bluuebunny/crossref_metadata_2025_split huggingface dataset:
The C3/C3aR pathway exacerbates acetaminophen‐induced mouse liver injury via upregulating podoplanin on the macrophage
Authors: Xie Zhanli , Jiang Jiang , Yang Fei , Han Jingjing , Ma Zhenni , Wen Tao , Bai Xia 
Published: January 2025

AbstractAcute liver failure (ALF) is a life‐threatening condition that occurs when the liver sustains severe damage and rapidly loses its function. The primary cause of ALF is the overdose of acetaminophen (APAP), and its treatment is relatively limited. The involvement of the complement system in the development of ALF has been implicated. However, the related mechanisms remain poorly understood. Complement 3 (C3) knockout mice, complement 3a receptor (C3aR) knockout mice, platelet C‐type lectin‐like receptor 2 (Clec‐2)–deficient mice, and myeloid cell podoplanin (Pdpn)‐deficient mice were generated. Liver tissues were collected for histological analysis, RNA sequencing, confocal immunofluorescence, and immunoblot analyses. Our data demonstrated that APAP activated the C3/C3aR pathway, leading to intrahepatic hemorrhage, ultimately resulting in hepatocyte necrosis. Deletion of C3 or C3aR mitigated APAP‐induced liver injury (AILI). C3/C3aR signaling upregulated the expression and phosphorylation of transcription factors STAT3 and c‐Fos in hepatic Kupffer cells, which in turn increased PDPN expression, promoting platelet recruitment to the Kupffer cells via the interaction of PDPN and the CLEC‐2 on platelets. Since the activation of platelets mediated by C3/C3aR occurs irrespective of the major hemostatic pathways, blocking the C3/C3aR pathway in ALF could be a coagulopathy‐sparing and novel therapeutic approach. In summary, this study unveiled the critical roles of the C3/C3aR pathway in developing AILI, providing evidence that the C3/C3aR pathway could be an effective therapeutic target for AILI.
The rectal microbiome: understanding its role in HIV transmission
Authors: Català-Moll Francesc , Paredes Roger 
Published: January 2025

Purpose of review
Condomless receptive anal intercourse stands out as the sexual practice with highest risk of HIV-1 infection. Recent studies have suggested that the gut microbiome influences susceptibility to HIV transmission. This review explores recent research on host risk factors, the rectal microbiome composition, local inflammation, and bacteria-derived mediators that may affect HIV transmission.

Recent findings
Constitutive host factors such as rectal mucosal structure and immune cell populations in the rectum contribute to increased susceptibility. Changes in the composition of the rectal microbiota, influenced by sexual practices and HIV infection modulate immune activation and inflammation, impacting HIV susceptibility. Bacteria-derived mediators may further influence immune responses and HIV replication in the rectal mucosa.

Summary
Understanding the role of the rectal microbiome in HIV transmission has important clinical implications. Targeted interventions that modulate the microbiome may reduce susceptibility to HIV transmission by regulating immune responses and inflammation. Further research into the host–microbiome interactions could lead to novel preventive and therapeutic strategies to mitigate HIV transmission.
Emerging role of natural killer cells in non-AIDS comorbidities during suppressive antiretroviral therapy
Authors: Alles Mario , Demberg Thorsten , Liyanage Namal P.M. 
Published: January 2025

Purpose of review
Despite decades of insights about the role of natural killer (NK) cells in HIV infection, their persistent dysregulation despite antiretroviral therapy (ART) and its pathological consequences have been incompletely delineated. In this review, we highlight recent findings on the immunophenotypic and functional alterations of NK cells during virally suppressed HIV infection and explore their potential impact on promoting non-AIDS related comorbidities among people living with HIV (PLWH).

Recent findings
Of note are the apparent persistent activated profiles of NK cells and pathophysiological events such as endoplasmic reticulum (ER) stress in potentially driving NK cell derived inflammation and tissue destruction. Additionally, recent interest in trained immunity is discussed as a potential mediator of ongoing NK cell dysregulation, contributing to comorbidities such as cardiovascular disease and neurocognitive disorders, both with an inflammatory etiology.

