bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of direct health facility financing on MNCH service provision: results from a comparative, before-after study in Pwani Region, Tanzania
Authors: Oh Kyoung Kyun , Ferdinand Joy G. , Kapologwe Ntuli A. , Ngaiza Benedicto M. , Gordon Joyce M. , Lim Doowon , Ngowi Alfred E. , Yusuph Swabaha A. , Kim Hayoung , Park Hansol , Ahn Sooyoung , Nam Bok Hyun , Kim Chang-yup 
Published: November 2024

Abstract
Background
Pwani Regional Secretariat in Tanzania implemented the Maternal, Neonatal, and Child Health Project (2016–2022) through Direct Health Facility Financing (DHFF), which allocates funds directly to health facilities. This study assessed the impact of the six-year DHFF project in Pwani region.

Methods
The study utilised District Health Information Software 2 data from 18 intervention health facilities in Pwani region. Control groups comprised an equal number of facilities from Pwani and Dodoma regions where the project was not implemented. Key indicators assessed included ‘ANC 4 + Rate (%)’, ‘Percentage of Mothers tested for Anaemia during ANC’, ‘Caesarean Section Delivery Rate (%)’, ‘Percentage of Mothers and Newborns receiving PNC services within 48 hours’, ‘Delivery Complication Rate (%)’, and ‘SBA Delivery Rate (%)’ which are associated with the project interventions. The impact of the project was analysed using a paired sample t-test comparing baseline and endline data. We evaluated the significance of the dependent variables using one-way ANOVA with control groups, with the Tukey-Kramer test for post hoc analysis. Chi-square test assessed the significance of Caesarean Section Delivery Rate and the relationship between variables and health facility conditions. Pearson correlation test was used for significance between funding size and the change of MNCH variables. Statistical significance at 0.05 was calculated.

Results
The project showed limited positive impacts, only in the ‘Percentage of Mothers tested for Anaemia during ANC’ (****p < 0.0001), ‘Percentage of Newborns receiving PNC within 48 hours’ (**p = 0.0095), and ‘SBA Delivery Rate’ (***p = 0.0043). The health facility assessment identified positively influencing factors on service delivery, such as facility type (*p = 0.0347), distance to the facility (****p < 0.0001), and internet connectivity (*p = 0.0186). We found that the project did not improve most MNCH indicators, including the CEmONC coverage (χ2 = 2.82, p = 0.2448, df = 2), which was known to be the leading outcome.

Conclusion
The project had limited impacts on MNCH outcomes due to various factors. While the health facility assessment highlighted positive influences on service delivery, significant areas for improvement remain, including referral systems and infrastructure. Operational research findings indicate that the effectiveness of the DHFF could be enhanced by refining its management and governance structures.
Assessing coronary artery stenosis exacerbated impact on left ventricular function and deformation in metabolic syndrome patients by 3.0 T cardiac magnetic resonance imaging
Authors: Jiang Yi-Ning , Gao Yue , Min Chen-Yan , Guo Ying‑Kun , Xu Rong , Shen Li-Ting , Qian Wen-lei , Li Yuan , Yang Zhi-Gang 
Published: November 2024

Abstract
Background
Metabolic syndrome (MetS) and coronary artery stenosis (CAS) independently increase the risk of cardiovascular events, while the impact of CAS on left ventricular (LV) function and deformation in MetS patients remains unclear. This study investigates how varying degrees of CAS exacerbate LV function and myocardial deformation in MetS patients.

Methods
One hundred thirty-one MetS patients who underwent CMR examinations were divided into two groups: the MetS(CAS−) group (n = 47) and the MetS(CAS+) group (n = 84). The MetS(CAS+) group was divided into MetS with non-obstructive CAS(NOCAS+) (n = 30) and MetS with obstructive CAS(OCAS+) group (n = 54). Additionally, 48 age- and sex-matched subjects were included as a control group. LV functional and deformation parameters were measured and compared among subgroups. The determinants of decreased LV global peak strains in all MetS patients were identified using linear regression. The receiver operating characteristic (ROC) curve and logistic regression model (LRM) evaluated the diagnostic accuracy of the degree of CAS for identifying impaired LV strain.

