tetsuro , Nakagawa Hiroaki , Takahashi Sei , Naganuma Toru , Anan Keisuke , Banno Masahiro , Hamaguchi Sugihiro
Published: June 2024

Background

Accurate prediction of bacteremia is essential for guiding blood culture collection and optimal antibiotic treatment. Shaking chills, defined as a subjective chill sensation with objective body shivering, have been suggested as a potential predictor of bacteremia; however, conflicting findings exist. To address the evidence gap, we conducted a systematic review and meta-analysis of studies to assess the diagnostic accuracy of shaking chills for predicting bacteremia among adult patients.

Methods

We included studies reporting the diagnostic accuracy of shaking chills or chills for bacteremia. Adult patients with suspected bacteremia who underwent at least one set of blood cultures were included. Our main analysis focused on studies that assessed shaking chills. We searched these studies through CENTRAL, MEDLINE, Embase, the World Health Organization ICTRP Search Portal, and ClinicalTrials.gov. Study selection, data extraction, evaluation for risk of bias, and applicability using the QUADAS-2 tool were conducted by two independent investigators. We estimated a summary receiver operating characteristic curve and a summary point of sensitivity and specificity of the index tests, using a hierarchical model and the bivariate model, respectively.

Results

We identified 19 studies with a total of 14,641 patients in which the accuracy of shaking chills was evaluated. The pooled sensitivity and specificity of shaking chills were 0.37 (95% confidence interval [CI], 0.29 to 0.45) and 0.87 (95% CI, 0.83 to 0.90), respectively. Most studies had a low risk of bias in the index test domain and a high risk of bias and a high applicability concern in the patient-selection domain.

Conclusions

Shaking chills are a highly specific but less sensitive predictor of bacteremia. Blood cultures and early initiation of antibiotics should be considered for patients with an episode of shaking chills; however, the absence of shaking chills must not lead to exclusion of bacteremia and early antibiotic treatment.
Understanding contextual and practical factors to inform WHO recommendations on using chest imaging to monitor COVID-19 pulmonary sequelae: a qualitative study exploring stakeholders’ perspective
Authors: Honein-AbouHaidar Gladys , Rizkallah Cynthia , Bou Akl Imad , Morgano Gian Paolo , Vrbová Tereza , van Deventer Emilie , del Rosario Perez Maria , Akl Elie A.
Published: June 2024

Background

A recommendation by the World Health Organization (WHO) was issued about the use of chest imaging to monitor pulmonary sequelae following recovery from COVID-19. This qualitative study aimed to explore the perspective of key stakeholders to understand their valuation of the outcome of the proposition, preferences for the modalities of chest imaging, acceptability, feasibility, impact on equity and practical considerations influencing the implementation of using chest imaging.

Methods

A qualitative descriptive design using in-depth interviews approach. Key stakeholders included adult patients who recovered from the acute illness of COVID-19, and providers caring for those patients. The Evidence to Decision (EtD) conceptual framework was used to guide data collection of contextual and practical factors related to monitoring using imaging. Data analysis was based on the framework thematic analysis approach.

Results

33 respondents, including providers and patients, were recruited from 15 different countries. Participants highly valued the ability to monitor progression and resolution of long-term sequelae but recommended the avoidance of overuse of imaging. Their preferences for the imaging modalities were recorded along with pros and cons. Equity concerns were reported across countries (e.g., access to resources) and within countries (e.g., disadvantaged groups lacked access to insurance). Both providers and patients accepted the use of imaging, some patients were concerned about affordability of the test. Facilitators included post- recovery units and protocols. Barriers to feasibility included low number of specialists in some countries, access to imaging tests among elderly living in nursing homes, experience of poor coordination of care, emotional exhaustion, and transportation challenges driving to a monitoring site.

Conclusion

We were able to demonstrate that there is a high value and acceptability using imaging but there were factors influencing feasibility, equity and some practical considerations associated with implementation. We had a few suggestions to be considered by the expert panel in the formulation of the guideline to facilitate its implementation such as using validated risk score predictive tools for lung complications to recommend the appropriate imaging modality and complementary pulmonary function test.
BATF promotes tumor progression and association with FDG PET-derived parameters in colorectal cancer
Authors: Lu Xia , Liu Jun , Feng Lijuan , Huang Yan , Xu Yanfeng , Li Cuicui , Wang Wei , Kan Yin , Yang Jigang , Zhang Mingyu
Published: June 2024

Purpose

The purpose of the study was to evaluate the expression and function of basic leucine zipper ATF-like transcription factor (BATF) in colorectal cancer (CRC), and its correlation with 2-deoxy-2[18F]fluoro-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) parameters.