Summary
Clinical and mechanistic evidence suggests persistent activation and dysregulation of the innate immune system are major drivers of non-AIDS comorbidities during virally suppressed HIV infection. Delineating the mechanistic role of specific components of innate immunity such as NK cells in inducing these pathologies will lead to the identification of novel therapeutic/prophylactic strategies to improve the overall health of PLWH.
Trauma history and persistent poor objective and subjective sleep quality among midlife women
Authors: Jakubowski Karen , Riedmann Carly A. , Chang Yuefang , Koenen Karestan C. , Maki Pauline M. , Thurston Rebecca C. 
Published: January 2025

Abstract

Objectives
Whereas some work links trauma exposure to poor subjective sleep quality, studies largely rely upon limited trauma measures and self-reported sleep at one time point. It is unknown whether trauma is related to persistent poor sleep, whether associations differ based on childhood versus adulthood trauma, and whether trauma exposure is related to poorer objectively assessed sleep. We tested whether childhood or adult trauma associated with persistent poor objectively and subjectively measured sleep at two time points in midlife women.

Methods
One hundred sixty-seven women aged 40-60 at baseline were assessed twice 5 years apart. At baseline, women reported childhood trauma (Child Trauma Questionnaire), adult trauma (Brief Trauma Questionnaire), demographics, depressive symptoms, apnea symptoms, and medical history, and provided physical measures. At both visits, women completed 3 days of actigraphy (total sleep time [TST], wake after sleep onset [WASO]) and reported sleep quality (Pittsburgh Sleep Quality Index). Relations of childhood and adult trauma exposure, respectively, with persistent poor sleep at both baseline and follow-up visits (TST [<6 hours], WASO [>30 minutes], Pittsburgh Sleep Quality Index [>5]) were assessed in logistic regression models, adjusted for age, race/ethnicity, education, body mass index, sleep medications, nightshift work, apnea, depressive symptoms, vasomotor symptoms, and alcohol use.

Results
Childhood trauma was related to persistent high WASO (odds ratio [95% confidence interval] = 2.16 [1.04-4.50], P = 0.039, multivariable). Adult trauma was related to persistent poor sleep quality (odds ratio [95% confidence interval] = 2.29 [1.07-4.93], P = 0.034, multivariable). Trauma was unrelated to persistent short TST.

Conclusions
Childhood and adult trauma, respectively, were related to persistent poor objective sleep continuity and subjective sleep quality in midlife women, independent of risk factors.
CD63-high macrophage-derived exosomal miR-6876-5p promotes hepatocellular carcinoma stemness via PTEN/Akt-mediated EMT pathway
Authors: Zhang Shuairan , Liu Shiqi , Dong Hang , Jin Xiuli , Sun Jing , Sun Ji , Wu Gang , Li Yiling 
Published: January 2025

Objective:
Accumulating evidence suggests that microRNAs derived from macrophage exosomes can regulate the stemness and progression of cancer. However, the interaction mechanisms between HCC cells and tumor-associated macrophages remain unclear.

Methods:
Exosomes were extracted from control or CD63 overexpression macrophages and co-cultured with HCC cells. The stemness, proliferation, epithelial-mesenchymal transition, and in vivo tumorigenicity of HCC cells were assessed to determine the role of CD63-high macrophage-derived exosomal miR-6876-5p in HCC. The binding relationship between miR-6876-5p and the PTEN/Akt axis was also investigated.

Results:
Elevated CD63 expression was associated with increased tumor-associated macrophage infiltration and poorer prognosis in HCC. CD63-high macrophage-derived exosomes enhanced HCC cell proliferation, stemness, and epithelial-mesenchymal transition. miR-6876-5p within these exosomes was identified as a key mediator, promoting HCC progression by targeting PTEN and activating the Akt signaling pathway. In vivo studies confirmed that CD63-high macrophage-derived exosomal miR-6876-5p accelerated tumor growth and enhanced stemness in HCC cells.

Conclusions:
CD63-high macrophage-derived exosomes, particularly those enriched with miR-6876-5p, play a pivotal role in HCC progression by enhancing stemness and promoting epithelial-mesenchymal transition through the PTEN/Akt pathway. Targeting these exosomes and their microRNAs offers a promising therapeutic strategy forHCC.
Acid sphingomyelinase deficiency and Gaucher disease: Underdiagnosed and often treatable causes of hepatomegaly, splenomegaly, and low HDL cholesterol in lean individuals
Authors: Mistry Pramod K. , Cassiman David , Jones Simon A. , Lachmann Robin , Lukina Elena , Prada Carlos E. , Wasserstein Melissa P. , Thurberg Beth L. , Foster Meredith C. , Patel Reema M. , Underhill Lisa H. , Peterschmitt M. Judith 
Published: January 2025

Background:
Acid sphingomyelinase deficiency (ASMD) and Gaucher disease type 1 (GD1) are rare inherited sphingolipid disorders with multisystemic manifestations, including liver disease and dyslipidemia. Despite effective treatments, insufficient disease awareness frequently results in diagnostic delays during which irreversible complications occur. We delineated the shared and distinctive features of hepatic, splenic, and lipoprotein phenotypes in ASMD and GD1.

