bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single-center, double-blind, randomized, placebo-controlled, two-arm study to evaluate the safety and efficacy of once-weekly sirolimus (rapamycin) on muscle strength and endurance in older adults following a 13-week exercise program
Authors: Stanfield Brad , Kaeberlein Matt , Leroux Brian , Jones Julie , Lucas Ruth , Arroll Bruce 
Published: October 2024

Abstract
Background
Aging leads to a decline in muscle mass and strength, contributing to frailty and decreased quality of life. Sirolimus (rapamycin) , an mTOR inhibitor, has shown potential in preclinical studies to extend lifespan and improve health span. This study evaluates the safety and efficacy of once-weekly sirolimus (rapamycin) administration on muscle strength and endurance in older adults engaged in a 13-week exercise program.

Methods
This randomized, double-blind, placebo-controlled trial will enroll 40 participants aged 65–85. Participants will be randomly assigned to receive either sirolimus (rapamycin) 6 mg/week or placebo for 13 weeks, in conjunction with an at-home exercise program. The primary outcome measure is the change in muscle strength and endurance, assessed by the 30-Second Chair-Stand Test. Secondary outcome measures include adverse events, changes in muscle strength and endurance as measured by the 6-min walk test, handgrip strength, and participant-reported outcomes using the SF-36 survey. Assessments will be conducted at baseline, mid-intervention (week 6), and post-intervention (week 13). Blood samples will be collected for hematology and biochemistry analyses, including full blood count, urea and electrolytes, liver function tests, HbA1c, lipids, serum IGF-1, and hs-CRP. DNA methylation will be analyzed using TruDiagnostic™ to explore changes in biological age.

Discussion
This study aims to provide insights into the potential benefits of intermittent sirolimus (rapamycin) administration on muscle performance in older adults. By alternating periods of mTOR inhibition through rapamycin and activation via exercise, this study will explore a novel approach to enhancing muscle strength and endurance in the aging population. The results could have significant implications for developing interventions to improve physical function and overall health outcomes in older adults. Safety and tolerability will also be closely monitored to ensure the feasibility of this regimen for wider application.

Trial registration
Australia New Zealand Clinical Trials Registry, ACTRN12624000790549. Registered on 26 June 2024 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12624000790549.
Contamination of trichlorobenzene isomers in food: toxicity, analytical methods, occurrence in food, and risk assessments
Authors: Lee Hyegyeong , Kim Kiyun , Park Junhyeong , Lee Joon-Goo 
Published: October 2024

AbstractTrichlorobenzenes (TCBs), comprising the isomers 1,2,3-, 1,2,4-, and 1,3,5-TCB, disrupt metabolic processes by inducing liver enzymes involved in xenobiotic metabolism, suggesting a broad toxicological impact. Specifically, exposure to TCBs is associated with significant organ-specific toxicities, such as increased liver and kidney weights in rodents and cytotoxic effects in mammalian cells, which include DNA damage without metabolic activation. Used extensively in industrial and agricultural sectors, TCBs are prevalent pollutants in various ecosystems, including air, food, surface water, groundwater, sediment, soil, and sewage. This is a concern because of their tendency to accumulate in lipid-containing tissues of animals and humans and potentially serious risks to human health and ecosystems. Information showing the presence of TCBs in food, drinking water, and even human breast milk underscores the need for ongoing assessment of the extent of these contaminants in food to measure the potential exposure to these chemicals. TCBs are extracted from various food sample matrices, and then instrumental analysis is performed, typically gas chromatography (GC) coupled with a variety of detectors. This review discusses the occurrence and risk assessment of TCBs in foods, as well as the toxicology and analytical methods related to TCBs.
Establishment of goat mammary organoid cultures modeling the mammary gland development and lactation
Authors: Jia Lei , Zhang Wenying , Luo Tao , Li Yongtao , Shu Jianhong , Strand Julie , Yue Yuan , Purup Stig , Liu Jianxin , Shi Hengbo 
Published: October 2024

Abstract
Background
Although several cell culture systems have been developed to investigate the function of the mammary gland in dairy livestock, they have potential limitations, such as the loss of alveolar structure or genetic and phenotypic differences from their native counterparts. Overcoming these challenges is crucial for lactation research. Development of protocols to establish lactating organoid of livestock represents a promising goal for the future. In this study, we developed a protocol to establish a culture system for mammary organoids in dairy goats to model the mammary gland development and lactation process.

