bluuebunny/crossref_metadata_2025_split huggingface dataset:
Jin-Gui-Shen-Qi Wan ameliorates diabetic retinopathy by inhibiting apoptosis of retinal ganglion cells through the Akt/HIF-1α pathway
Authors: Liang Dan , Qi Yulin , Liu Lu , Chen Zhaoxia , Tang Shiyun , Tang Jianyuan , Chen Nianzhi 
Published: October 2023

Abstract
Background
Jin-Gui-Shen-Qi Wan (JGSQ) has been used in China for thousands of years to treat various ailments, including frequent urination, blurred vision, and soreness in the waist and knees. It has traditional therapeutic advantages in improving eye diseases.

Aim of the study
Clinical studies have confirmed the therapeutic efficacy of JGSQ in improving diabetes and vision; however, its efficacy and pharmacological effects in treating diabetic retinopathy (DR) remain unclear. Therefore, the aim of this study was to investigate the specific pharmacological effects and potential mechanisms of JGSQ in improving DR through a db/db model.

Materials and methods
db/db mice were given three different doses of orally administered JGSQ and metformin for 8 weeks, and then PAS staining of the retinal vascular network patch, transmission electron microscopy, H&E staining, and TUNEL staining were performed to determine the potential role of JGSQ in improving DR-induced neuronal cell apoptosis. Furthermore, network pharmacology analysis and molecular docking were carried out to identify the main potential targets of JGSQ, and the efficacy of JGSQ in improving DR was evaluated through western blotting and immunofluorescence staining, revealing its mechanism of action.

Results
According to the results from H&E, TUNEL, and PAS staining of the retinal vascular network patch and transmission electron microscopy, JGSQ does not have an advantage in improving the abnormal morphology of vascular endothelial cells, but it has a significant effect on protecting retinal ganglion cells from apoptosis. Through network pharmacology and molecular docking, AKT, GAPDH, TNF, TP53, and IL-6 were identified as the main core targets of JGSQ. Subsequently, through western blot and immunofluorescence staining, it was found that JGSQ can inhibit HIF-1α, promote p-AKT expression, and inhibit TP53 expression. At the same time, inhibiting the release of inflammatory factors protects retinal ganglion cells and improves apoptosis in DR.

Conclusion
These results indicated that in the db/db DR mouse model, JGSQ can inhibit the expression of inflammatory cytokines and protect retinal ganglion cells from apoptosis, possibly by modulating the Akt/HIF-1α pathway.

Graphical Abstract
Generalized pairwise comparisons of prioritized outcomes are a powerful and patient-centric analysis of multi-domain scores
Authors: Deltuvaite-Thomas Vaiva , De Backer Mickaël , Parker Samantha , Deneux Marie , Polgreen Lynda E. , O’Neill Cara , Salvaggio Samuel , Buyse Marc 
Published: October 2023

Abstract
Background
Generalized pairwise comparisons (GPC) can be used to assess the net benefit of new treatments for rare diseases. We show the potential of GPC through simulations based on data from a natural history study in mucopolysaccharidosis type IIIA (MPS IIIA).

Methods
Using data from a historical series of untreated children with MPS IIIA aged 2 to 9 years at the time of enrolment and followed for 2 years, we performed simulations to assess the operating characteristics of GPC to detect potential (simulated) treatment effects on a multi-domain symptom assessment. Two approaches were used for GPC: one in which the various domains were prioritized, the other with all domains weighted equally. The net benefit was used as a measure of treatment effect. We used increasing thresholds of clinical relevance to reflect the magnitude of the desired treatment effects, relative to the standard deviation of the measurements in each domain.

Results
GPC were shown to have adequate statistical power (80% or more), even with small sample sizes, to detect treatment effects considered to be clinically worthwhile on a symptom assessment covering five domains (expressive language, daily living skills, and gross-motor, sleep and pain). The prioritized approach generally led to higher power as compared with the non-prioritized approach.

Conclusions
GPC of prioritized outcomes is a statistically powerful as well as a patient-centric approach for the analysis of multi-domain scores in MPS IIIA and could be applied to other heterogeneous rare diseases.
Dynamic DNA methylation turnover in gene bodies is associated with enhanced gene expression plasticity in plants
Authors: Williams Clara J. , Dai Dawei , Tran Kevin A. , Monroe J. Grey , Williams Ben P. 
Published: October 2023

Abstract
Background
In several eukaryotes, DNA methylation occurs within the coding regions of many genes, termed gene body methylation (GbM). Whereas the role of DNA methylation on the silencing of transposons and repetitive DNA is well understood, gene body methylation is not associated with transcriptional repression, and its biological importance remains unclear.

