bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing feasibility of a modified same-day test-and-treat model for hepatitis C among rural people who inject drugs
Authors: Hassan Muhammad Radzi Abu , Chan Huan-Keat , Nordin Mahani , Yahya Ranimah , Sulaiman Wan Ruzilasalwa Wan , Merican Siti Aminah Akbar , Lah Darisah , Sem Xiaohui , Shilton Sonjelle 
Published: April 2023

Abstract
Background
Despite advancements in hepatitis C virus (HCV) treatment, low uptake among hard-to-reach populations remains a global issue. The current study aimed to assess the feasibility of a modified same-day test-and-treat model in improving HCV care for people who inject drugs (PWID) living in resource-constrained rural areas.

Methods
A pilot study was conducted in four primary healthcare (PHC) centers in Malaysia. The model's key features included on-site HCV ribonucleic acid (RNA) testing using a shared GeneXpert® system; noninvasive biomarkers for cirrhosis diagnosis; and extended care to PWID referred from nearby PHC centers and outreach programs. The feasibility assessment focused on three aspects of the model: demand (i.e., uptake of HCV RNA testing and treatment), implementation (i.e., achievement of each step in the HCV care cascade), and practicality (i.e., ability to identify PWID with HCV and expedite treatment initiation despite resource constraints).

Results
A total of 199 anti-HCV-positive PWID were recruited. They demonstrated high demand for HCV care, with a 100% uptake of HCV RNA testing and 97.4% uptake of direct-acting antiviral treatment. The rates of HCV RNA positivity (78.4%) and sustained virologic response (92.2%) were comparable to standard practice, indicating the successful implementation of the model. The model was also practical, as it covered non-opioid-substitution-therapy-receiving individuals and enabled same-day treatment in 71.1% of the participants.

Conclusions
The modified same-day test-and-treat model is feasible in improving HCV care for rural PWID. The study finding suggests its potential for wider adoption in HCV care for hard-to-reach populations.
P38 MAPK activated ADAM17 mediates ACE2 shedding and promotes cardiac remodeling and heart failure after myocardial infarction
Authors: Chen Qi , Li Yilan , Bie Bike , Zhao Bin , Zhang Yanxiu , Fang Shaohong , Li Shuijie , Zhang Yao 
Published: April 2023

Abstract
Background
Heart failure (HF) after myocardial infarction (MI) is a prevalent disease with a poor prognosis. Relieving pathological cardiac remodeling and preserving cardiac function is a critical link in the treatment of post-MI HF. Thus, more new therapeutic targets are urgently needed. The expression of ADAM17 is increased in patients with acute MI, but its functional role in post-MI HF remains unclear.

Methods
To address this question, we examined the effects of ADAM17 on the severity and prognosis of HF within 1 year of MI in 152 MI patients with or without HF. In mechanistic studies, the effects of ADAM17 on ventricular remodeling and systolic function were extensively assessed at the tissue and cellular levels by establishing animal model of post-MI HF and in vitro hypoxic cell model.

Results
High levels of ADAM17 predicted a higher incidence of post-MI HF, poorer cardiac function and higher mortality. Animal studies demonstrated that ADAM17 promoted the occurrence of post-MI HF, as indicated by increased infarct size, cardiomyocyte hypertrophy, myocardial interstitial collagen deposition and cardiac failure. ADAM17 knock down significantly improved pathological cardiac remodeling and cardiac function in mice with MI. Mechanistically, activated ADAM17 inhibited the cardioprotective effects of ACE2 by promoting hydrolytic shedding of the transmembrane protein ACE2 in cardiomyocytes, which subsequently mediated the occurrence of cardiac remodeling and the progression of heart failure. Moreover, the activation of ADAM17 in hypoxic cardiomyocytes was dependent on p38 MAPK phosphorylation at threonine 735.

