bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe pulmonary hypertension–interstitial lung disease presenting as right ventricular failure: stabilisation with intravenous prostacyclin and maintenance with inhaled prostacyclin
Authors: Parikh Raj , Thomas Alysse , Sharofi Aldo , Moallem Niala , Fiscus Garrett , Farber Harrison W. 
Published: January 2024

BackgroundPulmonary hypertension (PH) leads to increased morbidity and mortality in interstitial lung disease (ILD). While the INCREASE trial highlighted the use of inhaled prostacyclin in PH-ILD patients, such therapy may be inadequate when right ventricular failure (RVF) is also present. In this study, we report the use of intravenous prostacyclin in three PH-ILD patients to stabilise right ventricular (RV) function, with a subsequent transition to maintenance therapy with inhaled prostacyclin.MethodsWe evaluated three consecutive PH-ILD patients with RVF. RV afterload and pulmonary vascular resistance (PVR) were treated with intravenous prostacyclin during the induction phase of the therapy. Patients transitioned from intravenous prostacyclin to the maintenance phase of the treatment with inhaled prostacyclin once three transition criteria were met: cardiac index (CI) >2 L·min−1·m−2, PVR <7 Wood units (WU) and tricuspid annular plane systolic excursion (TAPSE) change >1 mm or TAPSE >1.6 cm.ResultsPre-treatment parameters for the three patients were a mean PVR of 14.3 WU, a mean Fick CI of 1.8 L·min−1·m−2and a mean TAPSE of 1.4 cm. The average intravenous prostacyclin dose at the time of transition to maintenance therapy was 20.7 ng·kg−1·m−2of treprostinil. At 3-months follow-up, the mean PVR was 6.3 WU, Fick CI 2.2 L·min−1·m−2and TAPSE 1.7 cm.ConclusionThis case series of three PH-ILD patients with RVF introduces the concept of an initial intravenous prostacyclin induction phase, followed by a transition to maintenance therapy with inhaled prostacyclin. Further development of this treatment algorithm with a refinement of the transition criteria, potential testing in a clinical trial and a longer-term follow-up period is warranted to improve the outcomes of advanced PH-ILD patients with concomitant RVF.
Use of CompEx in eosinophilic patients with severe, uncontrolled asthma on benralizumab
Authors: Bolton Clare , Harrison Tim , Lugogo Njira , Fuhlbrigge Anne , Hirsch Ian , Bengtsson Thomas , Peterson Stefan , Sidaway Martin , Garcia Gil Esther , Fagerås Malin , Da Silva Carla A. 
Published: January 2024

BackgroundCompEx Asthma, a composite end-point for asthma exacerbations, captures clinically relevant, diary-based acute worsening events (AWEs) (defined as deterioration in daily peak expiratory flow concurrent with deterioration in asthma symptoms and/or rescue therapy use) and severe exacerbations (SevEx) (defined by American Thoracic Society/European Respiratory Society guidelines). We hypothesised that CompEx and SevEx would show similar benralizumab treatment effects and correlations to blood eosinophil counts in patients with severe asthma.MethodsThispost hocanalysis of pooled 12-month data from two phase 3 studies included patients aged ≥16 years with severe, uncontrolled asthma who were randomised to benralizumab 30 mg or placebo. Annualised event rates were analysed using a negative binomial model. The impact of blood eosinophil count on treatment effect was assessed.ResultsAmong patients with a blood eosinophil count ≥300 cells·µL−1(n=913), benralizumab reduced the annualised event rateversusplacebo for CompEx (1.57versus2.57; risk ratio 0.61, 95% CI 0.53–0.70, p<0.001), SevEx (0.94versus1.55; risk ratio 0.60, 95% CI 0.52–0.70, p<0.001) and AWE (0.92versus1.57; risk ratio 0.59, 95% CI 0.48–0.72, p<0.001), with greater treatment effects observed for higher blood eosinophil counts. In patients with blood eosinophil count ≥300 cells·µL−1, benralizumab was associated with shorter median event duration (CompEx: 10.5 daysversus17.0 days; SevEx: 10.0 daysversus15.0 days; AWE: 5.0 daysversus6.0 days).ConclusionsBenralizumab reduced the risk of CompEx events with treatment effects similar to those for SevEx and AWEs across a range of blood eosinophil counts. Use of CompEx supports the evaluation of benralizumab and other novel drugs in clinical studies.
Prioritization of Trypanosoma brucei editosome protein interactions interfaces at residue resolution through proteome-scale network analysis
Authors: Poorinmohammad Naghmeh , Salavati Reza 
Published: January 2024