Methods

The TIMER database, GEPIA database, TCGA, and GEO database were used to analyze the expression profile of BATF in human cancers. The reverse transcription‑quantitative PCR and western blot analyses were used to evaluate the mRNA level and protein expression in different CRC cell lines. The expression of BATF in SW620 and HCT116 cells was silenced and cell counting kit-8 assays and clonogenic assay were utilized to evaluate the role of BATF in CRC proliferation. The expression of tumor BATF and glucose transporter 1 (GLUT-1) were examined using immunohistochemical tools in 37 CRC patients undergoing preoperative 18F-FDG PET/CT imaging. The correlation between the PET/CT parameters and immunohistochemical result was evaluated.

Results

In database, BATF was highly expressed in pan-cancer analyses, including CRC, and was associated with poor prognosis in CRC. In vitro, the results showed that knocking down of BATF expression could inhibit the proliferation of SW620 and HCT116 cells. In CRC patients, BATF expression was upregulated in tumor tissues compared with matched para-tumoral tissues, and was related with gender and Ki-67 levels. BATF expression was positively related to GLUT-1 expression and PET/CT parameters, including tumor size, maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis. The multiple logistic analyses showed that SUVmax was an independent predictor of BATF expression. With 15.96 g/cm3 as the cutoff, sensitivity was 85.71%, specificity 82.61%, and area-under-the-curve 0.854.

Conclusion

BATF may be an oncogene associated with 18F-FDG PET/CT parameters in CRC. SUVmax may be an independent predictor of BATF expression.
Repositioning of antiarrhythmics for prostate cancer treatment: a novel strategy to reprogram cancer-associated fibroblasts towards a tumor-suppressive phenotype
Authors: Doldi Valentina , Tortoreto Monica , Colecchia Maurizio , Maffezzini Massimo , Percio Stefano , Giammello Francesca , Brandalise Federico , Gandellini Paolo , Zaffaroni Nadia
Published: June 2024

Background

Cancer-associated fibroblasts (CAFs) play a significant role in fueling prostate cancer (PCa) progression by interacting with tumor cells. A previous gene expression analysis revealed that CAFs up-regulate genes coding for voltage-gated cation channels, as compared to normal prostate fibroblasts (NPFs). In this study, we explored the impact of antiarrhythmic drugs, known cation channel inhibitors, on the activated state of CAFs and their interaction with PCa cells.

Methods

The effect of antiarrhythmic treatment on CAF activated phenotype was assessed in terms of cell morphology and fibroblast activation markers. CAF contractility and migration were evaluated by 3D gel collagen contraction and scratch assays, respectively. The ability of antiarrhythmics to impair CAF-PCa cell interplay was investigated in CAF-PCa cell co-cultures by assessing tumor cell growth and expression of epithelial-to-mesenchymal transition (EMT) markers. The effect on in vivo tumor growth was assessed by subcutaneously injecting PCa cells in SCID mice and intratumorally administering the medium of antiarrhythmic-treated CAFs or in co-injection experiments, where antiarrhythmic-treated CAFs were co-injected with PCa cells.

Results

Activated fibroblasts show increased membrane conductance for potassium, sodium and calcium, consistently with the mRNA and protein content analysis. Antiarrhythmics modulate the expression of fibroblast activation markers. Although to a variable extent, these drugs also reduce CAF motility and hinder their ability to remodel the extracellular matrix, for example by reducing MMP-2 release. Furthermore, conditioned medium and co-culture experiments showed that antiarrhythmics can, at least in part, reverse the protumor effects exerted by CAFs on PCa cell growth and plasticity, both in androgen-sensitive and castration-resistant cell lines. Consistently, the transcriptome of antiarrhythmic-treated CAFs resembles that of tumor-suppressive NPFs. In vivo experiments confirmed that the conditioned medium or the direct coinjection of antiarrhythmic-treated CAFs reduced the tumor growth rate of PCa xenografts.