Conclusions
These data highlight a novel and important mechanism for ADAM17 to cause post-MI HF, which will hopefully be a new potential target for early prediction or intervention of post-MI HF.
Serotonin acts through YAP to promote cell proliferation: mechanism and implication in colorectal cancer progression
Authors: Yu Huangfei , Qu Tianyin , Yang Jinlan , Dai Qing 
Published: April 2023

AbstractSerotonin, also known as 5-hydroxytryptamine (5-HT), is a key messenger that mediates several central and peripheral functions in the human body. Emerging evidence indicates that serotonin is critical in tumorigenesis, but its role in colorectal cancer remains elusive. Herein, we report that serotonin transporter (SERT) transports serotonin into colorectal cancer cells, enhancing Yes-associated protein (YAP) expression and promoting in vitro and in vivo colon cancer cell growth. Once within the cells, transglutaminase 2 (TG2) mediates RhoA serotonylated and activates RhoA-ROCK1/2 signalling to upregulate YAP expression in SW480 and SW1116 cells. Blocking SERT with citalopram reversed the serotonin-induced YAP expression and cell proliferation, inhibiting serotonin’s effects on tumour formation in mice. Moreover, SERT expression was correlated with YAP in pathological human colorectal cancer samples and the levels of 5-HT were highly significant in the serum of patients with colorectal cancer. Together, our findings suggested that serotonin enters cells via SERT to activate RhoA/ROCK/YAP signalling to promote colon cancer carcinogenesis. Consequently, targeting serotonin-SERT-YAP axis may be a potential therapeutic strategy for colorectal cancer.
Distinct phenotypes of multisystem inflammatory syndrome in children: a cohort study
Authors: Renson Thomas , Forkert Nils D. , Amador Kimberly , Miettunen Paivi , Parsons Simon J. , Dhalla Muhammed , Johnson Nicole A. , Luca Nadia , Schmeling Heinrike , Stevenson Rebeka , Twilt Marinka , Hamiwka Lorraine , Benseler Susanne 
Published: April 2023

Abstract
Background
Multisystem inflammatory syndrome in children (MIS-C) is a severe disease with an unpredictable course and a substantial risk of cardiogenic shock. Our objectives were to (a) compare MIS-C phenotypes across the COVID-19 pandemic, (b) identify features associated with intensive care need and treatment with biologic agents.

Methods
Youth aged 0–18 years, fulfilling the World Health Organization case definition of MIS-C, and admitted to the Alberta Children’s Hospital during the first four waves of the COVID-19 pandemic (May 2020-December 2021) were included in this cohort study. Demographic, clinical, biochemical, imaging, and treatment data were captured.

Results
Fifty-seven MIS-C patients (median age 6 years, range 0–17) were included. Thirty patients (53%) required intensive care. Patients in the third or fourth wave (indicated as phase 2 of the pandemic) presented with higher peak ferritin (µg/l, median (IQR) = 1134 (409–1806) vs. 370 (249–629), P = 0.001), NT-proBNP (ng/l, median (IQR) = 12,217 (3013–27,161) vs. 3213 (1216–8483), P = 0.02) and D-dimer (mg/l, median (IQR) = 4.81 (2.24–5.37) vs. 2.01 (1.27–3.34), P = 0.004) levels, and higher prevalence of liver enzyme abnormalities (n(%) = 17 (68) vs. 11 (34), P = 0.02), hypoalbuminemia (n(%) = 24 (100) vs. 25 (81), P = 0.03) and thrombocytopenia (n(%) 18 (72) vs. 11 (34), P = 0.007) compared to patients in the first two waves (phase 1). These patients had a higher need of non-invasive/mechanical ventilation (n(%) 4 (16) vs. 0 (0), P = 0.03). Unsupervised clustering analyses classified 47% of the patients in the correct wave and 74% in the correct phase of the pandemic. NT-proBNP was the only significant contributor to the need for intensive care in all applied multivariate regression models. Treatment with biologic agents was significantly associated with peak CRP (mg/l (median, IQR = 240.9 (132.9-319.4) vs. 155.8 (101.0-200.7), P = 0.02) and ferritin levels (µg/l, median (IQR) = 1380 (509–1753) vs. 473 (280–296)).

Conclusions
MIS-C patients in a later stage of the pandemic displayed a more severe phenotype, reflecting the impact of distinct SARS-CoV-2 variants. NT-proBNP emerged as the most crucial feature associated with intensive care need, underscoring the importance of monitoring.
Aged brain and neuroimmune responses to COVID-19: post-acute sequelae and modulatory effects of behavioral and nutritional interventions
Authors: Müller Ludmila , Di Benedetto Svetlana 
Published: April 2023

