bluuebunny/crossref_metadata_2025 huggingface dataset:
Hippocampus segmentation after brain tumor resection via postoperative region synthesis
Authors: Tao Changjuan , Gu Difei , Huang Rui , Zhou Ling , Hu Zhiqiang , Chen Yuanyuan , Zhang Xiaofan , Li Hongsheng
Published: September 2023

Purpose

Accurately segmenting the hippocampus is an essential step in brain tumor radiotherapy planning. Some patients undergo brain tumor resection beforehand, which can significantly alter the postoperative regions’ appearances and intensity of the 3D MR images. However, there are limited tumor resection patient images for deep neural networks to be effective.

Methods

We propose a novel automatic hippocampus segmentation framework via postoperative image synthesis. The variational generative adversarial network consists of intensity alignment and a weight-map-guided feature fusion module, which transfers the postoperative regions to the preoperative images. In addition, to further boost the performance of hippocampus segmentation, We design a joint training strategy to optimize the image synthesis network and the segmentation task simultaneously.

Results

Comprehensive experiments demonstrate that our proposed method on the dataset with 48 nasopharyngeal carcinoma patients and 67 brain tumor patients observes consistent improvements over state-of-the-art methods.

Conclusion

The proposed postoperative image synthesis method act as a novel and powerful scheme to generate additional training data. Compared with existing deep learning methods, it achieves better accuracy for hippocampus segmentation of brain tumor patients who have undergone brain tumor resection. It can be used as an automatic contouring tool for hippocampus delineation in hippocampus-sparing radiotherapy.
Kidney function decline associated with proton pump inhibitors: results from the ELSA-Brasil cohort
Authors: dos Santos Andrêza Soares , de Menezes Sara Teles , Silva Isabella Ribeiro , Oliveira William Neves , Pereira Mariana Linhares , Mill José Geraldo , Barreto Sandhi Maria , Figueiredo Roberta Carvalho
Published: September 2023

Objective

Investigate the longitudinal association of use and time of use of proton pump inhibitors (PPI) with incidence of chronic kidney disease (CKD) and kidney function change.

Methods

Prospective study with 13,909 participants from baseline (2008–2010) and second wave (2012–2014) of the ELSA-Brasil (mean interval between visits = 3.9 years (1.7–6.0)). Participants answered about use and time use of the PPI in the two weeks prior the interview. Renal function was assessed by glomerular filtration rate estimated by the Collaboration Equation for the Epidemiology of Chronic Kidney Disease. Values below 60ml/min/1.73 m² in wave 2 were considered incident CKD. Associations between PPI use and time of use at baseline and incident CKD and decline in renal function were estimated, respectively, by logistic regression and linear models with mixed effects, after adjusting for confounders.

Results

After adjustments, PPI users for more than six months had an increased risk of CKD compared to non-users. Compared to non-users, users PPIs for up to six months and above six months had greater decline in kidney function over time.

Conclusion

This cohort of adults and elderly, after a mean interval of 3.9 years, PPI use and initial duration were associated with kidney function change between visits.
Clinicopathological features and prognosis of patients with HER2-low breast cancer
Authors: Yang Xin , Li Yao , lu Xu , Ren Xiaotian , Hua Bin
Published: September 2023

Background

Low human epidermal growth factor receptor 2 (HER2) expression is an emerging concept in breast cancer that is defined as immunohistochemistry (IHC) 1 + or IHC 2 + and negative in situ hybridization (ISH) but has been poorly investigated. The aim of our study was to determine the frequency of low HER2 expression among HER2-negative breast cancers and compare the clinicopathological features and prognosis of HER2-low patients with those of HER2-zero patients.

Methods

We collected the data of 684 patients with primary HER2-negative breast cancer who underwent surgery between January 2012 and September 2021 from our self-built database. Clinicopathological features, recurrence-free interval (RFI) and breast cancer-specific survival (BCSS) were compared between HER2-low and HER2-zero (IHC 0) patients.

Results

Among the 684 patients, 512 (74.9%) patients had low HER2 expression, and 172 (25.1%) patients had zero HER2 expression. The average age was 57.7 ± 12.6 years, 472 (69.0%) patients were aged < 65 years, and 212 (31.0%) patients were aged ≥ 65 years. Compared to HER2-zero tumors, HER2-low tumors had a higher proportion of hormone receptor (HR)-positive cases (89.6% vs. 75.6%, P < 0.001) and a lower rate of histological grade III cases (29.4% vs. 38.8%, P < 0.001). Kaplan–Meier analysis showed that low HER2 expression was associated with prolonged RFI in breast cancer patients, especially in HR + breast cancer patients (P = 0.028) and < 65-year-old breast cancer patients (P = 0.000). Multivariate Cox regression analysis showed that low HER2 expression was a low-risk factor for RFI (HR: 0.531, 95% CI: 0.292–0.967, P = 0.038) but had no influence on BCSS (P = 0.272).