Conclusions

Collectively, such data suggest a new therapeutic strategy for PCa based on the repositioning of antiarrhythmic drugs with the aim of normalizing CAF phenotype and creating a less permissive tumor microenvironment.
Machine learning integrative approaches to advance computational immunology
Authors: Curion Fabiola , Theis Fabian J.
Published: June 2024

The study of immunology, traditionally reliant on proteomics to evaluate individual immune cells, has been revolutionized by single-cell RNA sequencing. Computational immunologists play a crucial role in analysing these datasets, moving beyond traditional protein marker identification to encompass a more detailed view of cellular phenotypes and their functional roles. Recent technological advancements allow the simultaneous measurements of multiple cellular components—transcriptome, proteome, chromatin, epigenetic modifications and metabolites—within single cells, including in spatial contexts within tissues. This has led to the generation of complex multiscale datasets that can include multimodal measurements from the same cells or a mix of paired and unpaired modalities. Modern machine learning (ML) techniques allow for the integration of multiple “omics” data without the need for extensive independent modelling of each modality. This review focuses on recent advancements in ML integrative approaches applied to immunological studies. We highlight the importance of these methods in creating a unified representation of multiscale data collections, particularly for single-cell and spatial profiling technologies. Finally, we discuss the challenges of these holistic approaches and how they will be instrumental in the development of a common coordinate framework for multiscale studies, thereby accelerating research and enabling discoveries in the computational immunology field.
Association of parent-child health parameters and lifestyle habits - the “epi-family health” longitudinal study protocol
Authors: Christofaro Diego Giulliano Destro , Tebar William Rodrigues , Silva Claudiele Carla Marques da , Saraiva Bruna Thamyres Ciccotti , Santos Amanda Barbosa , Antunes Ewerton Pegorelli , Leite Enrique Gervazoni Ferreira , Leoci Isabella Cristina , Beretta Victor Spiandor , Ferrari Gerson , Mota Jorge , Vanderlei Luiz Carlos Marques , Ritti-Dias Raphael Mendes
Published: June 2024

Background

Lifestyle and habits, cardiovascular risk factors (CRF), bone and mental health, dietary habits, physical activity, among others are developed in childhood and adolescence. Family environment has shown to play an important role in these outcomes. However, whether the parent-child relationship lifestyle habits and health parameters can be influenced by physical activity patterns still unclear. The objective of this study will be to monitor and investigate the associations between lifestyle habits between parents and their children longitudinally, as well as verify whether in more active parents, the possible associations with lifestyle habits are different from those of parents considered less active.

Methods

The sample will consist of parents (father, mother, or both) and their children /adolescents. The participants will be recruited through public call by flyers spread across all the regions of the city and also through social media. The health parameters will include cardiovascular (cardiac autonomic modulation, blood pressure and resting heart rate), bone mineral density, anthropometric indices, handgrip strength, mental health (quality of life, anxiety and depression symptoms and stress), self-reported morbidities and musculoskeletal pain. Lifestyle habits will include physical activity levels, sedentary behavior, sleep parameters, eating patterns, smoking and alcohol consumption. Sociodemographic variables of age, sex, ethnicity and socioeconomic status will be considered as covariates. The follow-up visits of data collection will be scheduled after a period of 12 months from the baseline assessment during every twelve months.

Discussion

The family environment has great potential to determine lifestyle habits in children and adolescents. Based on the results presented in the present study, we hope that health promotion actions can be better designed in the family environment.
UCHL1 promotes the proliferation of porcine granulosa cells by stabilizing CCNB1
Authors: Shi Shengjie , Yuan Huan , Zhang Lutong , Gao Lei , Zhao Lili , Zeng Xiangfang , Qiao Shiyan , Chu Guiyan , Cai Chuanjiang
Published: June 2024

Background

The proliferation of porcine ovarian granulosa cells (GCs) is essential to follicular development and the ubiquitin–proteasome system is necessary for maintaining cell cycle homeostasis. Previous studies found that the deubiquitinase ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) regulates female reproduction, especially in ovarian development. However, the mechanism by which UCHL1 regulates porcine GC proliferation remains unclear.

Results

UCHL1 overexpression promoted GC proliferation, and knockdown had the opposite effect. UCHL1 is directly bound to cyclin B1 (CCNB1), prolonging the half-life of CCNB1 and inhibiting its degradation, thereby promoting GC proliferation. What’s more, a flavonoid compound-isovitexin improved the enzyme activity of UCHL1 and promoted the proliferation of porcine GCs.

