bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mobile health van as an intervention to provide clinical support and health promotion to street children and marginalised populations in the National Capital Region of Delhi: a mixed-methods evaluation
Authors: Seth Rajeev , Girotra Tanu Girotra , Mohammad Id , Qaiyum Yawar , Taneja Indra , Raman Shanti 
Published: January 2025

BackgroundUrban health challenges, particularly for street and slum-dwelling children and families, have emerged as one of the most significant health concerns in India. While there is little published on effective healthcare delivery to these populations, mobile health vans (MHV) have been proposed as a proactive pathway to providing outreach healthcare. Our aims were to evaluate the impact of Bal Umang Drishya Sanstha (BUDS) MHV in providing health and support services to the urban slum populations in Delhi National Capital Region (NCR), focusing on benefits to children.MethodsThis was a mixed-methods evaluation, using routinely collected data. We collated and reviewed available data recorded by the BUDS staff in their health record system from June 2017 to December 2023. Qualitative data were provided by two recent focus group discussions carried out in the community; one with 18 mothers and another with a mixed group of 12 adults—all had used MHV clinics for children in their families. We chose two typical case studies that were reported to the funding bodies.ResultsBetween 2017 and 2023, there were a total of 41 062 clinic visits for children<18 years, with visits increasing steadily and peaking at 8864 in 2023. Just under 10% of encounters were referred to specialist services, 122 children were diagnosed with disability. Health education sessions were provided mainly in group settings, to over 70 000 children. Themes extracted from focus group discussions were enhanced access to healthcare, quality of care, value adds from MHV and suggestions for improvement. Families expressed overwhelming appreciation of BUDS MHV. Case studies illustrated the benefits of facilitated access to tertiary healthcare.ConclusionsMHV can serve as a valuable source of primary healthcare for street and slum-dwelling children and their families. Other benefits are empowering communities with health literacy and negotiating pathways to tertiary care.
Home high-flow therapy during recovery from severe chronic obstructive pulmonary disease (COPD) exacerbation: a mixed-methods feasibility randomised control trial
Authors: D'Cruz Rebecca F , Rossel Anne , Kaltsakas Georgios , Suh Eui-Sik , Douiri Abdel , Rose Louise , Murphy Patrick B , Hart Nicholas 
Published: January 2025

IntroductionPatients recovering from severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have a 30-day readmission rate of 20%. This study evaluated the feasibility of conducting a randomised controlled trial to evaluate clinical, patient-reported and physiological effects of home high-flow therapy (HFT) in addition to usual medical therapy, in eucapnic patients recovering from AECOPD to support the design of a phase 3 trial.MethodsA mixed-methods feasibility randomised controlled trial (quantitative primacy, concurrently embedded qualitative evaluation) (ISRCTN15949009) recruiting consecutive non-obese patients hospitalised with AECOPD not requiring acute non-invasive ventilation. Participants were randomised to receive usual care or usual care and home HFT (37°C, 30 L/min) with weekly home-based follow-up for 4 weeks to collect data on: device usage, breathlessness (modified Borg scale, visual analogue scale, Multidimensional Dyspnoea Profile), health-related quality of life (COPD Assessment Test (CAT), Clinical COPD Questionnaire), pulse oximetry, spirometry and inspiratory capacity, parasternal electromyography and actigraphy. Semistructured interviews were conducted in week 4. Trial progression criteria were: ≥40% of eligible patients randomised, ≤20% attrition, ≥70% complete data, and no device-related serious adverse events (SAE).Results18 of 45 eligible patients were randomised (age 69±5 years, 44% female, body mass index 23±5 kg/m2, forced expiratory volume in 1 second 32±12%). One withdrew following non-respiratory hospitalisation. Complete outcome measures were collected in >90% of home assessments. There were no device-related SAE. Daily HFT usage was 2.7±2.2 hours in week 1, falling to 2.3±1.4 hours by week 4. Temperature and flow settings were modified for comfort in 6 cases. Higher HFT usage was associated with lower symptom burden (CAT p=0.01). Interviews highlighted ease of device use, reduced salbutamol usage, and improved sputum production and clearance.ConclusionsThe data from this feasibility study support the progression to a phase 3 randomised clinical trial investigating the effect of home (HFT) on admission-free survival in COPD patients recovering from a severe exacerbation.Trial registration numberThe study received ethical approval (REC19/LO/0194) and was prospectively registered (ISRCTN15949009).
Emergency response planning for sudden cardiac arrest in amateur football clubs in Germany (federal state Saarland)
Authors: Egger Florian , Ukaj Ana , Meyer Tim 
Published: January 2025