AbstractAdvanced age is one of the significant risk determinants for coronavirus disease 2019 (COVID-19)-related mortality and for long COVID complications. The contributing factors may include the age-related dynamical remodeling of the immune system, known as immunosenescence and chronic low-grade systemic inflammation. Both of these factors may induce an inflammatory milieu in the aged brain and drive the changes in the microenvironment of neurons and microglia, which are characterized by a general condition of chronic inflammation, so-called neuroinflammation. Emerging evidence reveals that the immune privilege in the aging brain may be compromised. Resident brain cells, such as astrocytes, neurons, oligodendrocytes and microglia, but also infiltrating immune cells, such as monocytes, T cells and macrophages participate in the complex intercellular networks and multiple reciprocal interactions. Especially changes in microglia playing a regulatory role in inflammation, contribute to disturbing of the brain homeostasis and to impairments of the neuroimmune responses. Neuroinflammation may trigger structural damage, diminish regeneration, induce neuronal cell death, modulate synaptic remodeling and in this manner negatively interfere with the brain functions.In this review article, we give insights into neuroimmune interactions in the aged brain and highlight the impact of COVID-19 on the functional systems already modulated by immunosenescence and neuroinflammation. We discuss the potential ways of these interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and review proposed neuroimmune mechanisms and biological factors that may contribute to the development of persisting long COVID conditions. We summarize the potential mechanisms responsible for long COVID, including inflammation, autoimmunity, direct virus-mediated cytotoxicity, hypercoagulation, mitochondrial failure, dysbiosis, and the reactivation of other persisting viruses, such as the Cytomegalovirus (CMV). Finally, we discuss the effects of various interventional options that can decrease the propagation of biological, physiological, and psychosocial stressors that are responsible for neuroimmune activation and which may inhibit the triggering of unbalanced inflammatory responses. We highlight the modulatory effects of bioactive nutritional compounds along with the multimodal benefits of behavioral interventions and moderate exercise, which can be applied as postinfectious interventions in order to improve brain health.
Screening and identification of cyprinid herpesvirus 2 (CyHV-2) ORF55-interacting proteins by phage display
Authors: Qian Min , Xiao Simin , Yang Yapeng , Yu Fei , Wen Jinxuan , Lu Liqun , Wang Hao 
Published: April 2023

Abstract
Background
Cyprinid herpesvirus 2 (CyHV-2) is a pathogenic fish virus belonging to family Alloherpesviridae. The CyHV-2 gene encoding thymidine kinase (TK) is an important virulence-associated factor. Therefore, we aimed to investigate the biological function of open reading frame 55 (ORF55) in viral replication.

Methods
Purified CyHV-2 ORF55 protein was obtained by prokaryotic expression, and the interacting peptide was screened out using phage display. Host interacting proteins were then predicted and validated.

Results
ORF55 was efficiently expressed in the prokaryotic expression system. Protein and peptide interaction prediction and dot-blot overlay assay confirmed that peptides identified by phage display could interact with the ORF55 protein. Comparing the peptides to the National Center for Biotechnology Information database revealed four potential interacting proteins. Reverse transcription quantitative PCR results demonstrated high expression of an actin-binding Rho-activating protein in the latter stages of virus-infected cells, and molecular docking, cell transfection and coimmunoprecipitation experiments confirmed that it interacted with the ORF55 protein.

Conclusion
During viral infection, the ORF55 protein exerts its biological function through interactions with host proteins. The specific mechanisms remain to be further explored.
Mobile homes in the land of illness: the hospitality and hostility of language in doctor-patient relations
Authors: Milford Stephen R. 
Published: April 2023

AbstractIllness has a way of disorientating us, as if we are cast adrift in a foreign land. Like strangers in a dessert we seek oasis to recollect ourselves, find refuge and learn to build our own shelters. Using the philosophy of Levinas and Derrida, we can interpret health care providers (HCP), and the sites from which they act (e.g. hospitals), as dwelling hosts that offer hospitality to strangers in this foreign land. While often the dwellings are physical (e.g. hospitals), this is not always the case. Language represents a mobile home of refuge to the sick. Using language the HCP has built a shelter so as to dwell in the land of illness. However, while hospitality is an inviting concept, it also implies hostility. The door that opens may also be slammed shut. This article explores the paradox of the linguistic mobile home offered to patients. It highlights the power of language to construct a safe place in a strange land, but also explores the inherent violence. It ends with an exploration of the ways language can be used by HCP to assist patients to construct their own mobile shelters.
Alpha-lipoic acid supplementation corrects pathological alterations in cellular models of pantothenate kinase-associated neurodegeneration with residual PANK2 expression levels
Authors: Talaverón-Rey Marta , Álvarez-Córdoba Mónica , Villalón-García Irene , Povea-Cabello Suleva , Suárez-Rivero Juan M. , Gómez-Fernández David , Romero-González Ana , Suárez-Carrillo Alejandra , Munuera-Cabeza Manuel , Cilleros-Holgado Paula , Reche-López Diana , Piñero-Pérez Rocío , Sánchez-Alcázar José A. 
Published: April 2023