Results
Compared to MetS(CAS−), MetS(NOCAS+) showed a significantly increased LV mass index (p < 0.05). Global longitudinal peak strain was decreased gradually from MetS(CAS−) through MetS(NOCAS+) to MetS(OCAS+) (− 13.02 ± 2.32% vs. − 10.34 ± 4.05% vs. − 7.55 ± 4.48%, p < 0.05). MetS(OCAS+) groups showed significantly decreased LV global peak strain (GPS), PSSR and PDSR in radial and circumferential directions compared with MetS(NOCAS+) (all p < 0.05). The degree of CAS was independently associated with impaired global radial peak strain (GRPS) (β =  − 0.289, p < 0.001) and global longitudinal peak strain (GLPS) (β = 0.254, p = 0.004) in MetS patients. The ROC analysis showed that the degree of CAS can predict impaired GRPS (AUC = 0.730) and impaired GLPS (AUC = 0.685).

Conclusion
Besides traditional biochemical indicators, incorporating CAS assessment and CMR assessment of the LV into routine evaluations ensures a more holistic approach to managing MetS patients. Timely intervention of CAS is crucial for improving cardiovascular outcomes in this high-risk population.
Cooperative participation of CagA and NFATc1 in the pathogenesis of antibiotics-responsive gastric MALT lymphoma
Authors: Tsai Hui-Jen , Yeh Kun-Huei , Lin Chung-Wu , Wu Ming-Shiang , Liou Jyh-Ming , Hsu Ping-Ning , Zeng Yi-Shin , Wei Ming-Feng , Shun Chia-Tung , Wang Hsiu-Po , Chen Li-Tzong , Cheng Ann-Lii , Kuo Sung-Hsin 
Published: November 2024

Abstract
Background
This study aimed to explore whether cytotoxin-associated gene A (CagA) can inhibit cell cycle progression by activating nuclear factor of activated T cells (NFAT) in lymphoma B cells and contribute to Helicobacter pylori eradication (HPE) responsiveness (complete remission [CR] after HPE) in gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

Materials and Methods
We co-cultured three B-lymphoma cell lines (MA-1, OCI-Ly3, and OCI-Ly7) with HP strains (derived from HPE-responsive gastric MALT lymphoma) and evaluated the expression patterns of CagA, phosphorylated (p)-CagA (CagAP−Tyr), and CagA-signaling molecules, cell-cycle inhibitors, p-NFATc1 (Ser172), and NFATc1 using western blotting. Furthermore, we evaluated the association between nuclear NFATc1 expression in the tumor cells of 91 patients who received first-line HPE (59 patients with HPE responsiveness and 32 without HPE responsiveness) and HPE responsiveness and CagA expression in tumor cells.

Results
In HP strains co-cultured with B cell lymphoma cell lines, CagA was translocated to the nucleus through tyrosine phosphorylation (CagAP−Tyr) and simultaneously dephosphorylated NFATc1, subsequently causing nuclear NFATc1 translocation and stimulating the expression of p-SHP-2/p-ERK/Bcl-xL. Activated NFATc1 causes G1 cell cycle retardation in both MA-1 and OCI-Ly3 cells by triggering p21 and p27 production. Nuclear NFATc1 localization was significantly associated with the presence of CagA in gastric MALT lymphomas (80% [41/51] vs. 33% [13/40]; p < 0.001) and with HPE responsiveness (73% [43/59] vs. 25% [8/32]; p < 0.001). Patients exhibiting both the presence of CagA and nuclear NFATc1 localization responded more rapidly to HPE than those without (median interval to CR, 4.00 vs. 6.00 months, p = 0.003).

Conclusions
Our findings indicated that CagA and NFATc1 cooperatively participate in the lymphomagenesis of HPE-responsive gastric MALT lymphoma.
Physical, biochemical, and biological characterization of olive-derived lipid nanovesicles for drug delivery applications
Authors: Zhao Zhu , Lacombe Jerome , Simon Laurianne , Sanchez-Ballester Noelia M. , Khanishayan Ashkan , Shaik Naina , Case Kallie , Dugas Pierre-Yves , Repellin Mathieu , Lollo Giovanna , Soulairol Ian , Harris Ashlee F. , Gordon Michael , Begu Sylvie , Zenhausern Frederic 
Published: November 2024