Abstract
Background
Trypanosoma brucei is the causative agent for trypanosomiasis in humans and livestock, which presents a growing challenge due to drug resistance. While identifying novel drug targets is vital, the process is delayed due to a lack of functional information on many of the pathogen’s proteins. Accordingly, this paper presents a computational framework for prioritizing drug targets within the editosome, a vital molecular machinery responsible for mitochondrial RNA processing in T. brucei. Importantly, this framework may eliminate the need for prior gene or protein characterization, potentially accelerating drug discovery efforts.

Results
By integrating protein-protein interaction (PPI) network analysis, PPI structural modeling, and residue interaction network (RIN) analysis, we quantitatively ranked and identified top hub editosome proteins, their key interaction interfaces, and hotspot residues. Our findings were cross-validated and further prioritized by incorporating them into gene set analysis and differential expression analysis of existing quantitative proteomics data across various life stages of T. brucei. In doing so, we highlighted PPIs such as KREL2-KREPA1, RESC2-RESC1, RESC12A-RESC13, and RESC10-RESC6 as top candidates for further investigation. This includes examining their interfaces and hotspot residues, which could guide drug candidate selection and functional studies.

Conclusion
RNA editing offers promise for target-based drug discovery, particularly with proteins and interfaces that play central roles in the pathogen’s life cycle. This study introduces an integrative drug target identification workflow combining information from the PPI network, PPI 3D structure, and reside-level information of their interface which can be applicable to diverse pathogens. In the case of T. brucei, via this pipeline, the present study suggested potential drug targets with residue-resolution from RNA editing machinery. However, experimental validation is needed to fully realize its potential in advancing urgently needed antiparasitic drug development.
Comparative genomic analyses provide new insights into evolutionary history and conservation genomics of gorillas
Authors: van der Valk Tom , Jensen Axel , Caillaud Damien , Guschanski Katerina 
Published: January 2024

AbstractGenome sequencing is a powerful tool to understand species evolutionary history, uncover genes under selection, which could be informative of local adaptation, and infer measures of genetic diversity, inbreeding and mutational load that could be used to inform conservation efforts. Gorillas, critically endangered primates, have received considerable attention and with the recently sequenced Bwindi mountain gorilla population, genomic data is now available from all gorilla subspecies and both mountain gorilla populations. Here, we reanalysed this rich dataset with a focus on evolutionary history, local adaptation and genomic parameters relevant for conservation. We estimate a recent split between western and eastern gorillas of 150,000–180,000 years ago, with gene flow around 20,000 years ago, primarily between the Cross River and Grauer’s gorilla subspecies. This gene flow event likely obscures evolutionary relationships within eastern gorillas: after excluding putatively introgressed genomic regions, we uncover a sister relationship between Virunga mountain gorillas and Grauer’s gorillas to the exclusion of Bwindi mountain gorillas. This makes mountain gorillas paraphyletic. Eastern gorillas are less genetically diverse and more inbred than western gorillas, yet we detected lower genetic load in the eastern species. Analyses of indels fit remarkably well with differences in genetic diversity across gorilla taxa as recovered with nucleotide diversity measures. We also identified genes under selection and unique gene variants specific for each gorilla subspecies, encoding, among others, traits involved in immunity, diet, muscular development, hair morphology and behavior. The presence of this functional variation suggests that the subspecies may be locally adapted. In conclusion, using extensive genomic resources we provide a comprehensive overview of gorilla genomic diversity, including a so-far understudied Bwindi mountain gorilla population, identify putative genes involved in local adaptation, and detect population-specific gene flow across gorilla species.
Evaluating the usefulness of considering the size and morphological type of type B2 vessel area based on Japan Esophageal Society classification in estimating tumor invasion depth in superficial esophageal squamous cell carcinomas: study protocol for a prospective observational study (Japan BEES study)
Authors: Yoshida Masao , Mori Keita , Urabe Yuji , Hirasawa Dai , Sasaki Fumisato , Takeuchi Manabu , Kadota Tomohiro , Yoshio Toshiyuki , Yoshinaga Shigetaka , Kitamura Yoko , Ohno Kazuya , Ono Yoichiro , Igarashi Kimihiro , Takahashi Hiroaki , Ishihara Ryu 
Published: January 2024