Results
We report a newly discovered type of GbM in plants, which is under constitutive addition and removal by dynamic methylation modifiers in all cells, including the germline. Methylation at Dynamic GbM genes is removed by the DRDD demethylation pathway and added by an unknown source of de novo methylation, most likely the maintenance methyltransferase MET1. We show that the Dynamic GbM state is present at homologous genes across divergent lineages spanning over 100 million years, indicating evolutionary conservation. We demonstrate that Dynamic GbM is tightly associated with the presence of a promoter or regulatory chromatin state within the gene body, in contrast to other gene body methylated genes. We find Dynamic GbM is associated with enhanced gene expression plasticity across development and diverse physiological conditions, whereas stably methylated GbM genes exhibit reduced plasticity. Dynamic GbM genes exhibit reduced dynamic range in drdd mutants, indicating a causal link between DNA demethylation and enhanced gene expression plasticity.

Conclusions
We propose a new model for GbM in regulating gene expression plasticity, including a novel type of GbM in which increased gene expression plasticity is associated with the activity of DNA methylation writers and erasers and the enrichment of a regulatory chromatin state.
Factors that influence women’s enrolment and ongoing participation in a partially decentralised randomised controlled dermatology trial: a qualitative interview study with participants in the SAFA (Spironolactone for Adult Female Acne) trial
Authors: Boxall Cherish , Renz Susanne , Eminton Zina , Nuttall Jacqueline , Saji Alan , Cluff Charlotte , Wilcox Christopher , Muller Ingrid , Layton Alison M. , Soulsby Irene , Santer Miriam 
Published: October 2023

Abstract
Background
The use of decentralised clinical trials (which bring trials to patients through remote processes and technology versus central on-site visits) has been thought to be a potential solution to common recruitment and retention barriers. However, there is a lack of evidence to understand the experiences, needs and preferences of the public to inform trial methodologies that appeal to different populations. We report participant experiences of SAFA, a partially decentralised randomised clinical trial, to inform the methodology used in future dermatology trials that aim to appeal to women aged 18 and over.

Methods
Participants of the SAFA (Spironolactone for Adult Female Acne) trial were invited to take part in a qualitative semi-structured interview to explore their experience and perspectives of taking part in the trial. Questions focused on their experience of using decentralised methods to access and enrol in the trial (e.g. social media advertising), in addition to the decentralised trial visit and data collection methods used throughout. Interviews were conducted remotely, recorded, and transcribed. Data were analysed using reflexive thematic analysis.

Results
Twelve SAFA participants (all women, age range 22–36 years) were interviewed. Initially, participants were influenced to enrol by trusted online information, the feeling of validation the trial provided, and the convenience and flexibility offered by the decentralised methods and research staff made participants feel valued and enabled them to engage in the trial with minimal interference to existing commitments. SAFA participants were generally accepting of trial demands, such as the text-heavy paperwork and on-site visits for blood collection and highlighted several areas relevant for trial conduct going forwards including where decentralised methods may (and may not) be accepted and how trial accessibility and understanding could be improved.

Conclusions
The study has shown that decentralised methods used by responsive and approachable staff were widely accepted in the SAFA trial. Interviewees found the methods adopted in the SAFA trial helped the trial to fit with their needs and promoted a sense of feeling valued that encouraged ongoing trial engagement. Decentralised methods should be considered favourably when designing a dermatology trial as they can potentially enhance both recruitment and retention.

Trial registration number
ISRCTN 12892056. Registered on October 15, 2018.
An integrated personalized assistive devices approach to reduce the risk of foot ulcer recurrence in diabetes (DIASSIST): study protocol for a multicenter randomized controlled trial
Authors: Vossen Lisa E. , van Netten Jaap J. , Bakker Chantal D. , Berendsen Heleen A. , Busch-Westbroek Tessa E. , Peters Edgar J. G. , Sabelis Louise W. E. , Dijkgraaf Marcel G. W. , Bus Sicco A. 
Published: October 2023

Abstract
Background
Preventing foot ulcers in people with diabetes can increase quality of life and reduce costs. Despite the availability of various interventions to prevent foot ulcers, recurrence rates remain high. We hypothesize that a multimodal treatment approach incorporating various footwear, self-management, and education interventions that matches an individual person’s needs can reduce the risk of ulcer recurrence with beneficial cost-utility. The aim of this study is to assess the effect on foot ulcer recurrence, footwear adherence, and cost-utility of an integrated personalized assistive devices approach in high-risk people with diabetes.