AbstractExtracellular vesicles (EVs) have shown great promise as drug delivery system (DDS). However, their complex and costly production limit their development for clinical use. Interestingly, the plant kingdom can also produce EV-like nanovesicles that can easily be isolated and purified from a large quantity of raw material at a high yield. In this study, olive-derived nanovesicles (ODNVs) were isolated from raw fruits using serial centrifugations and their physical and biological features characterized to demonstrate their promising potential to be used as a DDS. Nanotracking particle analysis indicated an average size of 109.5 ± 3.0 nm and yield of 1012 ODNVs/mL for the purest fraction. Microscopy imaging, membrane fluidity assay and lipidomics analysis showed the presence of a rich lipid bilayer that significantly varied between different sources of ODNVs but showed a distinct signature compared to human EVs. Moreover, ODNVs were enriched in PEN1 and TET8 compared to raw fruits, suggesting an extracellular origin. Interestingly, ODNVs size and yield stayed unchanged after exposure to high temperature (70 °C for 1 h), wide pH range (5–10), and 50–100 nm extrusion, demonstrating high resistance to physical and chemical stresses. This high resistance allowed ODNVs to stay stable in water at 4 °C for a month, or with the addition of 25 mM trehalose for long-term freezing storage. Finally, ODNVs were internalized by both 2D and 3D cell culture without triggering significant cytotoxicity and immunogenicity. Importantly, the anticancer drug doxorubicin (dox) could be loaded by passive incubation within ODNVs and dox-loaded ODNVs decreased cell viability by 90% compared to only 70% for free dox at the same concentration, indicating a higher efficiency of drug delivery by ODNVs. In addition, this high cytotoxicity effect of dox-loaded ODNVs was shown to be stable after a 2-week storage at 4 °C. Together, these findings suggested that ODNVs represent a promising candidate as drug nanocarrier for various DDS clinical applications, as demonstrated by their biocompatibility, high resistance to stress, good stability in harsh environment, and improvement of anticancer drug efficacy.
The patient’s voice: a cross-sectional study of physical health and disability in juvenile idiopathic arthritis
Authors: Arneng Sofie Mikalsen , Jenssen Isabelle Pignatel , Lundestad Anette , Cetrelli Lena , Angenete Oskar , Nordal Ellen , Tylleskär Karin B. , Romundstad Pål Richard , Rygg Marite 
Published: November 2024

Abstract
Background
With increasing focus on patient-reported outcome measures (PROMs) in chronic rheumatic diseases, we aimed to evaluate the self-reported physical and psychosocial health in children with juvenile idiopathic arthritis (JIA) compared to matched population-based controls. Furthermore, we aimed to study the association of patient- and physician-reported outcome measures in JIA with patient-reported physical disability.

Methods
We used data from a Norwegian JIA cohort study (NorJIA), including clinical characteristics and outcome measures in participants with JIA and sex- and age-matched population-based controls. Self-reported physical and psychosocial health were assessed using the generic Child Health Questionnaire (CHQ). Comparisons between children with JIA and controls were performed by test of proportions for categorical variables and t-test for continuous variables. To evaluate the association of patient- and physician-reported outcome measures with patient-reported physical disability, assessed with the Child Health Assessment Questionnaire (CHAQ) in children with JIA, we used logistic regression to estimate adjusted odds ratio (OR) with 95% confidence interval (CI).

Results
In total, 221 participants with JIA (59.3% females, median age 12.7 years) and 207 controls with available data were included. In the JIA group, 24.3% scored below the norm for physical health (CHQ PhS < 40) and 8.7% scored below the norm for psychosocial health (CHQ PsS < 40). The corresponding numbers for the control group were 0.5% and 1.9%, respectively. In the JIA group, 57.9% reported physical disability (CHAQ > 0). Several patient-reported outcome measures, such as poor physical health (CHQ PhS < 40), disease-related pain, and the patient’s global assessment of disease impact on wellbeing, were strongly associated with self-reported physical disability (CHAQ > 0), adjusted OR 19.0 (95% CI 5.6, 64.1), 14.1 (95% CI 6.8, 29.2), and 14.0 (95% CI 6.2, 31.6), respectively.
Associations were also found for active disease according to Wallace (adjusted OR 36.3, 95% CI 10.3, 128.1), and physician-reported global assessment of disease activity (adjusted OR 6.2, 95% CI 3.1, 12.6).