ObjectiveWhile emergency care for sudden cardiac arrest (SCA) is strictly regulated in professional football, the situation in amateur football is unclear. This study investigated the emergency readiness for SCA in German amateur football clubs.MethodsA cross-sectional survey of 253 German amateur football clubs (fifth division and lower) was conducted between January and August 2023. Club representatives participated in a 30-point questionnaire on automated external defibrillator (AED) availability, visibility, purchase, usage, frequency of staff trained in cardiopulmonary resuscitation (CPR) and AED usage, regular CPR and AED training, and the existence of an emergency action plan (EAP).Results161 of 253 eligible clubs (64% response rate) participated. An AED was available in 48/161 (30%) clubs. 46 of 161 clubs (29%) had no CPR-trained staff. A high availability of CPR- and AED-trained staff (>75% likelihood of being present at the pitch) was more likely during a match (61% and 84%) than training (40% and 51%), respectively. Retrospectively, over 7 years, five clubs reported that CPR-trained staff used an AED, resulting in a survival rate of 80%. 16 clubs (10%) had an EAP in the event of an SCA.ConclusionGerman amateur football clubs show low emergency readiness for SCA despite a promising survival rate when an AED is used by CPR-trained staff on-site. Regular CPR and AED training for club members, increased availability of AEDs, and the development of EAPs might be beneficial in responding adequately to an SCA during football training and matches.
Targeted inhibition of Aurora kinase A promotes immune checkpoint inhibition efficacy in human papillomavirus-driven cancers
Authors: Ghosh Soma , O'Hara Madison P , Sinha Pragya , Mazumdar Tuhina , Yapindi Lacin , Sastry Jagannadha K , Johnson Faye M 
Published: January 2025

BackgroundHuman papillomavirus (HPV)-driven cancers include head and neck squamous cell carcinoma and cervical cancer and represent approximately 5% of all cancer cases worldwide. Standard-of-care chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICIs) are associated with adverse effects and limited responses in patients with HPV-driven cancers. The integration of targeted therapies with ICIs may improve outcomes. In a previous study, we demonstrated that Aurora kinase A (AURKA, Aurora A) inhibitors lead to apoptosis of human HPV-positive cancer cells in vitro and in vivo. Here, we explored the potential of Aurora A inhibition to enhance response to ICIs in immune-competent preclinical models of HPV-driven cancers.MethodsWe assessed the induction of apoptosis, DNA damage, and immunogenic cell death (ICD) in response to treatment with the Aurora A inhibitor alisertib in vitro and antitumor efficacy of alisertib as a monotherapy and in combination with ICIs that inhibit programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) in murine HPV-positive immune-competent tumor models. In each treatment group, we determined the tumor growth kinetics and long-term survival and assessed the tumor immune microenvironment using polychromatic flow cytometry.ResultsAurora A inhibition induced apoptosis, DNA damage, and ICD in vitro in multiple human and murine HPV-positive cancer cell lines. Importantly, Aurora A inhibition induced selective apoptotic depletion of myeloid-derived suppressor cells (MDSCs). In vivo experiments demonstrated that the combination of alisertib with ICIs, specifically anti-CTLA4, resulted in improved survival outcomes by altering the tumor immune microenvironment. This combination enhanced CD8 T-cell infiltration and decreased the frequencies of MDSCs, whereas neither alisertib nor ICIs (anti-PD-1/anti-CTLA-4) alone showed such effects.ConclusionOur study establishes the potential of Aurora A inhibition to sensitize HPV-positive tumors to ICIs, specifically anti-CTLA-4 treatment. This combination strategy resulted in enhanced antitumor efficacy, driven by systemic and intratumoral increases in CD8 T-cell responses and reduced immunosuppressive cell populations, specifically MDSCs. These findings offer insights into the synergistic effects of Aurora A inhibition and ICIs and argue for further investigation and optimization of this combination approach in HPV-driven cancers.
Anti-PD-1 amplifies costimulation in melanoma-infiltrating Th1-like Foxp3+regulatory T cells to alleviate local immunosuppression
Authors: Attias Mikhaël , Alvarez Fernando , Al-Aubodah Tho-Alfakar , Istomine Roman , McCallum Paige , Huang Fan , Sleiman Abrahim , Nishimura Tamiko , del Rincón Sonia V , Riazalhosseini Yasser , Piccirillo Ciriaco A 
Published: January 2025