Methods
In a parallel-group multicenter randomized controlled trial, 126 adult participants with diabetes mellitus type 1 or 2, loss of protective sensation based on the presence of peripheral neuropathy, a healed plantar foot ulcer in the preceding 4 years, and possession of any type of custom-made footwear will be included. Participants will be randomly assigned to either enhanced therapy or usual care. Enhanced therapy consists of usual care and additionally a personalized treatment approach including pressure-optimized custom-made footwear, pressure-optimized custom-made footwear for indoor use, at-home daily foot temperature monitoring, and structured education, which includes motivational interviewing and personalized feedback on adherence and self-care. Participants will be followed for 12 months. Assessments include barefoot and in-shoe plantar pressure measurements; questionnaires concerning quality of life, costs, disease, and self-care knowledge; physical activity and footwear use monitoring; and clinical monitoring for foot ulcer outcomes. The study is powered for 3 primary outcomes: foot ulcer recurrence, footwear adherence, and cost-utility, the primary clinical, patient-related, and health-economic outcome respectively.

Discussion
This is the first study to integrate multiple interventions for ulcer prevention into a personalized state-of-the-art treatment approach and assess their combined efficacy in a randomized controlled trial in people with diabetes at high ulcer risk. Proven effectiveness, usability, and cost-utility will facilitate implementation in healthcare, improve the quality of life of high-risk people with diabetes, and reduce treatment costs.

Trial registration
ClinicalTrials.gov NCT05236660. Registered on 11 February 2022.
Effect of music breathing, a program based on mindful breathing and music listening therapy for promoting sense of coherence in young people: study protocol for a randomized controlled trial
Authors: Cheng Winnie Lai-Sheung , Tang Anson Chui-Yan , Tsang Mark Cheuk-Man , Wong Lokki Lok-Ki , Körlin Dag 
Published: October 2023

Abstract
Background
The negative impacts of the COVID-19 pandemic on public health have affected people socially, psychologically, and physically. Young people particularly are having to adjust many aspects of their personal lives: including transitions to work, college, and independent living. Personal resources are important in mitigating stress and improve mental well-being during pandemic. Sense of coherence—an orientation to life—could be considered as a personal resource. Currently, a number of interventions have been developed to target the reduction of stress in young people. Little emphasis has been placed on developing sense of coherence to reduce stress and promote mental well-being among young people. Young people consider music as a preferred leisure activity and an important means of stress relief in their daily lives. However, little research concerning music therapy and sense of coherence exists.

Methods
In the proposed randomized controlled trial, a sample of 290 young people (aged 18–30) will be recruited and allocated randomly into one of two groups: the experimental group and the control group. Participants in the experimental group will participate in a 6-week Music Breathing program that will include music listening and mindful breathing guided by a certified music therapist. Participants in the control group will receive a control condition for 6 weeks Mental Health Education Programme. The primary outcome of the study will be measured using Sense of Coherence Scale. The secondary outcomes will be measured using the Coping Self-Efficacy Scale, Difficulties in Emotion Regulation Scale, Mindful Attention Awareness Scale, Depression Anxiety Stress Scales, BBC Subjective Well-being scale, and salivary cortisol levels. Repeated measures analysis will be used to compare the outcomes between the two groups.

Discussion
The results will inform practice in coping with stress through promoting sense of coherence. Individuals will benefit from the long-term effect of this intervention to enhance their sense of coherence to cope with stressful events and promote better mental well-being.

Trial registration
ClinicalTrials.gov Identifier: NCT05655234. Registered on December 8, 2022.
Synergistic roles of CBX4 chromo and SIM domains in regulating senescence of primary human osteoarthritic chondrocytes
Authors: Chen Yu-Hsiu , Zhang Xin , Attarian David , Kraus Virginia Byers 
Published: October 2023

Abstract
Background
Cellular senescence is a critical factor contributing to osteoarthritis (OA). Overexpression of chromobox homolog 4 (CBX4) in a mouse system was demonstrated to alleviate post-traumatic osteoarthritis (PTOA) by reducing cellular senescence. Additionally, replicative cellular senescence of WI-38 fibroblasts can be attenuated by CBX4. However, the mechanisms underlying this senomorphic function of CBX4 are not fully understood. In this study, we aimed to investigate the role of CBX4 in cellular senescence in human primary osteoarthritic chondrocytes and to identify the functional domains of CBX4 necessary for its function in modulating senescence.

Methods
Chondrocytes, isolated from 6 individuals undergoing total knee replacement for OA, were transduced with wild-type CBX4, mutant CBX4, and control lentiviral constructs. Senescence-related phenotypic outcomes included the following: multiple flow cytometry-measured markers (p16INK4A, senescence-associated β-galactosidase [SA-β-gal] activity and dipeptidyl peptidase-4 [DPP4], and proliferation marker EdU), multiplex ELISA-measured markers in chondrocyte culture media (senescence-associated secretory phenotypes [SASPs], including IL-1β, IL-6, IL-8, TNF-α, MMP-1, MMP-3, and MMP-9), and PCR array-evaluated senescence-related genes.