Conclusions

HER2-low tumors had a higher proportion of HR positivity and a lower rate of histological grade III than HER2-zero tumors. Low HER2 expression seemed to be a protective factor for RFI, especially in patients with HR + and those younger than 65 years.
Effect of serum lactate dehydrogenase-to-albumin ratio (LAR) on the short-term outcomes and long-term prognosis of colorectal cancer after radical surgery
Authors: Shu Xin-Peng , Xiang Ying-Chun , Liu Fei , Cheng Yong , Zhang Wei , Peng Dong
Published: September 2023

Background

Whether serum lactate dehydrogenase-to-albumin ratio (LAR) influenced the outcomes of colorectal cancer (CRC) patients after radical surgery remained unclear. Therefore, this study sought to examine how LAR influences the short-term and long-term outcomes of CRC patients who have undergone radical surgery.

Methods

This study retrospectively included CRC patients who underwent radical resection between January 2011 and January 2020. We compared short-term outcomes, as well as overall survival (OS) and disease-free survival (DFS), among various groups. Both univariate and multivariate logistic regression analyses were utilized to pinpoint independent risk factors associated with overall complications and major complications. Moreover, Cox regression analysis were conducted for OS and DFS. Odds ratio (OR) and Hazard ratio (HR) were adjusted.

Results

This study encompassed a cohort of 3868 patients. 3440 patients were in the low LAR group and 428 patients constituted the high LAR group. In the high LAR group, patients experienced significantly longer operative times (p < 0.01), larger intraoperative blood loss (p < 0.01), and extended postoperative hospital stays (p < 0.01). Additionally, the incidence of both overall complications (p < 0.01) and major complications (p < 0.01) was higher in the high LAR group compared to the low LAR group. Furthermore, LAR was emerged as an independent prognostic factor for overall complications [OR/95% CI: (1.555/1.237 to 1.954), p < 0.01] and major complications [OR/95% CI: (2.178/1.279 to 3.707), p < 0.01]. As for long-term survival, the high LAR group had worse OS in stage II (p < 0.01) and stage III (p < 0.01). In both stage II (p < 0.01) and stage III (p < 0.01), the high LAR group exhibited poorer DFS. Additionally, according to Cox regression analysis, LAR was identified as an independent predictor for both OS [HR/95% CI: (1.930/1.554 to 2.398), p < 0.01] and DFS [HR/95% CI: (1.750/1.427 to 2.146), p < 0.01].

Conclusion

LAR emerged as an independent predictor not only for overall complications and major complications but also for both OS and DFS, highlighting its significance and deserving the attention of surgeons.
Kidney involvement in children during the SARS-CoV-2 Omicron variant pandemic
Authors: Jung Jiwon , Lee Jina , Lee Joo Hoon
Published: September 2023

Background

As the coronavirus disease-2019 (COVID-19) pandemic continues, driven by the Omicron variant, infection rates in children have recently rapidly surged compared with previous years. We aimed to investigate the presentation of kidney involvement in children after Omicron variant severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

Methods

We retrospectively reviewed the medical records of pediatric patients who presented with kidney disease with a temporal relationship with COVID-19 between January and August 2022 in a single tertiary center in Korea.

Results

Fifteen children presented with kidney involvement after Omicron variant infection, with a median age of 10.6 (6.8–18.3) years. None of the patients exhibited severe respiratory symptoms apart from cough and sore throat. The median time from infection to renal symptom onset was 3 (0–49) days. Among 10 patients with underlying kidney disease, six had previously been diagnosed with nephrotic syndrome (NS) that relapsed after COVID-19 infection, two with immunoglobulin A nephropathy (IgAN) experienced transient gross hematuria (GHU) with or without acute kidney injury (AKI), and two with kidney transplantation presented with AKI. Of the five patients without underlying kidney disease, one patient had NS, and the other four patients had GHU and proteinuria (PU), of whom one was eventually diagnosed with Henoch Shönlein Purpura nephritis (HSPN), and one with rhabdomyolysis. The seven patients with NS (1 new-onset, 6 relapsed) had uneventful remission with corticosteroid therapy. Apart from one patient with new-onset HSPN, GHU and PU resolved spontaneously in all affected patients, and AKI also resolved with supportive care.

Conclusions

Kidney involvement subsequent to Omicron variant COVID-19 exhibited various, but mostly mild manifestations in children.
Day-to-day variability in accelerometer-measured physical activity in mid-aged Australian adults
Authors: Brady Ruth , Brown Wendy J. , Mielke Gregore I.
Published: September 2023

Purpose

The aim was to use accelerometer data to describe day-to-day variability in physical activity in a single week, according to sociodemographic variables, in mid-aged Australian adults.

Methods

Data were from participants in the How Areas in Brisbane Influence HealTh and AcTivity (HABITAT) study who took part in a 2014 sub-study (N = 612; Mean age 60.6 [SD 6.9; range 48-73]). Participants wore a triaxial accelerometer (ActiGraph wGT3X-BT) on their non-dominant wrist for seven days, and data were expressed as acceleration in gravitational equivalent units (1 mg = 0.001 g). These were, used to estimate daily acceleration (during waking hours) and daily time spent in moderate-vigorous physical activity (MVPA, defined as ≥ 100mg). Coefficient of variation (calculated as [standard deviation/mean of acceleration and MVPA across the seven measurement days] * 100%) was used to describe day-to-day variability.