BackgroundImmune checkpoint inhibitors targeting programmed cell death protein-1 (PD-1) are the first line of treatment for many solid tumors including melanoma. PD-1 blockade enhances the effector functions of melanoma-infiltrating CD8+T cells, leading to durable tumor remissions. However, 55% of patients with melanoma do not respond to treatment. As Foxp3+regulatory T (Treg) cells play an important role in tumor-induced immunosuppression and express PD-1, we hypothesized that anti-PD-1 also increases the functions of melanoma-infiltrating Tregcells, which could be detrimental to treatment efficacy.MethodsThe cellular and functional dynamics of Tregcells were evaluated in C57Bl/6 Foxp3-reporter mice bearing highly immunogenic and PD-1 blockade-sensitive Yale University Mouse Melanoma Exposed to Radiation 1.7 (YUMMER1.7) tumors. Tregcell responses in tumors and lymphoid compartments were examined throughout tumor growth or therapy and were assessed ex vivo by multiparametric flow cytometry analysis, with in vitro suppression assays using tumor-infiltrating lymphocytes isolated by fluorescence-activated cell sorting (FACS) andin situthrough spatial proteomic and transcriptomic profiling.ResultsIn this highly immunogenic melanoma model, anti-PD-1 monotherapy yielded high responders (HRs) and low responders (LRs). We show that the potent CD8+T cell responses characteristic of HR tumors paradoxically coincide with the expansion of highly-activated, Helios-expressing Tregcells. In both HRs and LRs, Tregcells co-localize with CD8+T cells in immunogenic regions of the tumor and display potent suppressive capacity in vitro. Further characterization revealed that melanoma-infiltrating Tregcells progressively acquire T-bet and interferon gamma expression, exclusively in HRs, and induction of this T helper cell 1 (Th1)-like phenotype in vitro led to CD8+T cell evasion from Tregcell-mediated suppression. Using spatial proteomic and transcriptomic profiling, we demonstrate that Tregcells display an increased activity of PI3K/Akt signaling in regions of HR tumors with an elevated CD8:Tregcell ratio.ConclusionsPD-1 blockade promotes the expansion of a subset of highly-activated Tregcells coexpressing PD-1 and Helios. While these cells are potently suppressive outside tumor environments, costimulatory and inflammatory signals present in the tumor microenvironment lead to their local acquisition of Th1-like characteristics and loss of suppression of effector T cells.
CREB3L1 facilitates pancreatic tumor progression and reprograms intratumoral tumor-associated macrophages to shape an immunotherapy-resistance microenvironment
Authors: Xu Haiyan , Xue Shengbai , Sun Yang , Ma Jingyu , Li Shumin , Wang Yanling , Mao Tiebo , Ge Weiyu , Yue Ming , Shentu Daiyuan , Lu Wenxin , Wang Yongchao , Hu Jiong , Cui Jiujie , Zhang Xiaofei , Cai Li , Wang Yu , Wang Liwei 
Published: January 2025