Conclusions

UCHL1 promoted the proliferation of porcine GCs by stabilizing CCNB1, and isovitexin enhanced the enzyme activity of UCHL1. These findings reveal the role of UCHL1 and the potential of isovitexin in regulating proliferation and provide insights into identifying molecular markers and nutrients that affect follicle development.
Shared genetic effect of kidney function on bipolar and major depressive disorders: a large-scale genome-wide cross-trait analysis
Authors: Yu Simin , Lin Yifei , Yang Yong , Jin Xi , Liao Banghua , Lu Donghao , Huang Jin
Published: June 2024

Background

Epidemiological studies have revealed a significant association between impaired kidney function and certain mental disorders, particularly bipolar disorder (BIP) and major depressive disorder (MDD). However, the evidence regarding shared genetics and causality is limited due to residual confounding and reverse causation.

Methods

In this study, we conducted a large-scale genome-wide cross-trait association study to investigate the genetic overlap between 5 kidney function biomarkers (eGFRcrea, eGFRcys, blood urea nitrogen (BUN), serum urate, and UACR) and 2 mental disorders (MDD, BIP). Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Psychiatric Genomics Consortium.

Results

Using LD score regression, we found moderate but significant genetic correlations between kidney function biomarker traits on BIP and MDD. Cross-trait meta-analysis identified 1 to 19 independent significant loci that were found shared among 10 pairs of 5 kidney function biomarkers traits and 2 mental disorders. Among them, 3 novel genes: SUFU, IBSP, and PTPRJ, were also identified in transcriptome-wide association study analysis (TWAS), most of which were observed in the nervous and digestive systems (FDR < 0.05). Pathway analysis showed the immune system could play a role between kidney function biomarkers and mental disorders. Bidirectional mendelian randomization analysis suggested a potential causal relationship of kidney function biomarkers on BIP and MDD.

Conclusions

In conclusion, the study demonstrated that both BIP and MDD shared genetic architecture with kidney function biomarkers, providing new insights into their genetic architectures and suggesting that larger GWASs are warranted.
Frailty risk assessment and impact on acute myeloid leukemia outcomes (FRAIL-AML): A population-based study from Ontario, Canada.
Authors: Gupta Gopila , Podolsky Sho , Liu Ning , Cheung Matthew , Bankar Aniket
Published: June 2024

6506

Background: In acute myeloid leukemia (AML), treatment decisions, specifically intensive versus non-intensive approaches, depend on the clinician’s assessment of patient fitness. Frailty as a measure of fitness is a broader concept than commodities and is associated with worse outcomes in many cancers. Frailty assessment is incorporated to provide the precision to oncology treatment selections in addition to disease-related factors. The impact of frailty on outcomes in AML is not well studied. Methods: This retrospective cohort study from population-based health administrative databases in Ontario, Canada (ICES) included all patients (pts) ≥18 years diagnosed with AML between 2006 and 2021, treated within 90 days after diagnosis. Frailty was measured using McIsaacs’s frailty index (MFI)- a validated tool. Progressively increasing tertiles of MFI were categorized as fit (FT), pre-frail (PFR), or frail (FR). Treatment intensity was classified as intensive (IT) or non-intensive (NIT) based on standard practices. The primary outcome was overall survival (OS). Association of frailty with OS was measured using Cox regression separately for IT and NIT AML. Results: Out of 5450 pts, with a median age of 65 (IQR 54-74), 55.8% were males and 44.2% were females. 65% (n=3543) received IT, out of which 29.4% and 35.5% pts were FR and PFR respectively. Remaining 35% (n=1907) received NIT, with 41.1% and 32.3% pts being FR and PFR. Median overall survival in months (OS, 95% CI) for the entire group, IT, and NIT were 12.5 (12.0-13.2), 16.7 (15.7-18.2), and 7.6 (7.0-8.2), respectively. OS (table) was notably lower in FR pts compared to fit pts (p<0.0001) in both IT and NIT. Univariate and multivariate analyses identified frailty, advanced age, and previous non-AML malignancy as risk factors associated with worse OS in both IT and NIT groups (table). Conclusions: Higher frailty is independently associated with worse OS in AML pts after adjusting for advanced age. A substantial proportion of AML pts in both IT and NIT groups exhibit a mismatch in treatment intensity assignments based on their frailty status, with about 30 % FR pts receiving IT and over 25 % FT pts receiving NIT. This study sheds light on the need for frailty evaluations using standardized tools to optimize treatment decisions in AML pts. [Table: see text]
PTPN11variants in chronic myelomonocytic leukemia: Phenotypic and prognostic correlates.
Authors: Natu Anuya Ajit , Csizmar Clifford Michael , Gurney Mark , Lasho Terra L. , Finke Christy , Dean Christopher , Mangaonkar Abhishek A , Al-Kali Aref , Gangat Naseema , Alkhateeb Hassan B. , Tefferi Ayalew , Patnaik Mrinal
Published: June 2024