Results

Average values for both acceleration (24.1-24.8 mg/day) and MVPA (75.9-79.7 mins/day) were consistent across days of the week, suggesting little day-to-day variability (at the group level). However, over seven days, average individual day-to-day variability in acceleration was 18.8% (SD 9.3%; range 3.4-87.7%) and in MVPA was 35.4% (SD 15.6%; range 7.3-124.6%), indicating considerable day-to-day variability in some participants. While blue collar workers had the highest average acceleration (28.6 mg/day) and MVPA (102.5 mins/day), their day-to-day variability was low (18.3% for acceleration and 31.9% for MVPA). In contrast, variability in acceleration was highest in men, those in professional occupations and those with high income; and variability in MVPA was higher in men than in women.

Conclusion

Results show group-level estimates of average acceleration and MVPA in a single week conceal considerable day-to-day variation in how mid-age Australians accumulate their acceleration and MVPA on a daily basis. Overall, there was no clear relationship between overall volume of activity and variability. Future studies with larger sample sizes and longitudinal data are needed to build on the findings from this study and increase the generalisability of these findings to other population groups.
Delays in the vaccination of infants between 2 and 18 months of age: associated factors in Chile
Authors: Leal Paula , Gaete Jorge , González Cecilia , Burgos Pamela
Published: September 2023

Introduction

Infant vaccination has significantly reduced the morbidity and mortality of transmittable diseases worldwide. Its coverage is high (85%); however, partial or suboptimal vaccination has been an important public health problem. This study aimed (1) to design and explore the psychometric features of a questionnaire to determine the reasons for this partial or suboptimal vaccination; and 2) to determine the factors associated with delaying Diphtheria, Tetanus, Poliomyelitis (DTaP) vaccination.

Material and methods

This study contained two parts. In Part One, a questionnaire was created by the research team and then validated by a committee of experts in the field and a group of parents. It included the following contents: sociodemographic variables, features of the vaccination services, history of vaccination, and attitudes and perceptions about vaccination. Part Two was a cross-sectional study, recruiting private and public healthcare centers to explore the psychometrics features of the instrument, performing exploratory factor analysis, and determining the associated factors with DTaP vaccination delay throughout multivariable regression models.

Results

Initially, six experts validated the questionnaire. For instance, on a scale of 1 to 5, the general evaluation of the questionnaire was ≥ 4 for all the experts. Additionally, five experts considered that most of the questions were easy to understand, and all thought the questionnaire had a clear and logical organization. The resulting questionnaire included the “Trust and positive attitude towards vaccination” scale, which had a good structure of items and internal consistency (α = 0.7918). Six healthcare centers were recruited in the second part of the study, and 715 people answered the questionnaire. Not being the mother who brings the child to the health center, having more than one child, and having a history of previous vaccination delays increased the risk of delaying vaccination. Attending the healthcare center for a reason other than only vaccination, obtaining information about vaccines from the Internet, and having higher trust and positive attitudes to vaccination reduced the risk of delay.

Conclusions

First study during the pandemic to explore the role of different factors on the risk of DTaP vaccination delay in Latin America. The findings highlighted the importance of trust in the vaccination system. The instrument presented in this article may help the scientific community evaluate future interventions to increase trust and positive attitudes toward the vaccination process.
Implementing palliative care education into primary care practice: a qualitative case study of the CAPACITI pilot program
Authors: Matthew Midori , Bainbridge Daryl , Bishop Valerie , Sinding Christina , Winemaker Samantha , Kilbertus Frances , Kortes-Miller Katherine , Seow Hsien
Published: September 2023

Background

CAPACITI is a virtual education program that teaches primary care teams how to provide an early palliative approach to care. After piloting its implementation, we conducted an in-depth qualitative study with CAPACITI participants to assess the effectiveness of the components and to understand the challenges and enablers to virtual palliative care education.

Methods

We applied a qualitative case study approach to assess and synthesize three sources of data collected from the teams that participated in CAPACITI: reflection survey data, open text survey data, and focus group transcriptions. We completed a thematic analysis of these responses to gain an understanding of participant experiences with the intervention and its application in practice.

Results

The CAPACITI program was completed by 22 primary care teams consisting of 159 participants across Ontario, Canada. Qualitative data was obtained from all teams, including 15 teams that participated in focus groups and 21 teams that provided reflection survey data on CAPACITI content and how it translated into practice. Three major themes arose from cross-analysis of the data: changes in practice derived from involvement in CAPACITI, utility of specific elements of the program, and barriers and challenges to enacting CAPACITI in practice. Importantly, participants reported that the multifaceted approach of CAPACITI was helpful to them building their confidence and competence in applying a palliative approach to care.

Conclusions

Primary care teams perceived the CAPACITI facilitated program as effective towards incorporating palliative care into their practices. CAPACITI warrants further study on a national scale using a randomized trial methodology. Future iterations of CAPACITI need to help mitigate barriers identified by respondents, including team fragmentation and system-based challenges to encourage interprofessional collaboration and knowledge translation.
In vitro trypanocidal activity of extracts and compounds isolated from Vitellaria paradoxa
Authors: Bairy Guerisson , Ozzin-Kholy Zolipou Cyrille Oliver , Nzoumbou-Boko Romaric
Published: September 2023

Background

Vitellaria paradoxa is used in traditional medicine for the treatment of various diseases in tropical countries; however, nothing is known about its anti-trypanosomal activity. Human African trypanosomiasis is a neglected tropical disease of Sub-Saharan Africa’s poorest rural regions, and the efficacy of its treatment remains a challenge. This study investigates the as-yet-unknown trypanocidal activity of this plant.