BackgroundTo date, a growing body of evidence suggests that unfolded protein response (UPR) sensors play a vital role in carcinogenesis. However, it remains unclear whether they are involved in pancreatic ductal adenocarcinoma (PDAC) and how they relate to clinical outcomes. This study aims to investigate the biological function and mechanism of how a novel UPR sensor, CREB3L1 works in PDAC and further evaluate its clinical application prospect.MethodsWe tested UPR signaling including CREB3L1 in Thapsigargin-treated PDAC cells. Subsequently, we defined CREB3L1 expression and further analyzed its expression with clinical characteristics in PDAC. Then, we established gene-modified cells to determine whether CREB3L1 functions in cell proliferation and migration capacity. Besides, we constructed subcutaneously and orthotopically transplanted mice models to verify their progrowing function and pulmonary metastasis models to prove their proinvasion role. What’s more, RNAseq, qPCR, Western blotting, immunohistochemistry and multicolor flow cytometry experiments were used to explore the mechanism of how CREB3L1 worked in PDAC. Lastly, CREB3L1 expression correlation with PDAC immunotherapy outcome and immune cell signatures were explored in the patients with advanced PDAC who received PD-1 antibody therapy.ResultsWe first confirmed CREB3L1 could be induced by endoplasmic reticulum stressor and found its aberrant activation was associated with poorer overall survival in PDAC patients indicating the protumor function of the new UPR sensor. Functionally, we confirmed CREB3L1 contributing to PDAC malignant progression including growth and metastasis by multiple in in vitro and in vivo models. Mechanistically, CREB3L1 upregulated COL3A1 and promoted dense stroma formation for facilitating PDAC and knocking down COL3A1 disrupted CREB3L1 protumor function. Furthermore, CREB3L1-induced TAM polarization toward an M2 phenotype and reduced the infiltration of CD8+T cells. Clinically, CREB3L1 correlated with immune cell signatures as well as immune checkpoint blockade (ICB) treatment response and outcome that CREB3L1aberrant activation indicated poorer efficacy and worse prognosis than the low in PDAC which might empower clinical decision.ConclusionsCollectively, this study revealed CREB3L1 facilitated PDAC progression, shaped an immune exclude tumor microenvironment and distinguished therapy response and outcome of ICB therapy indicating CREB3L1 could be a promising novel molecular target and biomarker for PDAC treatment.
Nivolumab plasma concentration and clearance associated with overall survival in patients with renal cell carcinoma
Authors: Maritaz Christophe , Combarel David , Dalban Cécile , Blondel Louis , Broutin Sophie , Marabelle Aurelien , Albiges Laurence , Paci Angelo 
Published: January 2025

BackgroundNivolumab is an immune checkpoint inhibitor (ICI) that selectively inhibits programmed cell death protein 1 activation, restoring antitumor immunity. ICIs are indicated for various types of advanced solid tumors; however, not all patients benefit from them, and tools that could be used in the clinic to predict response to treatment represent an unmet need. Here we describe the development of a new population pharmacokinetic (PPK) model in patients treated with nivolumab in clinical trials. Applying the model to a patient population with renal cell carcinoma identified nivolumab clearance and plasma concentration as predictors of overall survival (OS).MethodsA custom liquid chromatography with tandem mass spectrometry method for quantifying nivolumab plasma concentration was developed and validated following the European Medicines Agency guidelines for bioanalytical method validation. The PPK model was developed using data from patients treated in the NIVIPIT (n=38) and NIVOREN (n=137) trials of nivolumab in metastatic melanoma and renal cell carcinoma, respectively. The PPK model was used to determine pharmacokinetic (PK) parameters such as baseline clearance and simulate individual clearance changes over time. The relationship between PK characteristics (including clearance at Cycle 1 (CLC1), plasma concentration at Cycle 3 and clinical outcomes was assessed in 137 patients treated in NIVOREN. Kaplan-Meier methodology was used in time-to-event analyses.ResultsIn 137 patients, the median nivolumab CLC1 was 6 mL/hour and the median plasma concentration at Cycle 3 was 48 µg/mL. Median follow-up was 21.0 months (95% CI 20.2 to 22.5 months) with a survival rate at 6 months of 91.2% and 77.9% at 12 months. In univariate analysis, OS was significantly higher in patients with CLC1<6 mL/hour versus ≥6 mL/hour (HR 2.2 (95% CI 1.2 to 4.1), p=0.0146). Shorter OS was observed in patients with plasma concentration at Cycle 3 below the median (48 µg/mL) versus those above the median (HR 0.4 (95% CI 0.2 to 0.8), p=0.0069). Multivariate analysis showed a trend towards lower clearance, but this did not reach statistical significance (p=0.0694).ConclusionsResults of the study may potentially be used to predict outcomes of nivolumab therapy in patients with renal cell carcinoma. Additional applications may include guiding dose adjustments of nivolumab in those who are less likely to respond to the initial dose.
Association between resolution of MRI-detected inflammation and improved clinical outcomes in axial spondyloarthritis under long-term anti-TNF therapy
Authors: Torgutalp Murat , Rademacher Judith , Proft Fabian , Hermann Kay-Geert , Althoff Christian , Haibel H , Protopopov Mikhail , Sieper Joachim , Rios Rodriguez Valeria , Poddubnyy Denis 
Published: January 2025