6513

Background: PTPN11 (Ch12q24) is a proto-oncogene that codes for SHP2, a regulatory protein tyrosine phosphatase that impacts RAS/MAPK signaling. Germline variants have been described in juvenile myelomonocytic leukemia, while somatic variants have been associated with inferior survival in acute myeloid leukemia. PTPN11 variants are infrequent in chronic myelomonocytic leukemia (CMML), and their impact on disease phenotype and survival remains unclear. Methods: After IRB approval, 396 molecularly annotated CMML patients at Mayo Clinic were screened for somatic PTPN11 variants within 12 months of diagnosis while still in chronic phase disease. Overall (OS), acute myeloid leukemia (AML)-free survival (LFS), and predictors of survival were estimated using standard statistical measures. Results: 396 patients (median age 71 years; males 67%) with CMML were considered; pathogenic PTPN11 variants were seen in 12 (3%) with a median VAF of 20.5% (range: 4-50): A72T (n = 2), F285S (n = 2), and A72S (n = 2). Variants were most likely to be seen in the N-terminal SH2 domain (n = 7), followed by the PTP domain (n = 6), and the C-terminal SH2 domain (n = 1). PTPN11 variants clustered with CMML-2 (p = 0.02), higher absolute neutrophil count (p = 0.04), peripheral blood (p = 0.06) and bone marrow (p = 0.02) blast %, older age (p <0.01), and were less likely to have SRSF2 comutations (p = 0.02). After a median follow-up of 18 months (range 0-193), 253 (64%) deaths and 68 (17%) AML transformations were recorded. PTPN11 variants negatively and independently impacted both OS (median 13 vs. 31 months; p <0.01) and LFS (AML events: 42% (5/12) vs. 16% (63/384); p <0.01). In age-adjusted multivariate analysis restricted to genetic risk factors, survival was negatively affected by abnormal karyotype and mutations involving PTPN11, DNMT3A, and SETBP1, and positively by TET2 mutations. All but SETBP1 retained significance in the presence of additional independent risk factors, namely male sex (p <0.01) and leukocyte count (p <0.01); HR in the latter analysis was 4.3 for PTPN11, 2.8 for DNMT3A, and 1.6 for abnormal karyotype. A similar analysis for LFS identified, as risk factors, PTPN11 (p = 0.01), DNMT3A (p <0.01), and ASXL1 (p = 0.03) mutations, as well as bone marrow blast % (p <0.01), absolute monocyte count ≥10 (p = 0.02), and immature circulating myeloid cells (p <0.01). Conclusions: The current study identifies PTPN11 and DNMT3A mutations as independent risk factors for both OS and LFS in CMML. In regard to additional genetic risk factors, OS was positively affected by TET2 mutations and negatively by abnormal karyotype, while LFS was negatively affected by ASXL1 mutations.
Biomarkers in a phase 1b study of investigational microbiome therapeutic SER-155 in adults undergoing allogeneic hematopoietic cell transplantation (allo-HCT).
Authors: Ponce Doris M. , Pandian Swarna , van den Brink Marcel R. M. , Kosuri Satyajit , Khera Nandita , DeFilipp Zachariah Michael , Tejura Bindu , Lichter David I , Chafee Meghan , Bardhan Kankana , Hicks Nathan D , Walsh Emily , Lombardo Mary-Jane , Ford Christopher B. , von Moltke Lisa , Henn Matthew R. , Peled Jonathan U. ,   Seres Therapeutics SER-155 Team
Published: June 2024