Abstract
Background
Accurate evaluation of tumor invasion depth is essential to determine the appropriate treatment strategy for patients with superficial esophageal cancer. The pretreatment tumor depth diagnosis currently relies on the magnifying endoscopic classification established by the Japan Esophageal Society (JES). However, the diagnostic accuracy of tumors involving the muscularis mucosa (MM) or those invading the upper third of the submucosal layer (SM1), which correspond to Type B2 vessels in the JES classification, remains insufficient. Previous retrospective studies have reported improved accuracy by considering additional findings, such as the size and macroscopic type of the Type B2 vessel area, in evaluating tumor invasion depth. Therefore, this study aimed to investigate whether incorporating the size and/or macroscopic type of the Type B2 vessel area improves the diagnostic accuracy of preoperative tumor invasion depth prediction based on the JES classification.

Methods
This multicenter prospective observational study will include patients diagnosed with MM/SM1 esophageal squamous cell carcinoma based on the Type B2 vessels of the JES classification. The tumor invasion depth will be evaluated using both the standard JES classification (standard-depth evaluation) and the JES classification with additional findings (hypothetical-depth evaluation) for the same set of patients. Data from both endoscopic depth evaluations will be electronically collected and stored in a cloud-based database before endoscopic resection or esophagectomy. This study’s primary endpoint is accuracy, defined as the proportion of cases in which the preoperative depth diagnosis matched the histological depth diagnosis after resection. Outcomes of standard- and hypothetical-depth evaluation will be compared.

Discussion
Collecting reliable prospective data on the JES classification, explicitly concerning the B2 vessel category, has the potential to provide valuable insights. Incorporating additional findings into the in-depth evaluation process may guide clinical decision-making and promote evidence-based medicine practices in managing superficial esophageal cancer.

Trial registration
This trial was registered in the Clinical Trials Registry of the University Hospital Medical Information Network (UMIN-CTR) under the identifier UMIN000051145, registered on 23/5/2023.
PerSurge (NOA-30) phase II trial of perampanel treatment around surgery in patients with progressive glioblastoma
Authors: Heuer Sophie , Burghaus Ina , Gose Maria , Kessler Tobias , Sahm Felix , Vollmuth Philipp , Venkataramani Varun , Hoffmann Dirk , Schlesner Matthias , Ratliff Miriam , Hopf Carsten , Herrlinger Ulrich , Ricklefs Franz , Bendszus Martin , Krieg Sandro M. , Wick Antje , Wick Wolfgang , Winkler Frank 
Published: January 2024

Abstract
Background
Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been discovered that excitatory synapses of the AMPA-receptor subtype form between non-malignant brain neurons and tumor cells. This neuron-tumor network connectivity contributed to glioma progression and could be efficiently targeted with the EMA/FDA approved antiepileptic AMPA receptor inhibitor perampanel in preclinical studies. The PerSurge trial was designed to test the clinical potential of perampanel to reduce tumor cell network connectivity and tumor growth with an extended window-of-opportunity concept.

Methods
PerSurge is a phase IIa clinical and translational treatment study around surgical resection of progressive or recurrent glioblastoma. In this multicenter, 2-arm parallel-group, double-blind superiority trial, patients are 1:1 randomized to either receive placebo or perampanel (n = 66 in total). It consists of a treatment and observation period of 60 days per patient, starting 30 days before a planned surgical resection, which itself is not part of the study interventions. Only patients with an expected safe waiting interval are included, and a safety MRI is performed. Tumor cell network connectivity from resected tumor tissue on single cell transcriptome level as well as AI-based assessment of tumor growth dynamics in T2/FLAIR MRI scans before resection will be analyzed as the co-primary endpoints. Secondary endpoints will include further imaging parameters such as pre- and postsurgical contrast enhanced MRI scans, postsurgical T2/FLAIR MRI scans, quality of life, cognitive testing, overall and progression-free survival as well as frequency of epileptic seizures. Further translational research will focus on additional biological aspects of neuron-tumor connectivity.