ObjectivesIn this post-hoc analysis of ESTHER trial, we aimed to investigate the longitudinal relationship between inflammation on MRI and the achievement of inactive disease/low disease activity in patients with axial spondyloarthritis (axSpA) treated with long-term tumor necrosis factor (TNF) inhibitor etanercept.MethodsOf the 76 patients with active axSpA in the ESTHER trial, we included all patients treated with etanercept for at least 6 months for main analysis. All clinical and MRI data from 4.5 years of follow-up were used in the analysis. MRIs of the spine and sacroiliac (SI) joints were performed at baseline, week 24, week 48 and yearly thereafter and were evaluated for active inflammatory lesions according to the Berlin MRI score.ResultsLongitudinal analysis showed that higher SI joint osteitis score was associated with higher Axial Spondyloarthritis Disease Activity Score (ASDAS) at the same time point (β=0.08, 95% CI (0.05; 0.11)) and at the next time point 6 months later (β=0.05, 95% CI (0.02; 0.07)). Furthermore, resolution of osteitis in the SI joint (Berlin MRI osteitis score of ≤1) was associated with lower ASDAS at the next time point (β=−0.26, 95% CI (−0.42; −0.09)), higher odds of achieving ASDAS low disease activity (OR=5.61, 95% CI (1.06; 29.67)) and inactive disease status (OR=2.23, 95% CI (1.01; 4.94)) at the next time point.ConclusionsThe presence of inflammation on SI joints-MRI is associated with higher disease activity in axSpA. Resolution of inflammation on MRI is associated with better clinical outcomes in the long-term follow-up. Thus, achieving complete resolution of inflammation is favourable for meeting the treatment goals in axSpA.Trial registration numberNCT00844142.
Evaluation of rheumatoid arthritis-associated interstitial lung disease in patients treated with JAK inhibitors: a MAJIK-SFR cohort study
Authors: Triboulet Félicien , Juge Pierre-Antoine , Truchetet Marie-Elise , Pham Thao , Roux Nicolas , Flipo René-Marc , Leské Charles , Roux Christian Hubert , Seror Raphaele , Basch André , Brocq Olivier , Chazerain Pascal , Coury-Lucas Fabienne , Damade Richard , Dernis Emanuelle , Gottenberg Jacques-Eric , Ramon André , Ruyssen-Witrand Adeline , Salmon Jean Hugues , Shipley Émilie , Tournadre Anne , Prati Clement , Dieudé Philippe , Avouac Jerome 
Published: January 2025

ObjectiveTo examine the course of interstitial lung disease associated with rheumatoid arthritis (RA-ILD) in France on treatment with Janus kinase inhibitors (JAKis) using the MAJIK-SFR registry.MethodsProspective national multicentre observational study identifying patients with RA-ILD from the MAJIK-SFR registry. Pulmonary assessment data were collected at JAKi initiation and follow-up visits (6 months, 12 months and a median of 21 months postinclusion), including chest high-resolution CT (HRCT), pulmonary function tests (forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO)), acute exacerbations of ILD, respiratory infections and lung cancers.ResultsWe enrolled 42 patients (26 women, 62%) with RA-ILD with a mean age of 61±13 years and a mean disease duration of 16±10 years. Compared with the 778 RA patients without ILD from the MAJIK registry, RA-ILD patients were older, displayed more severe and active disease and had more prevalent comorbidities. Non-specific interstitial pneumonia and usual interstitial pneumonia accounted for 46% and 43% of the chest HRCT ILD patterns, respectively. No significant changes in FVC and DLCO were observed during the follow-up period. Chest HRCT lesions remained stable in 69% of patients. Progressive ILD was identified in 8 patients (19%). 16 (38%) respiratory tract infections were observed. Only one acute regressive exacerbation of ILD was noted, and no lung cancer was diagnosed. No deaths occurred. JAKi was discontinued in 17 patients including 8 for inefficacy on joint involvement and 5 for intolerance.ConclusionThe analysis indicates stability of RA-ILD in patients treated with JAKi. The tolerance profile of JAKi in this higher risk population did not reveal new safety signal.