Results
The organoids cultured within an extracellular matrix gel maintained a bilayer structure that closely resembled the native architecture of mammary tissue. The expansion of mammary organoids was significantly promoted by growth factors containing epidermal growth factor and fibroblast growth factor 2 whereas the proliferative index of the organoids was significantly inhibited by the treatment with WNT inhibitors. Upon stimulation with a lactogenic medium containing prolactin, the mammary organoids exhibited efficient lactation, characterized by the accumulation of lipid droplets in the lumen space. The lactation could be sustained for more than 3 weeks. Importantly, the expression patterns of genes related to fatty acid synthesis and milk proteins in lactating organoids closely mirrored those observed in mammary tissues. These observations were confirmed by data from proteomic analysis that the bulk of milk proteins was produced in the lactating organoids.

Conclusion
This study is the first to establish a mammary organoid culture system modeling the mammary gland development and lactation process in ruminants. The efficient induction of lactation in ruminant mammary organoids holds promises for advancing the field of cell-based milk bio-manufacture in the food industry.
Combined inhibition of MET and VEGF enhances therapeutic efficacy of EGFR TKIs in EGFR-mutant non-small cell lung cancer with concomitant aberrant MET activation
Authors: Huang Shanshan , Long Yaling , Gao Yuan , Lin Wanling , Wang Lei , Jiang Jizong , Yuan Xun , Chen Yuan , Zhang Peng , Chu Qian 
Published: October 2024

Abstract
Background
Aberrant activation of mesenchymal epithelial transition (MET) has been considered to mediate primary and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, mechanisms underlying this process are not wholly clear and the effective therapeutic strategy remains to be determined.

Methods
The gefitinib-resistant NSCLC cell lines were induced by concentration increase method in vitro. Western blot and qPCR were used to investigate the relationship between MET and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway. Double luciferase reporter gene and co-immunoprecipitation were used to further reveal the regulation mechanism between MET and VEGF/VEGFR2. The effect of combined inhibition of MET and VEGF/VEGFR2 signaling pathway on the therapeutic sensitivity of EGFR-TKI in gefitinib resistant cell lines with MET aberration was verified ex vivo and in vivo.

Results
We successfully obtained two gefitinib-resistant NSCLC cell lines with EGFR mutation and abnormal activation of MET. We observed that MET formed a positive feedback loop with the VEGF/VEGFR2 signaling, leading to persistent downstream signaling activation. Specifically, MET up-regulated VEGFR2 expression in a MAPK/ERK/ETS1-dependent manner, while VEGF promoted physical interaction between VEGFR2 and MET, thereby facilitating MET phosphorylation. A MET inhibitor, crizotinib, combined with an anti-VEGF antibody, bevacizumab, enhanced the sensitivity of NSCLC cells to gefitinib and synergistically inhibited the activation of downstream signaling in vitro. Dual inhibition of MET and VEGF combined with EGFR TKIs markedly restrained tumor growth in both human NSCLC xenograft models and in an EGFR/MET co-altered case.

Conclusions
Our work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance.
The relationship between co-occurring traumatic experiences and co-occurring mental health domains for veterans resident in Northern Ireland
Authors: Hitch Catherine , Spikol Erik , Toner Paul , Armour Cherie 
Published: October 2024

Abstract
Introduction
Veterans residing in Northern Ireland (NI) likely experience higher levels of co-occurring lifetime trauma exposure and associated co-occurring mental health symptoms, due to the Troubles. As NI veterans have been subject to little exploration it is difficult to know how to support them. This exploratory study explored the co-occurrence of mental health symptoms as a function of co-occurring traumatic experiences.

Methods
Two latent class analyses (LCA) were conducted on NI veteran data (n = 609). One LCA factored endorsements of 16-lifetime traumatic events, with a separate LCA exploring the co-occurrence of symptoms across six mental health domains. Mental health symptom classes were considered as a function of trauma classes, military-specific variables, gender and age.

Results
Three trauma classes were identified: High Multi Trauma (10.84%); High Combat/Conflict (47.62%); Moderate Combat Conflict (41.54%), and three mental health symptom classes: High Co-occurring Mental Health (19.38%); High Depression Moderate Anxiety/Alcohol (24.63%); Moderate Alcohol/Normative (55.99%). Significant predictors of High Co-occurring Mental Health class membership were UDR service, ‘Worst’ military trauma and High Multi Trauma class membership. Both combat classes had a negative relationship with the High Co-occurring Mental Health. Predictors of the High Depression Moderate Anxiety/Alcohol class were High Multi Trauma class membership and UDR service, with Age and Moderate Combat Class membership having a negative relationship.