Methods

V. paradoxa, commonly known as shea tree, was selected for study based on an ethnobotanical investigation. Ultrasonicated extracts from bark and seeds were successively treated with ethyl acetate and water. Column chromatography, NMR spectroscopy and mass spectrometry were used to identify isolated compounds. Purified trypanosomes (Trypanosoma brucei brucei) were incubated with serial dilutions of the extracts and isolated compounds at 37 °C in 5% CO2 for 24 h. Parasite viability was evaluated under a microscope.

Results

The ethyl acetate extracts of the bark showed the higher in vitro trypanocidal activity against T. brucei brucei with median inhibitory concentration (IC50) of 3.25 µg/mL. However, the triterpene 1α,2β,3β,19α-tretrahydroxyurs-12-en-28-oic acid and the pentadecanoic acid isolated from the ethyl acetate extract of the seeds showed in vitro trypanocidal activity with IC50 of 11.30 and 70.1 µM, respectively.

Conclusion

The results obtained contribute to the validation of the traditional medicinal use of V. paradoxa. Our results encourage further investigations of this plant, mainly with respect to its in vivo efficacy and toxicity.
Canine ehrlichiosis seropositivity and associated factors in Kenya and Tanzania: a retrospective study
Authors: Judy Laboso , David Kihurani , Peter Kimeli , Dhaval Shah
Published: September 2023

Canine ehrlichiosis is an important tick-borne disease caused by bacteria in the Ehrlichia genus with species such as E. canis, E. ewingii and E. chaffeensis resulting in a severe dog illness. This study determined the occurrence of canine ehrlichiosis antibodies and its associated factors in Kenya and Tanzania. This was a retrospective study that evaluated laboratory records of 400 samples from Kenya and Tanzania submitted to Pathologists Lancet Kenya for the IDEXX SNAP 4Dx™ Plus test between the years 2016 and 2021. Records of all samples submitted to the Pathologists Lancet Kenya veterinary laboratory for the diagnostic tests were retrieved, examined, and compiled. Descriptive statistics and univariable and multivariable logistic regression were considered during analysis. The overall proportion of samples that tested positive for canine ehrlichiosis was 23% (92/400). Samples from Kenya accounted for 61% (245/400) of samples, and the percent positive was 31% (29/245). The samples from Tanzania accounted for 39% (155/400), and the percent positive was 69% (63/155). In the final model, the odds of a sample testing positive was 1.7 times for those submitted from July to December compared with those submitted from January to June. Blood samples of dogs from Tanzania had 5.31 times the odds of testing positive on the SNAP test when compared with those from Kenya. This study reports high percent positive in samples originating from Tanzania and those received during the year's second half.
Lung immune signatures define two groups of end-stage IPF patients
Authors: Cruz Tamara , Mendoza Núria , Casas-Recasens Sandra , Noell Guillaume , Hernandez-Gonzalez Fernanda , Frino-Garcia Alejandro , Alsina-Restoy Xavi , Molina María , Rojas Mauricio , Agustí Alvar , Sellares Jacobo , Faner Rosa
Published: September 2023

Background

The role of the immune system in the pathobiology of Idiopathic Pulmonary Fibrosis (IPF) is controversial.

Methods

To investigate it, we calculated immune signatures with Gene Set Variation Analysis (GSVA) and applied them to the lung transcriptome followed by unbiased cluster analysis of GSVA immune-enrichment scores, in 109 IPF patients from the Lung Tissue Research Consortium (LTRC). Results were validated experimentally using cell-based methods (flow cytometry) in lung tissue of IPF patients from the University of Pittsburgh (n = 26). Finally, differential gene expression and hypergeometric test were used to explore non-immune differences between clusters.

Results

We identified two clusters (C#1 and C#2) of IPF patients of similar size in the LTRC dataset. C#1 included 58 patients (53%) with enrichment in GSVA immune signatures, particularly cytotoxic and memory T cells signatures, whereas C#2 included 51 patients (47%) with an overall lower expression of GSVA immune signatures (results were validated by flow cytometry with similar unbiased clustering generation). Differential gene expression between clusters identified differences in cilium, epithelial and secretory cell genes, all of them showing an inverse correlation with the immune response signatures. Notably, both clusters showed distinct features despite clinical similarities.

Conclusions

In end-stage IPF lung tissue, we identified two clusters of patients with very different levels of immune signatures and gene expression but with similar clinical characteristics. Weather these immune clusters differentiate diverse disease trajectories remains unexplored.
Assessment of immigration law enforcement presence in a teaching hospital along the US/Mexico border
Authors: Lamneck Claire , Alvarez Alexander , Zaragoza Cazandra , Rahimian Rombod , Trejo Mario Jesus , Lebensohn Patricia
Published: September 2023

Background

Over the past decade, the United States (US) has seen a spike in migration across the US-Mexico border with an increase in hospital admissions of migrants and asylum-seekers under the custody of immigration law enforcement (ILE). This study aimed to determine how the presence of ILE officials affects patient care and provider experience in a teaching hospital setting.

Methods

This cross-sectional online survey solicited quantitative and qualitative feedback from medical students, residents, and attending physicians (n = 1364) at a teaching hospital system with two campuses in Arizona. The survey included participant demographics and addressed participants’ experience caring for patients in ILE custody, including the perception of respect, violations of patients’ privacy and autonomy, and the comfort level with understanding hospital policies and patient rights. Thematic analyses were also performed based on respondent comments.