Methods:
We analyzed baseline hepatic, splenic, and lipoprotein phenotypes of untreated adults in pivotal trials of ASMD (ASCEND, N=36) and GD1 (ENGAGE, N=40).

Results:
The mean cohort ages were 34.8 years in ASMD and 31.8 years in GD1. Most patients had normal or low body mass index. Moderate hepatosplenomegaly (mean volume in multiples of normal) was common in both cohorts (hepatomegaly 1.53±0.42 and 1.40±0.32, respectively; splenomegaly 11.45±4.36 and 13.20±5.91, respectively). Liver function tests were mildly elevated in ASMD but normal in GD1. In both disorders, mean HDL cholesterol (mg/dL) was profoundly low (22.23±9.14 ASMD; 26.25±8.08 GD1) and correlated inversely with liver volume (r=−0.45 ASMD, p=0.005; r=−0.50 GD1, p=0.001) and spleen volume (r=−0.60 ASMD, p=0.0001; r=−0.63 GD1, p<0.0001). Mean LDL cholesterol (mg/dL) was elevated in ASMD (145.86±49.80) but low in GD1 (68.85±22.53). HDL cholesterol correlated inversely with serum concentrations of lyso-sphingomyelin in ASMD (r=−0.48, p=0.003) and glucosylsphingosine in GD1 (r=−0.63, p<0.0001).

Conclusions:
ASMD and GD1 should be considered in differential diagnosis of patients with unexplained liver and lipid abnormalities, especially young, lean adults with very low HDL and hepatosplenomegaly. HDL emerged as a potential biomarker of disease activity in these sphingolipid disorders.
Increased MASH-associated liver cancer in younger demographics
Authors: Danpanichkul Pojsakorn , Pang Yanfang , Suparan Kanokphong , Auttapracha Thanida , Sirimangklanurak Supapitch , Attia Abdelrahman M. , Thimphitthaya Chanattha , Ni Law Michelle Shi , Yu Zhenning , Soliman Mostafa A. , Polpichai Natchaya , Kanitthamniyom Chanakarn , Kim Donghee , Noureddin Mazen , Singal Amit G. , Wijarnpreecha Karn , Yang Ju Dong 
Published: January 2025

Background:
The incidence of cancer and the prevalence of metabolic disease and metabolic dysfunction–associated steatotic liver disease is increasing in young adults. However, updated global data on metabolic dysfunction–associated steatohepatitis (MASH)-associated primary liver cancer (PLC) in young adults remains scarce.

Methods:
This study analyzed data from the Global Burden of Disease study between 2000 and 2021 to assess the age-standardized incidence, mortality, and disability-adjusted life years rates from MASH-associated PLC in young adults (15–49 y).

Results:
In 2021, there were 4300 incidence cases, 3550 deaths, and 179,340 disability-adjusted life years from MASH-associated PLC in young adults. Among various etiologies of PLC in young adults, only MASH-associated PLC had increased incidence rates (annual percent change: +0.26, 95% CI: 0.16%–0.35%), with the Eastern Mediterranean region having the largest observed increase (annual percent change: 1.46%, 95% CI: 1.40%–1.51%). In 2021, MASH-associated PLC in young adults made up 6% (+1% from 2000) incident cases, 6% (+2% from 2000) deaths, and 6% (+2% from 2000) disability-adjusted life years of all PLC in this age group. Over half of the countries exhibited an increase in age-standardized incidence rate from MASH-associated PLC in young adults from 2000 to 2021.