Discussion
NI veterans could be labelled as ‘traumatised’ due to high levels of combat/conflict exposure, yet the two combat classes seemed unrelated to membership of poorer mental health classes. UDR membership indicated that living in one’s theatre of war could have mental health implications. It was concerning that 45% experienced some co-occurring mental health symptoms with 19% experiencing the poorest symptoms. Hazardous alcohol use appeared unrelated to poor mental health. Further research is needed, utilising robust methods. No clinical inferences are to be made from this exploratory study.
An early and stable mouse model of polymyxin-induced acute kidney injury
Authors: Liu Linqiong , Liu Yuxi , Xin Yu , Liu Yanqi , Gao Yan , Yu Kaijiang , Wang Changsong 
Published: October 2024

Abstract
Background
Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results.

Methods
In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury.

Results
Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman’s rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group.

Conclusion
The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups.
Advances and prospects of multi-modal ophthalmic artificial intelligence based on deep learning: a review
Authors: Wang Shaopan , He Xin , Jian Zhongquan , Li Jie , Xu Changsheng , Chen Yuguang , Liu Yuwen , Chen Han , Huang Caihong , Hu Jiaoyue , Liu Zuguo 
Published: October 2024

Abstract
Background
In recent years, ophthalmology has emerged as a new frontier in medical artificial intelligence (AI) with multi-modal AI in ophthalmology garnering significant attention across interdisciplinary research. This integration of various types and data models holds paramount importance as it enables the provision of detailed and precise information for diagnosing eye and vision diseases. By leveraging multi-modal ophthalmology AI techniques, clinicians can enhance the accuracy and efficiency of diagnoses, and thus reduce the risks associated with misdiagnosis and oversight while also enabling more precise management of eye and vision health. However, the widespread adoption of multi-modal ophthalmology poses significant challenges.

Main text
In this review, we first summarize comprehensively the concept of modalities in the field of ophthalmology, the forms of fusion between modalities, and the progress of multi-modal ophthalmic AI technology. Finally, we discuss the challenges of current multi-modal AI technology applications in ophthalmology and future feasible research directions.

Conclusion
In the field of ophthalmic AI, evidence suggests that when utilizing multi-modal data, deep learning-based multi-modal AI technology exhibits excellent diagnostic efficacy in assisting the diagnosis of various ophthalmic diseases. Particularly, in the current era marked by the proliferation of large-scale models, multi-modal techniques represent the most promising and advantageous solution for addressing the diagnosis of various ophthalmic diseases from a comprehensive perspective. However, it must be acknowledged that there are still numerous challenges associated with the application of multi-modal techniques in ophthalmic AI before they can be effectively employed in the clinical setting.
Cannabis-related information sources among US residents: A probability-weighted nationally representative survey
Authors: Boehnke Kevin F. , Smith Tristin , Elliott Michael R. , Wilson-Poe Adrianne R. , Kruger Daniel J. 
Published: October 2024

Abstract
Introduction
The Department of Health and Human Services recently recommended rescheduling cannabis from Schedule I to Schedule III, which might have broad effects on public health outcomes related to cannabis. In this changing environment, understanding national patterns in how people obtain information about cannabis is critical to informing public health outreach and education.

Methods
We surveyed American adults (≥ 18 years) between June 22nd-26th, 2023 using the AmeriSpeak panel. We assessed past year cannabis use, intentions for cannabis use, and where participants got their information about cannabis. We investigated differences by past year use and explored associations between demographic and cannabis use characteristics with information sources using logistic regression.

Results
Participants (n = 1,161) were 48.3±27.3 years of age (mean±standard deviation), 51% female, and 27% reported past year cannabis use. The most common information sources used were friends/family (35.6%) and websites (33.7%), while the least common information sources were health/medical care providers (9.3%), employees at place of purchase (8.6%), and government agencies (4.7%). Past year cannabis use was positively associated with all information sources except government agencies and popular media articles. A higher proportion of those using cannabis medically (with or without recreational use) obtained information from a healthcare provider (16.4% vs. 5.2%, p = 0.006).

Conclusions
As cannabis accessibility increases and legality continues changing, there is a strong need for better clinician education, improved public health outreach, and improved communication between patients and clinicians about cannabis.
Precision diagnosis and treatment of vitamin metabolism-related epilepsy
Authors: Gan Yajing , Li Guoyan , Wei Zihan , Feng Yan , Shi Yuqing , Deng Yanchun 
Published: October 2024