Results

332 individuals (24%) responded to the survey. Quantitative analyses revealed that 14% of participants described disrespectful behaviors of ILE officials, mainly toward detained patients. Qualitative thematic analyses of respondent comments revealed details on such disrespectful encounters including ILE officers violating the Health Insurance Portability and Accountability Act (HIPAA) and using intimidation tactics with patients. Nearly half of the respondents did not have knowledge of policies about ILE detainees’ medical care, detainees’ privacy rights, or ILE’s authority in patient care.

Conclusions

This study points out the complexities, challenges, and ethical considerations of caring for patients in ILE custody in the hospital setting and the need to educate healthcare professionals on both patient and provider rights. It describes the lived experiences and difficulties that providers on the border face in trying to achieve equity in the care they provide to detained migrant patients.
Efficacy of cell-free DNA methylation-based blood test for colorectal cancer screening in high-risk population: a prospective cohort study
Authors: Zhao Fuqiang , Bai Ping , Xu Jianfeng , Li Zitong , Muhammad Shan , Li Diange , Zhang Zeyue , Gao Yibo , Liu Qian
Published: September 2023

Background

Although colonoscopy is the standard screening test for colorectal cancer (CRC), its use is limited by a poor compliance rate, the need for extensive bowel preparation, and the risk of complications. As an alternative, an FDA-approved stool-based DNA test, Cologuard, has demonstrated satisfactory detection performance for CRC, but its compliance rate remains suboptimal, primarily attributable to individuals’ reluctance to provide stool samples.

Methods

We developed a noninvasive blood-based CRC test, ColonSecure, based on cell-free DNA containing cancer-specific CpG island methylation patterns. We initially screened publicly available datasets for differentially methylated CpG sites in CRC with prediction potential. Subsequently, we performed two sequential bisulfite-free methylation sequencing on blood samples obtained from CRC patients and non-cancer controls. Through rigorous evaluation of each marker and machine learning-assisted feature selection, we identified 149 hypermethylated markers from over 193,000 CpG sites. These markers were then utilized to construct the ColonSecure model, enabling accurate CRC detection.

Results

We validated the efficacy of our cell-free DNA methylation-based blood test for CRC screening with 3493 high-risk individuals identified from 114,136 urban residents. The ColonSecure test identified 89 out of 103 CRC patients diagnosed by the follow-up colonoscopy, outperforming CEA, CRP, and CA19-9 (with a sensitivity of 86.4% compared to 45.6%, 39.8%, and 25.2% for CEA, CRP, and CA19-9 respectively; an AUROC of 0.956 compared to an AUROC of < 0.77 for other methods).

Conclusion

Our observations emphasize the potential of our multiple cfDNA methylation marker-based test for CRC screening in high-risk populations.
Critical contributions of protein cargos to the functions of macrophage-derived extracellular vesicles
Authors: Liu Baolong , Nguyen Phuong Linh , Yu Han , Li Xingzhi , Wang Huiren , Price Jeffrey , Niu Meng , Guda Chittibabu , Cheng Xiao , Sun Xinghui , Moreau Regis , Ramer-Tait Amanda , Naldrett Michael J. , Alvarez Sophie , Yu Jiujiu
Published: September 2023

Background

Macrophages are highly plastic innate immune cells that play key roles in host defense, tissue repair, and homeostasis maintenance. In response to divergent stimuli, macrophages rapidly alter their functions and manifest a wide polarization spectrum with two extremes: M1 or classical activation and M2 or alternative activation. Extracellular vesicles (EVs) secreted from differentially activated macrophages have been shown to have diverse functions, which are primarily attributed to their microRNA cargos. The role of protein cargos in these EVs remains largely unexplored. Therefore, in this study, we focused on the protein cargos in macrophage-derived EVs.

Results

Naïve murine bone marrow-derived macrophages were treated with lipopolysaccharide or interlukin-4 to induce M1 or M2 macrophages, respectively. The proteins of EVs and their parental macrophages were subjected to quantitative proteomics analyses, followed by bioinformatic analyses. The enriched proteins of M1-EVs were involved in proinflammatory pathways and those of M2-EVs were associated with immunomodulation and tissue remodeling. The signature proteins of EVs shared a limited subset of the proteins of their respective progenitor macrophages, but they covered many of the typical pathways and functions of their parental cells, suggesting their respective M1-like and M2-like phenotypes and functions. Experimental examination validated that protein cargos in M1- or M2-EVs induced M1 or M2 polarization, respectively. More importantly, proteins in M1-EVs promoted viability, proliferation, and activation of T lymphocytes, whereas proteins in M2-EVs potently protected the tight junction structure and barrier integrity of epithelial cells from disruption. Intravenous administration of M2-EVs in colitis mice led to their accumulation in the colon, alleviation of colonic inflammation, promotion of M2 macrophage polarization, and improvement of gut barrier functions. Protein cargos in M2-EVs played a key role in their protective function in colitis.