Conclusions:
The incidence of MASH-associated PLC in young adults is significantly increasing, signaling likely future increases in PLC incidence among older adults as this cohort ages. This trend necessitates urgent strategies worldwide to mitigate the epidemics of MASH-associated PLC in young adults.
Health-related Quality of Life in Children and Adolescents After Successful Treatment of Chronic Hepatitis C With Sofosbuvir/Velpatasvir: One-year Outcomes
Authors: Pokorska-Śpiewak Maria , Dobrzeniecka Anna , Talarek Ewa , Aniszewska Małgorzata , Pluta Magdalena , Marczyńska Magdalena , Indolfi Giuseppe 
Published: January 2025

Background and aims:
The aim of this study was to assess the health-related quality of life (HRQL) of children with chronic hepatitis C (CHC) at 1 year after the effective treatment with sofosbuvir/velpatasvir (SOF/VEL).

Methods:
All 50 patients treated for CHC with a fixed dose SOF/VEL in the noncommercial, nonrandomized, open-label PANDAA-PED study achieved sustained virologic response at 12 weeks after the end of treatment. Evaluation of HRQL at 1-year posttreatment was compared with the baseline (before the treatment) assessment. KIDSCREEN-27 questionnaires, which included 5 dimensions of HRQL, for child self-reporting and parent proxy reporting were used. The normal range for the population was set to T values of 40–60 points. Child–parent agreement was analyzed using the intraclass correlation coefficient (ICC).

Results:
Mean T values were within the normal range for all HRQL dimensions. A significant improvement in “autonomy & parent relation” in children’s self-assessment (from 48.3 to 51.5, P = 0.03) was observed. In parent proxy assessment, a significant decrease occurred in “school” dimension (from 49.5 to 45.8, P = 0.03), which was not revealed at 3-month posttreatment. Older age was associated with worse HRQL scores in all dimensions. Evaluation of the ICC for child self-reports versus parent proxy reports revealed poor-to-moderate agreement for most single measures, lower than at 3-month posttreatment analysis.

Conclusions:
This is the first study to present the long-term influence of treatment with direct-acting antivirals on patient-reported outcomes in children. At 1 year after effective treatment with SOF/VEL, an improvement in some areas of children’s well-being was revealed, which may indicate also some patient-reported outcomes benefits of direct-acting antiviral therapy. Despite the improvement in the child self-report of “autonomy & parent relation,” there was a more pronounced discrepancy between children self-reports and parents proxy reports in all dimensions of HRQL. Older patients’ age correlated with worse HRQL assessment. If this finding is mediated by the duration of hepatitis C virus infection, it would support recommendation for the treatment of younger children.
Surgical treatment of congenital pseudarthrosis of the tibia in children: CPAM-LRC consensus and guidelines
Authors: Song Wenqi , Zhou Runhua , Liu Pei , Guo Yanjie , Shao Lei , Liu Delin , Xu Jia , Wu Tianyi , Bai Zhong , Su Chi , Liu Fuyun , Liu Jun , Kang Qinglin , Lu Shengdi 
Published: January 2025

Purpose:
Congenital pseudarthrosis of the tibia (CPT) is a rare condition typically manifesting within the first decade of life. The primary objectives of surgical intervention for CPT include achieving long-term bony union of the tibia, preventing or minimizing limb length discrepancies (LLD), avoiding mechanical axis deviations of the tibia and adjacent joints, and preventing refracture. This study aims to conduct a systematic review of current treatment methods for CPT to determine the most effective non-surgical and surgical management strategies for pediatric patients with this condition.

Methods:
A review of the literature was performed according to the PRISMA guidelines. A comprehensive search of PubMed, Medline, CINAHL, Cochrane, Embase, and Google Scholar databases was performed over the years 1989 to 2024. Randomized controlled trials, cohort studies and case-control studies on the surgical treatments of CPT in children were included. Random-effects models were used to estimate the pooled primary union rate, primary union time and refracture rate. Then a consensus statement of surgical treatment of CPT in children was achieved based on Delphi methodology which included 2 rounds of electronic questionnaires and 1 round of virtual consensus meeting.