Conclusions
The strong association between patient- and physician-reported outcome measures and patient-reported physical disability strengthens the importance of including the patient’s voice in a comprehensive evaluation of patient outcome in JIA.

Trial registration
ClinicalTrials.gov (No: NCT03904459).
Psychotropic drug-induced adverse drug reactions in 462,661 psychiatric inpatients in relation to age: results from a German drug surveillance program from 1993–2016
Authors: Seifert Johanna , Reinhard Matthias A. , Bleich Stefan , Erfurth Andreas , Greil Waldemar , Toto Sermin , Grohmann Renate , Glocker Catherine 
Published: November 2024

Abstract
Background
Clinical practice suggests that older adults (i.e., ≥ 65 years of age) experience adverse drug reactions (ADRs) more often than younger patients (i.e., < 65 years of age). ADRs such as falls, extrapyramidal symptoms (EPS), metabolic disorders, sedation, and delirium are particularly worrisome and often associated with psychotropic drugs.

Methods
This observational study investigated the risk for psychotropic drug-related ADRs in older (n = 99,099) and younger adults (n = 363,562) in psychiatric inpatients using data from the German pharmacovigilance program “Arzneimittelsicherheit in der Psychiatrie” (AMSP) from 1993–2016. The aim was to assess whether age influenced the risk of specific ADR types and if certain psychotropic drugs posed particular concerns.

Results
The risk for ADRs did not differ between older and younger patients (relative risk 0.98, 95% confidence interval 0.92–1.05). However, older patients had a higher risk for delirium (2.35, 1.85–2.99), hyponatremia (3.74, 2.85–4.90), and orthostatic syncope (2.37, 1.72–3.26), as well as certain types of EPS, e.g., parkinsonism (1.89, 1.45–2.48) and Pisa-/metronome syndrome (3.61, 2.51–5.18). The risk for other ADRs, such as acute dystonia (0.20, 0.10–0.37), akathisia (0.47, 0.29–0.76), liver dysfunction (0.63, 0.48–0.82), weight gain (0.07, 0.04–0.14), sexual dysfunction (0.03, CI 0.00–0.25), and hyperprolactinemia/galactorrhea (0.05, 0.02–0.17) was significantly lower for older patients. Older patients treated with any type of antidepressant drug (1.33, 1.26–1.40)—especially selective serotonin reuptake inhibitors (1.57, 1.26–1.40) and selective serotonin-norepinephrine reuptake inhibitors (2.03, 1.80–2.29)—and lithium (1.74, 1.52–2.00) had a higher ADR risk than younger patients. Second-generation antipsychotic drugs had a lower (0.74, 0.71–0.77) and low-potency first-generation antipsychotic drugs a higher (1.19, 1.07–1.33) ADR risk in older patients. The risk for ADRs involving multiple drugs was higher in older patients (1.28, 1.22–1.34). ADRs in older patients were 6.4 times more likely to result in death.

Conclusions
Clinicians and pharmacists should be aware of the types of ADRs and high-risk drugs across age groups and provide appropriate monitoring. Pharmacovigilance is crucial in psychiatric patients of all ages and should not be neglected, even for drugs generally considered “safe”.
The KLF16/MYC feedback loop is a therapeutic target in bladder cancer
Authors: Zheng Lisi , Wang Jingxuan , Han Shan , Zhong Li , Liu Zefu , Li Bin , Zhang Ruhua , Zhou Liwen , Zheng Xianchong , Liu Zhenhua , Zeng Cuiling , Li Ruonan , Zou Yezi , Wang Liqin , Wu Yuanzhong , Kang Tiebang 
Published: November 2024

Abstract
Background
Bladder cancer (BLCA) is a common malignancy characterized by dysregulated transcription and a lack of effective therapeutic targets. In this study, we aimed to identify and evaluate novel targets with clinical potential essential for tumor growth in BLCA.

Methods
CRISPR-Cas9 screening was used to identify transcription factors essential for bladder cancer cell viability. The biological functions of KLF16 in bladder cancer were investigated both in vitro and in vivo. The regulatory mechanism between KLF16 and MYC was elucidated through a series of analyses, including RNA sequencing, quantitative polymerase chain reaction (qPCR), RNA immunoprecipitation, Western blotting, Mass spectrometry, Dual-luciferase reporter assays, Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, OptoDroplets assays, and RNA stability assay. The clinical relevance of KLF16 and MYC in bladder cancer was evaluated through analyses of public databases and immunohistochemistry.