Conclusion

This study has yielded a comprehensive unbiased dataset of protein cargos in macrophage-derived EVs, provided a systemic view of their potential functions, and highlighted the important engagement of protein cargos in the pathophysiological functions of these EVs.
Programmable DNA hydrogel provides suitable microenvironment for enhancing autophagy-based therapies in intervertebral disc degeneration treatment
Authors: Qingxin Song , Kai Jiang , Dandan Zheng , Linyu Jin , Xiuyuan Chen , Yubo Feng , Kun Wang , Yingchao Han , Hao Chen , Jie Song , Zhi Chen , Hongxing Shen
Published: September 2023

The pathogenesis of intervertebral disc degeneration (IVDD) is attributed to metabolic dysregulation within the extracellular matrix and heightened apoptosis of nucleus pulposus cells (NPC). Therefore, a potential therapeutic strategy for managing IVDD involves the reestablishment of metabolic equilibrium within the extracellular matrix and the suppression of excessive myeloid cell apoptosis. The microRNA, miR-5590, displays marked differential expression in degenerative nucleus pulposus (NP) tissues and exerts a direct influence on the regulation of DDX5 expression. This, in turn, modulates mammalian target of rapamycin (mTOR) phosphorylation, thereby impacting autophagy and apoptosis. However, ensuring the smooth delivery of miRNA to a specific injury site poses a significant challenge. To address this issue, a multifunctional DNA hydrogel was developed and subsequently loaded with miR-5590 via spherical nucleic acids (SNAs) for the treatment of IVDD. The hydrogel, which exhibits versatility, has the potential to be administered through injection at the site of injury, resulting in a consistent and prolonged release of miR-5590. This leads to the creation of a genetic microenvironment within the NP, which triggers the onset of autophagy in NPCs and subsequently suppresses apoptosis. As a result, this process regulates the metabolic equilibrium within the extracellular matrix, thereby impeding the in vitro and in vivo progression of IVDD. The amalgamation of miRNAs and biomaterials offers a promising therapeutic strategy for the management of IVDD in clinical settings.
RU.521 mitigates subarachnoid hemorrhage-induced brain injury via regulating microglial polarization and neuroinflammation mediated by the cGAS/STING/NF-κB pathway
Authors: Shao Jiang , Meng Yuxiao , Yuan Kaikun , Wu Qiaowei , Zhu Shiyi , Li Yuchen , Wu Pei , Zheng Jiaolin , Shi Huaizhang
Published: September 2023

Background

The poor prognosis of subarachnoid hemorrhage (SAH) is often attributed to neuroinflammation. The cGAS-STING axis, a cytoplasmic pathway responsible for detecting dsDNA, plays a significant role in mediating neuroinflammation in neurological diseases. However, the effects of inhibiting cGAS with the selective small molecule inhibitor RU.521 on brain injury and the underlying mechanisms after SAH are still unclear.

Methods

The expression and microglial localization of cGAS following SAH were investigated with western blot analysis and immunofluorescent double-staining, respectively. RU.521 was administered after SAH. 2’3’-cGAMP, a second messenger converted by activated cGAS, was used to activate cGAS-STING. The assessments were carried out by adopting various techniques including neurological function scores, brain water content, blood–brain barrier permeability, western blot analysis, TUNEL staining, Nissl staining, immunofluorescence, morphological analysis, Morris water maze test, Golgi staining, CCK8, flow cytometry in the in vivo and in vitro settings.

Results

Following SAH, there was an observed increase in the expression levels of cGAS in rat brain tissue, with peak levels observed at 24 h post-SAH. RU.521 resulted in a reduction of brain water content and blood–brain barrier permeability, leading to an improvement in neurological deficits after SAH. RU.521 had beneficial effects on neuronal apoptosis and microglia activation, as well as improvements in microglial morphology. Additionally, RU.521 prompted a shift in microglial phenotype from M1 to M2. We also noted a decrease in the production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, and an increase in the level of the anti-inflammatory cytokine IL-10. Finally, RU.521 treatment was associated with improvements in cognitive function and an increase in the number of dendritic spines in the hippocampus. The therapeutic effects were mediated by the cGAS/STING/NF-κB pathway and were found to be abolished by 2’3’-cGAMP. In vitro, RU.521 significantly reduced apoptosis and neuroinflammation.

Conclusion

The study showed that SAH leads to neuroinflammation caused by microglial activation, which contributes to early brain injury. RU.521 improved neurological outcomes and reduced neuroinflammation by regulating microglial polarization through the cGAS/STING/NF-κB pathway in early brain injury after SAH. RU.521 may be a promising candidate for the treatment of neuroinflammatory pathology after SAH.
The effectiveness and cost-effectiveness of a group domestic abuse perpetrator programme: protocol for a randomised controlled trial
Authors: Morgan Karen , Man Mei-See , Bloomer Rachael , Cochrane Madeleine , Cole Melissa , Dheensa Sandi , Eisenstadt Nathan , Feder Gene , Gaunt Daisy M. , Leach Rwth , Kandiyali Rebecca , Noble Sian , Peters Tim J. , Shirkey Beverly A. , Cramer Helen
Published: September 2023

Background

In contrast to evidence for interventions supporting victim/survivors of domestic violence and abuse (DVA), the effectiveness of perpetrator programmes for reduction of abuse is uncertain. This study aims to estimate the effectiveness and cost-effectiveness of a perpetrator programme for men.