Abstract
Background
Neurodegeneration with brain iron accumulation (NBIA) disorders are a group of neurodegenerative diseases that have in common the accumulation of iron in the basal nuclei of the brain which are essential components of the extrapyramidal system. Frequent symptoms are progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. One of the most prevalent subtypes of NBIA is Pantothenate kinase-associated neurodegeneration (PKAN). It is caused by pathogenic variants in the gene of pantothenate kinase 2 (PANK2) which encodes the enzyme responsible for the first reaction on the coenzyme A (CoA) biosynthesis pathway. Thus, deficient PANK2 activity induces CoA deficiency as well as low expression levels of 4′-phosphopantetheinyl proteins which are essential for mitochondrial metabolism.

Methods
This study is aimed at evaluating the role of alpha-lipoic acid (α-LA) in reversing the pathological alterations in fibroblasts and induced neurons derived from PKAN patients. Iron accumulation, lipid peroxidation, transcript and protein expression levels of PANK2, mitochondrial ACP (mtACP), 4′′-phosphopantetheinyl and lipoylated proteins, as well as pyruvate dehydrogenase (PDH) and Complex I activity were examined.

Results
Treatment with α-LA was able to correct all pathological alterations in responsive mutant fibroblasts with residual PANK2 enzyme expression. However, α-LA had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of α-LA in particular pathogenic variants was also confirmed in induced neurons derived from mutant fibroblasts.

Conclusions
Our results suggest that α-LA treatment can increase the expression levels of PANK2 and reverse the mutant phenotype in PANK2 responsive pathogenic variants. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of α-LA.
Androgen-induced exosomal miR-379-5p release determines granulosa cell fate: cellular mechanism involved in polycystic ovaries
Authors: Salehi Reza , Wyse Brandon A. , Asare-Werehene Meshach , Esfandiarinezhad Fereshteh , Abedini Atefeh , Pan Bo , Urata Yoko , Gutsol Alex , Vinas Jose L. , Jahangiri Sahar , Xue Kai , Xue Yunping , Burns Kevin D. , Vanderhyden Barbara , Li Julang , Osuga Yutaka , Burger Dylan , Tan Seang-Lin , Librach Clifford L. , Tsang Benjamin K. 
Published: April 2023

AbstractPolycystic ovarian syndrome (PCOS) is a complex multi-factorial syndrome associated with androgen excess and anovulatory infertility. In the current study, we investigated the role of dihydrotestosterone-induced exosomal miR-379-5p release in determining the destiny of the developing follicles. Our hypothesis was that androgen regulates granulosa cell miR-379-5p content by facilitating its exosomal release in a follicular-stage dependent manner, a process which determines granulosa cell fate. Compared to human non-PCOS subjects, individuals with PCOS exhibit higher follicular fluid free testosterone levels, lower exosomal miR-379-5p content and granulosa cell proliferation. Androgenized rats exhibited lower granulosa cell miR-379-5p but higher phosphoinositide-dependent kinase-1 (PDK1; a miR-379-5p target) content and proliferation. Androgen reduced granulosa cell miR-379-5p content by increasing its exosomal release in preantral follicles, but not in antral follicles in vitro. Studies with an exosomal release inhibitor confirmed that androgen-induced exosomal miR-379-5p release decreased granulosa cell miR-379-5p content and proliferation. Ovarian overexpression of miR-379-5p suppressed granulosa cell proliferation, and basal and androgen-induced preantral follicle growth in vivo. These findings suggest that increased exosomal miR-379-5p release in granulosa cells is a proliferative response to androgenic stimulation specific for the preantral stage of follicle development and that dysregulation of this response at the antral stage is associated with follicular growth arrest, as observed in human PCOS.
Effects of prebiotic supplement on gut microbiota, drug bioavailability, and adverse effects in patients with colorectal cancer at different primary tumor locations receiving chemotherapy: study protocol for a randomized clinical trial
Authors: Chen Ya , Liao Xiaowei , Li Yanmin , Cao Hong , Zhang Feng , Fei Bojian , Bao Chuanqing , Cao Huaxiang , Mao Yong , Chen Xiaoping , Gao Xiang , Zhao Wei , Xu Jianmin 
Published: April 2023