Results
Krüppel-like factor 16 (KLF16) was essential for BLCA cell viability. Elevated expression of KLF16 was observed in bladder cancer tissues, and higher expression levels of KLF16 were correlated with poor progression-free survival (PFS) and cancer-specific survival (CSS) probabilities in BLCA patients. Mechanistically, KLF16 mRNA competed with the mRNA of dual-specificity phosphatase 16 (DUSP16) for binding to the RNA-binding protein, WW domain binding protein 11 (WBP11), resulting in destabilization of the DUSP16 mRNA. This, in turn, led to activation of ERK1/2, which stabilized the MYC protein. Furthermore, KLF16 interacted with MYC to form nuclear condensates, thereby enhancing MYC’s transcriptional activity. Additionally, MYC transcriptionally upregulated KLF16, creating a positive feedback loop between KLF16 and MYC that amplified their oncogenic functions. Targeting this loop with bromodomain inhibitors, such as OTX015 and ABBV-744, suppressed the transcription of both KLF16 and MYC, resulting in reduced BLCA cell viability and tumor growth, as well as increased sensitivity to chemotherapy.

Conclusions
Our study revealed the crucial role of the KLF16/MYC regulatory axis in modulating tumor growth and chemotherapy sensitivity in BLCA, suggesting that combining bromodomain inhibitors, such as OTX015 or ABBV-744, with DDP or gemcitabine could be a promising therapeutic intervention for BLCA patients.
Permissive weight bearing versus restrictive weight bearing in surgically treated trauma patients with displaced intra-articular calcaneal fractures (the PIONEER study): study protocol for a multicenter randomized controlled trial
Authors: Verstappen Coen , Driessen Mitchell L. S. , Kalmet Pishtiwan H. S. , Brandts Lloyd , Kimman Merel , Edwards Michael , Hermans Erik , Poeze Martijn 
Published: November 2024

Abstract
Background
Following successful treatment, displaced intra-articular calcaneal fractures (DIACFs) necessitate an extensive rehabilitation regimen, significantly influencing functional and socio-economic outcomes. Apart from surgical intervention, the implementation of a comprehensive rehabilitation protocol is crucial to optimize foot stability and functional recovery. The objective of this study is to ascertain the optimal rehabilitation protocol for patients with surgically treated DIACFs, either permissive weight bearing (PWB) or Restricted Weight Bearing, focusing on functional outcomes, health-related quality of life (HRQoL), radiographic parameters, cost-effectiveness, and incidence of complications.

Methods
Study design: A prospective multicenter randomized controlled trial. Study population: Presence of surgically (extended lateral, sinus tarsi, or percutaneous approach) treated unilateral DIACFs (Sanders type II to IV), aged 18–67 years (labor force). Patients must be able to understand and follow weight bearing instructions. N = 115 patients with DIACFs will be included. Interventions: Patients with DIACFs will be randomly allocated to one of the rehabilitation protocols, either PWB or RWB. Primary outcome measure: Functional outcome, measured with the American Orthopaedic Foot & Ankle Society Score (AOFAS)). Secondary outcomes: Functional outcome (Maryland Foot Score, MFS), HRQoL (EuroQol-5D, EQ-5D), differences in radiographic parameters, cost-effectiveness, and complications. Nature and extent of burden: The PWB protocol is aimed to be non-inferior to the RWB protocol. Previous analysis of this protocol in other lower extremity fractures has shown a safe complication rate. Follow-up is standardized according to current trauma guidelines, namely at time points 2, 6, 12 weeks, and 6 months. The radiation exposure for both groups will differ from standard care (one extra CT scan of the foot will be made). Therefore, the burden for participants is considered minimal, with no significant health risks.

Discussion
This study will be the first study to define an optimal rehabilitation regime for surgically treated patients with DIACFs. The limitations of this study include the absence of patient blinding, as this is impossible in rehabilitation. Additionally, the primary outcome measure (AOFAS) has limited validity for DIACFs. However, it is the most commonly used questionnaire in the literature on DIACFs. There is an apparent need since current literature is lacking on this specific topic.

Trial registration
ClinicalTrials.gov NCT05721378, accepted on February 7, 2023.