Methods

Pragmatic two-group individually randomised controlled trial (RCT) with embedded process and economic evaluation. Five centres in southwest England and South Wales aim to recruit 316 (reduced from original target of 366) male domestic abuse perpetrators. These will be randomised 2:1 to a community-based domestic abuse perpetrator programme (DAPP) or usual care comparator with 12-month follow-up. Female partners/ex-partners will be invited to join the study.

The intervention for men comprises 23 weekly sessions of a group programme delivered in voluntary sector domestic abuse services. The intervention for female partners/ex-partners is one-to-one support from a safety worker. Men allocated to usual care receive no intervention; however, they are free to access other services. Their partners/ex-partners will be signposted to support services.

Data is collected at baseline, and 4, 8 and 12 months’ follow-up. The primary outcome is men’s self-reported abusive behaviour measured by the Abusive Behaviour Inventory (ABI-29) at 12 months. Secondary measures include physical and mental health status and resource use alongside the abuse measure ABI (ABI-R) for partners/ex-partners and criminal justice contact for men.

A mixed methods process evaluation and qualitative study will explore mechanisms of effectiveness, judge fidelity to the intervention model using interviews and group observations.

The economic evaluation, over a 1-year time horizon from three perspectives (health and social care, public sector and society), will employ a cost-consequences framework reporting costs alongside economic outcomes (Quality-Adjusted Life Years derived from EQ-5D-5L, SF-12 and CHU-9D, and ICECAP-A) as well as the primary and other secondary outcomes.

Discussion

This trial will provide evidence of the (cost)effectiveness of a DAPP. The embedded process evaluation will further insights in the experiences and contexts of participants and their journey through a perpetrator programme, and the study will seek to address the omission in other studies of economic evaluations.

Trial registration

ISRCTN15804282, April 1, 2019
Effect of a telerehabilitation exercise program versus a digital booklet with self-care for patients with chronic non-specific neck pain: a protocol of a randomized controlled trial assessor-blinded, 3 months follow-up
Authors: Barbosa Juliene Corrêa , Comachio Josielli , Marques Amelia Pasqual , Saragiotto Bruno Tirotti , Magalhaes Mauricio Oliveira
Published: September 2023

Background

Neck pain is the fourth worldwide leading cause of disability and represents 22% of musculoskeletal disorders. Conservative intervention has been strongly recommended to treat chronic neck pain and Telerehabilitation is the alternative for the treatment of musculoskeletal conditions. There is a lack of high-quality research on the effects of telerehabilitation in patients with neck pain and functional disability. Therefore, this study aims to evaluate the effect of a telerehabilitation exercise program versus a digital booklet only with self-care information in individuals with non-specific chronic neck pain.

Methods

This is a prospectively registered, assessor-blinded, two-arm randomized controlled trial comparing a telerehabilitation exercise program versus a digital booklet with self-care information. Seventy patients will be recruited with non-specific chronic neck pain. Follow-ups will be conducted post-treatment, 6 weeks, and 3 months after randomization. The primary outcome will be disability at post-treatment (6 weeks) measured using neck pain disability. Secondary outcomes will be pain intensity levels, global perceived effect, self-efficacy, quality of life, kinesiophobia, and adherence to treatment. In our hypothesis, patients allocated to the intervention group experience outcomes that are similar to those of those assigned to the self-care digital booklet. Our hypothesis can then be approved or disapproved based on the results of the study.

Discussion

This randomized clinical trial will provide reliable information on the use of telerehabilitation to treat patients with chronic non-specific neck pain.

Trial registration

The study was prospectively registered at the Brazilian Registry of Clinical Trials (number: RBR-10h7khvk). Registered on 16 September 2022.
Solving singularly perturbed fredholm integro-differential equation using exact finite difference method
Authors: Badeye Solomon Regasa , Woldaregay Mesfin Mekuria , Dinka Tekle Gemechu
Published: September 2023

Objectives

In this paper, a numerical scheme is designed for solving singularly perturbed Fredholm integro-differential equation. The scheme is constructed via the exact (non-standard) finite difference method to approximate the differential part and the composite Simpson’s 1/3 rule for the integral part of the equation.

Result

The stability and uniform convergence analysis are demonstrated using solution bound and the truncation error bound. For three model examples, the maximum absolute error and the rate of convergence for different values of the perturbation parameter and mesh size are tabulated. The computational result shows, the proposed method is second-order uniformly convergent which is in a right agreement with the theoretical result.
Burden and predictors of diabetic kidney disease in an adult Ugandan population with new-onset diabetes
Authors: Kibirige Davis , Sekitoleko Isaac , Lumu William
Published: September 2023

Background

Despite the growing evidence of diabetic kidney disease (DKD) in adult patients with long-standing diabetes in sub-Saharan Africa, data on its burden and correlates in adult African patients with new-onset diabetes are limited. We, therefore, undertook this study to determine the burden and predictors of DKD in an adult population with new-onset diabetes in Uganda.

Methods

We collected data on the relevant sociodemographic, clinical, anthropometric, and metabolic characteristics in 519 participants with newly diagnosed diabetes recruited from seven tertiary hospitals. A spot mid-stream urine sample was collected for determination of the urine albumin creatinine ratio (UACR) using Clinitek® microalbumin strips and a point-of-care Clinitek® status analyser. The estimated glomerular filtration rate (e-GFR) was determined using the Chronic Kidney Disease Epidemiology formula. The presence of DKD was defined as a spot UACR ≥ 3 mg/mmol with or without an e-GFR < 60 ml/min/1.73m2.