Abstract
Background
The prevalence of colorectal cancer (CRC) worldwide is a huge challenge to human health. Primary tumor locations found to impact prognosis and response to therapy. The important role of gut microbiota in the progression and treatment of CRC has led to many attempts of alleviating chemotherapy-induced adverse effects using microecologics. However, the underlying mechanism of the difference in the prognosis of different primary tumor locations and the synergistic effect of prebiotics on chemotherapy need to be further elucidated. This study aims to explore the differences in tumor microbiota and examine the effectiveness of xylooligosaccharides (XOS) on gut microbiota, adverse effects, and bioavailability of chemotherapy drugs in CRC patients at different primary tumor locations.

Methods
This is a double-blinded, randomized, parallel controlled clinical trial. Participants with left-sided CRC (LSCRC, n = 50) and right-sided CC (RSCC, n = 50) will randomly allocated to prebiotic group (n = 25) or control group (n = 25) and will receive either a daily XOS (3 g/day) or placebo, respectively, for 12 weeks. The primary outcomes will be the differences in the mucosa microbiota composition at different tumor locations and differences in gut microbiota composition, adverse effects, and blood concentration of capecitabine posttreatment. The secondary outcomes will include other blood indicators, short-chain fatty acids (SCFAs) concentration, quality of life, and mental health.

Discussion
This study will reveal the potential benefits of prebiotic for improving the gut microbiota composition, alleviating the adverse effects, and improving the efficacy of chemotherapy in patients with CRC. In addition, this study will provide data on the different distribution of tumor microbiota and the different changes of gut microbiota during treatment in LSCRC and RSCC, which may provide novel insights into personalized cancer treatment strategies based on primary tumor locations and gut microbiota in the future.

Trial registration
Chinese Clinical Trial Registry (www.chictr.org.cn): ChiCTR2100046237. Registered on 12 May 2021.
Re-thinking osteoarthritis pathogenesis: what can we learn (and what do we need to unlearn) from mouse models about the mechanisms involved in disease development
Authors: Poulsen Raewyn C. , Jain Lekha , Dalbeth Nicola 
Published: April 2023

AbstractEfforts to develop effective disease-modifying drugs to treat osteoarthritis have so far proved unsuccessful with a number of promising drug candidates from pre-clinical studies failing to show efficacy in clinical trials. It is therefore timely to re-evaluate our current understanding of osteoarthritis pathogenesis and the similarities and differences in disease development between commonly used pre-clinical mouse models and human patients. There is substantial heterogeneity between patients presenting with osteoarthritis and mounting evidence that the pathways involved in osteoarthritis (e.g. Wnt signalling) differ between patient sub-groups. There is also emerging evidence that the pathways involved in osteoarthritis differ between the STR/ort mouse model (the most extensively studied mouse model of spontaneously occurring osteoarthritis) and injury-induced osteoarthritis mouse models. For instance, while canonical Wnt signalling is upregulated in the synovium and cartilage at an early stage of disease in injury-induced osteoarthritis mouse models, this does not appear to be the case in the STR/ort mouse. Such findings may prove insightful for understanding the heterogeneity in mechanisms involved in osteoarthritis pathogenesis in human disease. However, it is important to recognise that there are differences between mice and humans in osteoarthritis pathogenesis. A much more extensive array of pathological changes are evident in osteoarthritic joints in individual mice with osteoarthritis compared to individual patients. There are also specified differences in the pathways involved in disease development. For instance, although increased TGF-β signalling is implicated in osteoarthritis development in both mouse models of osteoarthritis and human disease, in mice, this is mainly mediated through TGF-β3 whereas in humans, it is through TGF-β1. Studies in other tissues have shown TGF-β1 is more potent than TGF-β3 in inducing the switch to SMAD1/5 signalling that occurs in osteoarthritic cartilage and that TGF-β1 and TGF-β3 have opposing effects on fibrosis. It is therefore possible that the relative contribution of TGF-β signalling to joint pathology in osteoarthritis differs between murine models and humans. Understanding the similarities and differences in osteoarthritis pathogenesis between mouse models and humans is critical for understanding the translational potential of findings from pre-clinical studies.