Discussion
This trial is set up to assess first indications of clinical efficacy and tolerability of perampanel in recurrent glioblastoma, a repurposed drug which inhibits neuron-glioma synapses and thereby glioblastoma growth in preclinical models. If perampanel proved to be successful in the clinical setting, it would provide the first evidence that interference with neuron-cancer interactions may indeed lead to a benefit for patients, which would lay the foundation for a larger confirmatory trial in the future.

Trial registration
EU-CT number: 2023-503938-52-00 30.11.2023.
Enhanced tumor control activities of anti-mPD-L1 antibody and antigen-presenting cell-like natural killer cell in an allograft model
Authors: Hung Yi-Ping , Tu Chia-Chun , Lai Jiun-I , Yang Muh-Hwa , Lee Jan-Mou , Chao Yee 
Published: January 2024

Abstract
Background
Despite the utilization of immune checkpoint inhibitors (ICIs) in treating numerous types of cancers being approved, their efficacy in tumor control in the clinic is not satisfactory. Since adoptive cell therapy (ACT) can alter the tumor microenvironment, we hypothesized that ACT potentially synergized with ICI in tumor control and examined this hypothesis via a murine allograft model.

Methods
Female C57BL/6 mice were stimulated with interleukin 15 and granulocyte monocyte-colony stimulating factor, followed by collecting their bone marrow cells for murine NKDC cultivation. Then, female C57BL/6 mice, inoculated with lymphoma cancer cell line E.G7-OVA, were administrated with murine NKDC cells, murine anti-program cell death ligand-1 antibody (α-mPD-L1), or both for 28 days. After 28 days of treatment, mice were sacrificed whose inoculated tumors, spleen, sentinel lymph nodes, and peripheral blood were collected to measure tumor size, lymphocyte infiltration, and change of immune cell profile.

Results
Combined treatment of NKDCs with α-mPD-L1 exhibited significantly stronger tumor control efficacy than treatment of NKDCs or α-mPD-L1 alone. NKDCs/α-mPD-L1 combination increased migration of dendritic cells, CD4, CD8 T cells, and activated CD8 T cells to the tumor-bedding site, and promoted endogenous tumor-specific cytotoxic T-cell response.

Conclusion
The current study confirmed our hypothesis that combining NKDC ACT with ICI therapy can potentiate tumor control efficacy by manipulating the tumor microenvironment. This study provided a novel circumstance on tumor immunotherapy.
Changes in patient care through flexible and integrated treatment programs in German psychiatric hospitals: meta-analyses based on a series of controlled claims-based cohort studies
Authors: Neumann Anne , Schmitt Jochen , Seifert Martin , Kliemt Roman , March Stefanie , Häckl Dennis , Swart Enno , Pfennig Andrea , Baum Fabian 
Published: January 2024

Abstract
Background
Global treatment budgets, i.e. predefined budgets for patients treated in hospital independent of the setting within the hospital, together with flexible and integrated treatment (FIT) have been introduced in some German psychiatric hospitals since 2013. We investigated pooled changes in inpatient, day-care, outpatient treatment, and continuity of care for patients with mental disorders in 12 FIT-hospitals.

Methods
We conducted a series of 12 controlled cohort studies regarding FIT hospitals using anonymized patient claims data from more than 70 German statutory health insurance funds. Each study compared one FIT-hospital to matched patients from equivalent non-FIT-hospitals (routine care). We included only those patients without treatment in the respective hospital within two years prior to first hospital treatment (either FIT or routine care). We contrasted results between the year prior to with the first and second year after patient’s first treatment (treatment continuity: only group comparison) using multivariate multi-level models. To approximate the difference-in-difference effect in the meta-analysis, we used the interaction terms group (FIT hospital vs. routine care) x time (year before vs. first or second patient year after study inclusion) in the Poisson models.

Results
The 12 studies included 36,069 patients with 2,358 patients from a Department of child and adolescent psychiatry. The pooled effect revealed a 5.1 days lower increase in inpatient treatment in FIT-hospitals during the first patient year compared to routine care. Results were statistically significant for adult care FIT-hospitals but not for child and adolescent FIT-hospitals. Utilization of day-care treatment increased more in most FIT-hospitals during the first year, while outpatient contacts increased in some and decreased in others. The odds of treatment continuity increased by 1.4 in FIT-hospitals compared to non-FIT-hospitals.