Results

The median (IQR) age, UACR, and e-GFR of the participants were 48 years (39–57), 2.27 mg/mmol (1.14–3.41), and 121.8 ml/min/1.73m2 (105.4-133.9). UACR ≥ 3 mg/mmol and e-GFR < 60 ml/min/1.73m2 was noted in 175 (33.7%) and 7 (1.4%) participants, respectively. DKD was documented in 175 participants (33.7%). Compared with those without DKD, participants with DKD were more likely to be ≥ 50 years of age (53.7% vs. 43%, p = 0.02) and to have co-existing hypertension at the time of diagnosis (40.6% vs. 30.1%, p = 0.02). On multivariate analysis, self-reported hypertension comorbidity (OR 1.76 95% CI 1.24–2.48, p = 0.002) and body mass index (BMI) ≥ 30 kg/m2 (OR 0.61 95% CI 0.41–0.91, p = 0.02) were noted to independently predict DKD.

Conclusion

In this study population, DKD was relatively common and was independently associated with self-reported hypertension comorbidity and BMI ≥ 30 kg/m2.
Effect of women’s fertility and sexual development on epigenetic clock: Mendelian randomization study
Authors: Zhang Boxin , Yuan Qizhi , Luan Yining , Xia Jian
Published: September 2023

Background and objectives

In observational studies, women’s fertility and sexual development traits may have implications for DNA methylation patterns, and pregnancy-related risk factors can also affect maternal DNA methylation patterns. The aim of our study is to disentangle any potential causal associations between women’s fertility and sexual development traits and epigenetic clocks, as well as to search for probable mediators by using the Mendelian randomization (MR) method.

Methods

Instrumental variables for exposures, mediators, and outcomes were adopted from genome-wide association studies data of European ancestry individuals. The potential causal relationship between women’s fertility and sexual development traits and four epigenetic clocks were evaluated by inverse variance weighted method and verified by other two methods. Furthermore, we employed multivariable MR (MVMR) adjusting for hypertension, hyperglycemia, BMI changes, and insomnia. Then, combining the MVMR results and previous research, we performed two-step MR to explore the mediating effects of BMI, AFS, and AFB. Multiple sensitivity analyses were further performed to verify the robustness of our findings.

Results

Leveraging two-sample MR analysis, we observed statistically significant associations between earlier age at first birth (AFB) with a higher HannumAge, PhenoAge and GrimAge acceleration(β = − 0.429, 95% CI [− 0.781 to − 0.077], p = 0.017 for HannumAge; β = − 0.571, 95% CI [− 1.006 to − 0.136], p = 0.010 for PhenoAge, and β = − 1.136, 95% CI [− 1.508 to − 0.765], p = 2.03E−09 for GrimAge respectively) and age at first sexual intercourse (AFS) with a higher HannumAge and GrimAge acceleration(β = − 0.175, 95% CI [− 0.336 to − 0.014], p = 0.033 for HannumAge; β = − 0.210, 95% CI [− 0.350 to − 0.070], p = 0.003 for GrimAge, respectively). Further analyses indicated that BMI, AFB and AFS played mediator roles in the path from women’s fertility and sexual development traits to epigenetic aging.

Conclusions

Our study suggested that AFS and AFB are associated with epigenetic aging. These findings may prove valuable in informing the development of prevention strategies and interventions targeted towards women’s fertility and sexual development experiences and their relationship with epigenetic aging-related diseases.
Sexual differences in locus coeruleus neurons and related behavior in C57BL/6J mice
Authors: Mariscal Patricia , Bravo Lidia , Llorca-Torralba Meritxell , Razquin Jone , Miguelez Cristina , Suárez-Pereira Irene , Berrocoso Esther
Published: September 2023

Background

In addition to social and cultural factors, sex differences in the central nervous system have a critical influence on behavior, although the neurobiology underlying these differences remains unclear. Interestingly, the Locus Coeruleus (LC), a noradrenergic nucleus that exhibits sexual dimorphism, integrates signals that are related to diverse activities, including emotions, cognition and pain. Therefore, we set-out to evaluate sex differences in behaviors related to LC nucleus, and subsequently, to assess the sex differences in LC morphology and function.

Methods

Female and male C57BL/6J mice were studied to explore the role of the LC in anxiety, depressive-like behavior, well-being, pain, and learning and memory. We also explored the number of noradrenergic LC cells, their somatodendritic volume, as well as the electrophysiological properties of LC neurons in each sex.

Results

While both male and female mice displayed similar depressive-like behavior, female mice exhibited more anxiety-related behaviors. Interestingly, females outperformed males in memory tasks that involved distinguishing objects with small differences and they also showed greater thermal pain sensitivity. Immunohistological analysis revealed that females had fewer noradrenergic cells yet they showed a larger dendritic volume than males. Patch clamp electrophysiology studies demonstrated that LC neurons in female mice had a lower capacitance and that they were more excitable than male LC neurons, albeit with similar action potential properties.

Conclusions

Overall, this study provides new insights into the sex differences related to LC nucleus and associated behaviors, which may explain the heightened emotional arousal response observed in females.