Results:
Seventy-four studies were included, 23 of which on intramedullary rods (IMR) involving 364 patients, 15 on Ilizarov methods with 230 patients, and 23 studies combining IMR with Ilizarov involving 458 patients. The pooled primary union rate for IMR, Ilizarov method, and Ilizarov combined with IMR was 69% (95% CI: 0.55–0.82), 89% (95% CI: 0.77–0.98) and 85% (95% CI: 0.74–0.94), respectively. The pooled primary union time for IMR, Ilizarov method, and Ilizarov combined with IMR was 8.95 months (95% CI: 6.53–11.37), 7.14 months (95% CI: 5.53–8.74), and 5.62 months (95% CI: 4.89–6.35), respectively. The pooled refracture rate among primary unions for IMR, Ilizarov method, and Ilizarov combined with IMR was 85% (95% CI: 0.60–1.00), 81% (95% CI: 0.56–0.98), and 60% (95% CI: 0.26–0.90), respectively. After 2 rounds of electronic questionnaires and 1 round of virtual consensus meeting, a consensus statement and guidelines of surgical treatment of CPT in children was provided.

Conclusion:
The CPAM-LRC consensus panel provided recommendations to improve management of pediatric patients with CPT in clinical practice. Combined techniques for pediatric patients after fracture or the formation of pseudarthrosis commonly include excision of the pseudarthrosis site, external fixation, intramedullary fixation, and autogenous bone grafting. Vascularized fibular graft and cross-union can be considered a viable alternative to corticocancellous autograft. Use of recombinant bone morphogenic protein (rhBMP) is not currently conclusive.
Changes in Self-Directed Learning Among Doctor of Physical Therapy Students Across Didactic Curriculum: A Mixed-Methods Analysis
Authors: Getz Emily N. , Langerwerf Leigh , Young Jodi L. , Bliss Rebecca 
Published: January 2025

Introduction.
Physical therapy education best practice includes the development of adaptive lifelong learners because of a constantly changing health care landscape. The purpose of this study was to identify how self-directed learning (SDL) changes in traditional Doctor of Physical Therapy (DPT) students over the course of the didactic curriculum.

Review of literature.
The Master Adaptive Learning (MAL) framework has been proposed as a framework that physical therapy educators adopt to create and educate physical therapists who embrace continuous change and build a culture of creativity and innovation.

Subjects.
Fifty students from a midwestern DPT program participated in the quantitative portion, and 14 participated in the qualitative portion of the study.

Methods.
A mixed-methods approach was used to assess students’ SDL using the Motivated Strategies of Learning Questionnaire (MSLQ) and the Short Grit scale across the 3-year curriculum. Focus group interviews were conducted following quantitative data collection to develop themes and determine relationships of these themes with existing learning paradigms.

Results.
There was a statistically significant decrease in students' MSLQ scores from the students’ first semester to third and sixth semesters. In the sixth and eighth semester, scores stabilized or had limited improvement. Grit scores remained consistent. Themes that emerged from focus group interviews included deep learning, habits of the heart, and vulnerability. Multiple subthemes were also found that overlap with the MAL framework.

Discussion and Conclusion.
This study provides preliminary data to understand DPT students’ SDL journey in a traditional DPT program and highlights the need for continued research and efforts toward improving SDL strategies in DPT students. Providing students with necessary resources and support to transition to more self-directed behaviors aligns with the recent call to action to infuse the MAL framework into the PT educational continuum.
A Collaborative Model for Pediatric Clinical Education: From Design to Implementation
Authors: Ardolino Elizabeth M. , Flores Megan B , Sawyer Kathryn 
Published: January 2025

Background and Purpose.
Collaborative clinical education models where 2 or more students are supervised by one clinical instructor in a clinical setting effectively support student learning and self-confidence. Use of collaborative models in specialized clinical education settings has not been widely adopted. This paper explores using Kern's 6-step approach to develop and implement a collaborative clinical education model.

Method/Model Description and Evaluation.
The process began with a general needs assessment focused on the scarcity of clinical placements in specialized fields, culminating with a decision to pilot a collaborative clinical education model. In step 2, a targeted needs assessment identified a specific pediatric clinic in which to implement the model. During steps 3 and 4, the faculty and clinical partner developed overarching goals and educational strategies for the clinical education experience. Step 5 focused on implementation, including securing institutional support, preparing students, and addressing logistical challenges. The final step of the model was assessment through review of objective data.

Outcomes.
All overarching goals and objectives of the program were met. Evaluation using interviews with students, clinical instructors, and patient caregivers indicated high satisfaction and achievement of clinical competence.

Discussion and Conclusions.
The collaborative model successfully met educational requirements and improved patient outcomes. This paper underscores the necessity of innovative clinical education strategies to meet growing demands and suggests that such models can effectively prepare students for specialized practice areas. This approach demonstrates the feasibility and value of using a framework to implement a clinical education model.