Results
Compared with control, CBX4 overexpression in OA chondrocytes decreased DPP4 expression and SASP secretion and increased chondrocyte proliferation confirming CBX4 senomorphic effects on primary human chondrocytes. Point mutations of the chromodomain domain (CDM, involved in chromatin modification) alone were sufficient to partially block the senomorphic activity of CBX4 (p16INK4A and DPP4 increased, and EdU decreased) but had minimal effect on SASP secretion. Although having no effect on p16INK4A, DPP4, and EdU, deletion of two small-ubiquitin-like-modifier-interaction motifs (CBX4 ΔSIMs) led to increased SASP secretion (IL-1β, TNF-α, IL-8). The combination CBX4 CDMΔSIMs altered all these measures adversely and to a greater degree than the single domain mutants. Deletion of the C-terminal (CBX4 ΔC-box) involved with transcriptional silencing of polycomb group proteins increased IL-1β slightly but significantly but altered none of the other senescence outcome measures.

Conclusions
CBX4 has a senomorphic effect on human osteoarthritic chondrocytes. CDM is critical for CBX4-mediated regulation of senescence. The SIMs are supportive but not indispensable for CBX4 senomorphic function while the C-box is dispensable.
Sustain release of dexamethasone from polyvinyl alcohol microparticle produced via coaxial microfluidic system
Authors: Abdi Majareh Melika , Davachi Seyed Mohammad , Tavakoli Moghaddam Yasaman , Khanmohammadi Mehdi 
Published: October 2023

Abstract
Objective
Polyvinyl alcohol (PVA) as a synthetic biopolymer has unique physicochemical properties to achieve an efficient drug carrier. In this study phenol-substituted polyvinyl alcohol (PVAPh) microparticle was made through a microfluidic system and peroxidase-mediated reaction in the presence of hydrogen peroxide and in following dexamethasone (Dex) release characteristics from this vehicle were elaborated for sustained drug delivery applications.

Results
PVAPh was synthesized by esterification and amidation reactions respectively. Then, the synthesized PVAPh solution containing peroxidase and Dex flowed within the inner channel of the coaxial microfluidic device while liquid paraffin saturated with H2O2 flowed from the outer channel. The monodisperse microparticles were produced in a spherical shape with an average diameter of 160 μm. The Dex was successfully encapsulated in PVAPh MP and its sustained release profile was maintained for up to 7 days. It was found that exposure of Dex-loaded PVAPh MPs to subcultured mouse embryonic fibroblast 10T1/2 cells had no deleterious effects on cell viability, morphology and growth rate. Moreover, the sustained release of Dex and the high mechanical durability of PVAPh MPs suggest an excellent prospect for the synthesized PVAPh and the developed method as a biocompatible carrier required for drug delivery and regenerative medicine.
Hydrocarbon ingestions among individuals younger than 20 years old reported to United States Poison Centers, 2000–2021
Authors: Palmer Samiza B. , Spiller Henry A. , Kistamgari Sandhya , Casavant Marcel J. , Rine Natalie I. , Yang Jingzhen , Zhu Motao , Smith Gary A. 
Published: October 2023

Abstract
Background
Hydrocarbon-based products have many household and commercial uses and exposure to these substances is common. Severe clinical effects can occur if these products are ingested. This study investigated the characteristics and trends of hydrocarbon ingestions reported to United States Poison Centers.

Methods
Data from the National Poison Data System were analyzed for cases of hydrocarbon ingestion among individuals < 20 years old reported to United States Poison Centers from January 1, 2000 through December 31, 2021.

Results
There were 284,085 hydrocarbon ingestions reported during the 22-year study period in which a hydrocarbon was the first-ranked substance. Most of these cases occurred among children < 6 years old (83.2%), males (64.6%), at a residence (96.5%), were single-substance exposures (98.3%), and were managed on-site rather than in a health care facility (74.9%). However, 4.5% of cases were associated with a serious medical outcome, including 34 deaths. Thirty-two deaths were among children < 6 years old and most were associated with aspiration. Gasolines accounted for 24.6% of total cases, followed by lubricating oils and/or motor oils (19.9%), other types of hydrocarbons (14.9%), lamp oils (11.3%), and lighter fluids and/or naphtha (10.3%). The rate of hydrocarbon ingestions among United States youth < 20 years old decreased significantly (p < 0.0001) by 66.5% from 2000 to 2021. The greatest rate decrease was observed among lamp oils (− 78.4%, p < 0.0001), followed by gasolines (− 75.9%, p < 0.0001).

Conclusions
Although the rate of hydrocarbon ingestions decreased during the study period and most reported cases resulted in non-serious outcomes, the number of cases remains high with a non-trivial minority (4.5%) of cases associated with a serious medical outcome, including death. Most deaths were among children < 6 years old. This underscores the need to increase primary prevention efforts, especially for young children.