6554

Background: Acute graft- versus-host disease (aGvHD) is a life-threatening complication following allo-HCT. Microbiome dysfunction and associated GI barrier disruption may contribute to aGvHD via activation of inflammatory immune responses. Circulating biomarkers in the peri-transplant period are correlated with risk of severe aGvHD, including suppression of tumorigenicity 2 (ST2), regenerating islet-derived 3-alpha (Reg3a) and inflammatory cytokines (IL6, IFNϒγ & TNFα). SER-155 is an investigational cultivated oral microbiome therapeutic designed to restructure the GI microbiome, improve GI barrier integrity and reduce GI inflammation and is being assessed in a 2-part Phase 1b study in adults undergoing allo-HCT. We present preliminary safety, GvHD, PK, and exploratory biomarker data from the completed open-label Cohort 1 through Day 100 post-HCT. Methods: Adult recipients of allo-HCT were eligible. HCT conditioning and aGvHD prophylaxis were per investigator discretion. Patients received 2 courses of SER-155 (pre-HCT and post-neutrophil engraftment, each comprised of 4 days of microbiome conditioning with oral vancomycin followed by 10 days oral SER-155. The primary endpoint was safety. Strain engraftment (PK) and biomarkers were assessed in stool and plasma samples. Results: Fifteen adults enrolled; 13 received at least 1 course of study drug (median age 67; 54% male), and 11 underwent allo-HCT. Following each course, the majority of the 16 SER-155 strains were detected in stool. Treatment-emergent adverse events (AEs) were reported in all patients with GI AEs the most common. No serious AEs (SAEs) were deemed related to SER-155. Most SAEs and AEs of special interest (ie, BSIs, invasive or GI infections) occurred between HCT and the 2nd SER-155 course. There were no deaths before Day 100. No BSIs were attributable to SER-155 strains. The rate of grade 2-4 aGvHD based on MAGIC criteria through Day 100 was 45.5%; no severe grade 3-4 aGvHD was observed. Median levels of plasma biomarkers REG3α, ST2 and inflammatory cytokines were not elevated relative to a reference range (Table). Conclusions: In this small open-label cohort, SER-155 was generally well-tolerated through Day 100 without drug-related SAEs and no severe aGvHD. Plasma biomarkers were not elevated at HCT Day 0 or neutrophil recovery. These preliminary observations align with the design and preclinical evaluation of SER-155. Clinical trial information: NCT04995653 . [Table: see text]
Thiotepa/cyclophosphamide (TT/Cy) preparative regimen for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic stem cell transplantation.
Authors: Nichols Cydney , Ervin Kirsten , Schmidt Caitlin , Schwartz Jennifer E. , Abu Zaid Mohammad Issam , Robertson Michael J. , Abonour Rafat , Grove Meagan , Thakrar Teresa , Farag Sherif
Published: June 2024

6556

Background: Total body irradiation (TBI)-based preparative regimens have been standard for patients with ALL undergoing allogeneic stem cell transplant (SCT). It is unclear if chemotherapy-only regimens are equally efficacious. Here, we present the largest reported experience with myeloablative TT/Cy in patients with ALL undergoing allogeneic SCT and compare outcomes with TBI-based regimens. Methods: Patients with ALL receiving myeloablative allogeneic SCT at Indiana University from 2007-2020 were included. TT/Cy consisted of TT 15 mg/kg and Cy 120 mg/kg. TBI/Cy consisted of 13.2 Gy in 8 fractions and Cy 3600 mg/m2 or etoposide 60 mg/kg. The primary endpoint was overall survival (OS). Secondary endpoints included relapse-free survival (RFS), engraftment, and toxicities within the first 100 days. Median follow up for surviving patients is 2,532 (range 599-4,762) days. Results: 80 patients with ALL of median age 40 (range 22-59 years) received conditioning with TT/Cy (n=25) versus TBI/Cy or TBI/etoposide (n=55). Baseline characteristics were similar. For patients receiving TT/Cy, the median OS was not reached, and the 4-year OS was 54.5% (95% confidence interval [CI], 34.3-74.7%), compared with a median OS of 1,491 days and a 4-year OS of 50.9% (95% CI, 37.8-64.2%) for those receiving TBI-based conditioning (p=.75). Similarly, for TT/Cy patients, the median RFS was 847 days and 4-year RFS was 43.2% (95% CI, 23.4-63%), not significantly different from median RFS of 1491 days and 4-year RFS 50.2% (95% CI 36.9-63.5; p=.232) for recipients of TBI regimens. On multivariable analysis, only a higher disease risk index was associated with significantly worse OS (p<.001), while conditioning regimen was not predictive of OS. Similarly, there was no significant difference in RFS between TT/Cy and TBI-based regimens on either univariable or multivariable analysis. Secondary endpoints are summarized in the table. As shown, TT/Cy was associated with significantly lower incidence of mucositis, TPN usage, bacterial infection, sinusoidal obstruction syndrome (SOS), and longer length of stay of primary transplant admission. Conclusions: While there was no significant difference in OS or RFS for patients receiving either TT/Cy or TBI-based conditioning, TBI was associated with greater toxicity. Our data suggests that TT/Cy is an acceptable alternative to TBI-based conditioning for ALL patients undergoing myeloablative allogeneic SCT. [Table: see text]