Conclusions
Global treatment budgets lead to the intended changes in mental health care in the majority of FIT-hospitals compared to routine care in this large real-world evidence study from Germany. For child and adolescent psychiatry, more evidence is needed to draw firm conclusions.

Trial registration
This study was registered in the database “Health Services Research Germany” (trial number: VVfD_EVA64_15_003713).
Comparison of the prevalence of osteoporosis in people with spinal cord injury according to bone mineral density reference values for the diagnosis of osteoporosis: a retrospective, cross-sectional study
Authors: Lim Jisun , Kim Onyoo 
Published: January 2024

AbstractBackgroundSpinal cord injury (SCI) is a complex cause of rapid low bone mass that easily predisposes the affected individuals to osteoporosis-induced fractures. Several studies have investigated osteoporosis pathophysiology in SCI; however, those associated with its diagnosis in SCI are limited. Additionally, errors in osteoporosis diagnosis and its prevalence vary based on the bone mineral density (BMD) reference values (BMDRV), and no studies have reported BMDRV application for osteoporosis diagnosis in individuals with SCI. Therefore, this study aimed to compare the prevalence of osteoporosis among Korean adults aged ≥ 50 years with SCI according to BMDRV for diagnosing osteoporosis.MethodsOverall, 855 patients with SCI who underwent BMD tests of the lumbar spine, femoral neck, and total hip at the National Rehabilitation Center (NRC) in Korea between 2010 and 2020 were included in this retrospective cross-sectional study. Osteoporosis was diagnosed in patients with SCI by comparing the differences in prevalence, diagnostic consistency, and risk factors according to the region-based BMDRV of the dual-energy x-ray absorptiometry (DXA) manufacturer and international BMDRV based on the Third National Health and Nutrition Examination Survey (NHANES III) data of females aged 20–29 years.ResultsThe prevalence of osteoporosis according to the T-score provided by a single reference population of the NHANES III (TNHA) (PONHA) (males: 26.69%; females: 69.35%) was significantly higher in females and males than that according to the T-scores provided by the DXA manufacturer (TDXA) (PODXA) (males: 15.32%; females: 43.15%). The lumbar spine and femoral neck were major osteoporosis diagnosis sites for the PODXA and PONHA, respectively. Risk factors for osteoporosis differed based on the probability of osteoporosis (also known as the OZ ratio) according to the BMD criteria; however, the risk factors were similar according to old age, female sex, low body mass index (BMI), and long SCI period. No significant relationship was noted between the different SCI-related clinical factors (p > 0.05).ConclusionsThe osteoporosis diagnostic site and prevalence in SCI differed according to the regional-based TDXA and international standards of the TNHA. Therefore, further studies on BMDRV are warranted to establish accurate diagnostic criteria for osteoporosis prevention in patients with SCI.
Energy-efficient access point clustering and power allocation in cell-free massive MIMO networks: a hierarchical deep reinforcement learning approach
Authors: Tan Fangqing , Deng Quanxuan , Liu Qiang 
Published: January 2024

AbstractCell-free massive multiple-input multiple-output (CF-mMIMO) has attracted considerable attention due to its potential for delivering high data rates and energy efficiency (EE). In this paper, we investigate the resource allocation of downlink in CF-mMIMO systems. A hierarchical depth deterministic strategy gradient (H-DDPG) framework is proposed to jointly optimize the access point (AP) clustering and power allocation. The framework uses two-layer control networks operating on different timescales to enhance EE of downlinks in CF-mMIMO systems by cooperatively optimizing AP clustering and power allocation. In this framework, the high-level processing of system-level problems, namely AP clustering, enhances the wireless network configuration by utilizing DDPG on the large timescale while meeting the minimum spectral efficiency (SE) constraints for each user. The low layer solves the link-level sub-problem, that is, power allocation, and reduces interference between APs and improves transmission performance by utilizing DDPG on a small timescale while meeting the maximum transmit power constraint of each AP. Two corresponding DDPG agents are trained separately, allowing them to learn from the environment and gradually improve their policies to maximize the system EE. Numerical results validate the effectiveness of the proposed algorithm in term of its convergence speed, SE, and EE.