AbstractEpilepsy is a chronic disorder of the nervous system caused by abnormal discharges from brain cells. Structural, infectious, metabolic, immunologic, and unknown causes can contribute to the development of seizures. In recent years, there has been increasing attention on epilepsy caused by genetic metabolic disorders. More than two hundred inherited metabolic disorders have been identified as potential cause of seizures, and they are mainly associated with energy deficiency in the brain, accumulation of toxic substances, abnormal neurotransmitter transmission, and deficiency of cofactors. Vitamins play a crucial role as components of several enzymes or coenzymes. Impaired metabolism of thiamine, biotin, vitamin B6, vitamin B12 and folic acid can contribute to early-onset seizures and developmental abnormalities in infants. However, timely supplementation therapy can significantly improve patient prognosis of affected patients. Therefore, a thorough understanding and investigation of the metabolic basis of epilepsy is essential for the development of precise therapeutic approaches, which could provide significant therapeutic benefits for patients.
Use of implementation mapping to develop a multifaceted implementation strategy for an electronic prospective surveillance model for cancer rehabilitation
Authors: Lopez Christian J. , Neil-Sztramko Sarah E. , Tanyoas Mounir , Campbell Kristin L. , Bender Jackie L. , Strudwick Gillian , Langelier David M. , Reiman Tony , Greenland Jonathan , Jones Jennifer M. ,   on behalf of the Canadian Cancer Rehabilitation Team
Published: October 2024

Abstract
Background
Electronic Prospective Surveillance Models (ePSMs) remotely monitor the rehabilitation needs of people with cancer via patient-reported outcomes at pre-defined time points during cancer care and deliver support, including links to self-management education and community programs, and recommendations for further clinical screening and rehabilitation referrals. Previous guidance on implementing ePSMs lacks sufficient detail on approaches to select implementation strategies for these systems. The purpose of this article is to describe how we developed an implementation plan for REACH, an ePSM system designed for breast, colorectal, lymphoma, and head and neck cancers.

Methods
Implementation Mapping guided the process of developing the implementation plan. We integrated findings from a scoping review and qualitative study our team conducted to identify determinants to implementation, implementation actors and actions, and relevant outcomes. Determinants were categorized using the Consolidated Framework for Implementation Research (CFIR), and the implementation outcomes taxonomy guided the identification of outcomes. Next, determinants were mapped to the Expert Recommendations for Implementing Change (ERIC) taxonomy of strategies using the CFIR-ERIC Matching Tool. The list of strategies produced was refined through discussion amongst our team and feedback from knowledge users considering each strategy’s feasibility and importance rating via the Go-Zone plot, feasibility and applicability to the clinical contexts, and use among other ePSMs reported in our scoping review.

Results
Of the 39 CFIR constructs, 22 were identified as relevant determinants. Clinic managers, information technology teams, and healthcare providers with key roles in patient education were identified as important actors. The CFIR-ERIC Matching Tool resulted in 50 strategies with Level 1 endorsement and 13 strategies with Level 2 endorsement. The final list of strategies included 1) purposefully re-examine the implementation, 2) tailor strategies, 3) change record systems, 4) conduct educational meetings, 5) distribute educational materials, 6) intervene with patients to enhance uptake and adherence, 7) centralize technical assistance, and 8) use advisory boards and workgroups.

Conclusion
We present a generalizable method that incorporates steps from Implementation Mapping, engages various knowledge users, and leverages implementation science frameworks to facilitate the development of an implementation strategy. An evaluation of implementation success using the implementation outcomes framework is underway.
Evaluation of treatment-related problems in hemodialysis patients in Egypt: a prospective observational study
Authors: Helmy Noha H. , Hussein Amal , Sadek Eman Mohamed , Alarfaj Sumaiah J. , El Minshawy Osama , Wahsh Engy A. 
Published: October 2024

Abstract
Background
Hemodialysis (HD) patients often have multiple comorbidities, leading to care from various prescribers and a complex medication regimen. Patients on HD are particularly vulnerable to treatment-related problems (TRPs). This study aimed to evaluate the impact of the lack of clinical pharmacy services on HD care by assessing the types and frequencies of TRPs encountered in HD units.

Patients and methods
This was a prospective observational study. Data were collected from medical records and medication reconciliation of HD patients attending to a large Hospital specialized in Nephrology and Urology at the Minia region in Egypt. The frequencies and percentages of demographic data were calculated. Standard multiple regression analysis was conducted to assess predictors of TRPs.

Results
A total of 103 patients were included. The mean age was 47.6 ± 15.1 years; patients had been on HD for 5.95 ± 5.04 years, had 2.47 ± 0.57 comorbidities and took 7.02 ± 1.35 different medications. Within the included patients, 121 TRPs were identified. The most common TRPs were the need for more frequent monitoring, followed by inappropriate dose/dosing frequency and the need for additional therapy (33.9%, 26.2%, and 15.5%, respectively). We did not identify any predictors of TRP in this study.

Conclusion
In the Minia HD population of Egypt, TRPs affected 75% of the patients. Therefore, involving clinical pharmacy services to tailor the optimal management plan for each patient is crucial to reduce the frequency of TRPs in this vulnerable patient population.