bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-cost users: drivers of inpatient healthcare expenditure concentration in urban China
Authors: Fan Qiuyan , Wang Jian , Nicholas Stephen , Maitland Elizabeth 
Published: November 2022

Abstract
Background
Total healthcare expenditures are concentrated among a small number of patients. To date, studies on the concentration of health care expenditures in developing countries are limited, mainly focusing on concentration measures and the demographic, clinical and socioeconomic characteristics of high-cost users (HCU). The drivers of the skewed overall distribution of health care expenditures are opaque. Using inpatient administrative claims data, this study provides new evidence on the concentration of healthcare expenditures in China; the demographic and clinical characteristics of high-cost users; and the drivers of the overall distribution of healthcare expenditures.

Methods
Utilizing administrative claims data for hospitalization in a prefecture-level city in China, we investigated the concentration of healthcare expenditure. We used recentered influence function (RIF) regression to examine the drivers of healthcare expenditure concentration, decomposing and estimating the effects of demographic and disease characteristics on the overall distribution of health care expenditures.

Results
Using a sample of 87,841 adults, we found extreme skewness in the distribution of inpatient medical expenditures in China, with approximately 49% of annual medical expenditures generated by the top 10% of inpatient groups. HCUs tend to be elderly and male, with high-frequency hospitalizations and long lengths of stay. In addition, healthcare expenditure concentration was related to diseases of the circulatory system, malignant neoplasms, diseases of the musculoskeletal system and connective tissue, diseases of the digestive system, injury and poisoning, and diseases of the respiratory system. Malignant and major diseases reinforced the concentration of healthcare spending, and a 10% increase in the prevalence of malignancy would result in a predicted Gini coefficient increase of 7.2%, heart disease of 0.92% and cerebrovascular disease of 1.5%. The above significant positive effects were not observed for hypertension and diabetes mellitus.

Conclusions
Our study provides new insights into the concentration of inpatient medical expenditures in China, including the precise picture of HCU expenditure concentration, the drivers of HCU expenditure concentration and the magnitude of their impact. With the aging of China's population and the profound shift in the disease spectrum, policymakers need to strengthen the early detection and intervention management of specific chronic diseases and high-risk populations, especially the early diagnosis and treatment of key cancers.
Induction of pyroptotic cell death as a potential tool for cancer treatment
Authors: Faria Sara Socorro , Fernando Anuruddika Jayawanthi , de Lima Vladmir Cláudio Cordeiro , Rossi Adriano Giorgio , de Carvalho Juliana Maria Andrade , Magalhães Kelly Grace 
Published: November 2022

AbstractCancer is a complex pathological disease and the existing strategies for introducing chemotherapeutic agents have restricted potential due to a lack of cancer cell targeting specificity, cytotoxicity, bioavailability, and induction of multi-drug resistance. As a prospective strategy in tackling cancer, regulating the inflammatory pyroptosis cell death pathway has been shown to successfully inhibit the proliferation and metastasis of various cancer cell types. Activation of inflammasomes such as the NLRP3 results in pyroptosis through cleavage of gasdermins, which forms pores in the cell membranes, inducing membrane breakage, cell rupture, and death. Furthermore, pyroptotic cells release pro-inflammatory cytokines such as IL-1β and IL-18 along with various DAMPs that prime an auxiliary anti-tumor immune response. Thus, regulation of pyroptosis in cancer cells is a way to enhance their immunogenicity. However, immune escape involving myeloid-derived suppressor cells has limited the efficacy of most pyroptosis-based immunotherapy strategies. In this review, we comprehensively summarize the cellular and molecular mechanisms involved in the inflammasome-mediated pyroptosis pathways in cancer cells, exploring how it could modulate the tumor microenvironment and be beneficial in anti-cancer treatments. We discuss various existing therapeutic strategies against cancer, including immunotherapy, oncolytic virus therapy, and nanoparticle-based therapies that could be guided to trigger and regulate pyroptosis cell death in cancer cells, and reduce tumor growth and spread. These pyroptosis-based cancer therapies may open up fresh avenues for targeted cancer therapy approaches in the future and their translation into the clinic.
DNA methylation predicts the outcome of COVID-19 patients with acute respiratory distress syndrome
Authors: Bradic Martina , Taleb Sarah , Thomas Binitha , Chidiac Omar , Robay Amal , Hassan Nessiya , Malek Joel , Ait Hssain Ali , Abi Khalil Charbel 
Published: November 2022

AbstractBackgroundCOVID-19 infections could be complicated by acute respiratory distress syndrome (ARDS), increasing mortality risk. We sought to assess the methylome of peripheral blood mononuclear cells in COVID-19 with ARDS.MethodsWe recruited 100 COVID-19 patients with ARDS under mechanical ventilation and 33 non-COVID-19 controls between April and July 2020. COVID-19 patients were followed at four time points for 60 days. DNA methylation and immune cell populations were measured at each time point. A multivariate cox proportional risk regression analysis was conducted to identify predictive signatures according to survival.ResultsThe comparison of COVID-19 to controls at inclusion revealed the presence of a 14.4% difference in promoter-associated CpGs in genes that control immune-related pathways such as interferon-gamma and interferon-alpha responses. On day 60, 24% of patients died. The inter-comparison of baseline DNA methylation to the last recorded time point in both COVID-19 groups or the intra-comparison between inclusion and the end of follow-up in every group showed that most changes occurred as the disease progressed, mainly in the AIM gene, which is associated with an intensified immune response in those who recovered. The multivariate Cox proportional risk regression analysis showed that higher methylation of the “Apoptotic execution Pathway” genes (ROC1, ZNF789, and H1F0) at inclusion increases mortality risk by over twofold.ConclusionWe observed an epigenetic signature of immune-related genes in COVID-19 patients with ARDS. Further, Hypermethylation of the apoptotic execution pathway genes predicts the outcome.Trial registration: IMRPOVIE study, NCT04473131.
Targeted delivery of ZNF416 siRNA-loaded liposomes attenuates experimental pulmonary fibrosis
Authors: Cheng Demin , Li Ziwei , Wang Yue , Xiong Haojie , Sun Wenqing , Zhou Siyun , Liu Yi , Ni Chunhui 
Published: November 2022

Abstract
Background
Pulmonary fibrosis is a chronic progressive fibrotic interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition caused by activated fibroblasts. Increasing evidence shows that matrix stiffness is essential in promoting fibroblast activation and profibrotic changes. Here, we investigated the expression and function of matrix stiffness-regulated ZNF416 in pulmonary fibrotic lung fibroblasts.

Methods
1 kappa (soft), 60 kappa (stiff) gel-coated coverslips, or transforming growth factor-beta 1 (TGF-β1)-cultured lung fibroblasts and the gain- or loss- of the ZNF416 function assays were performed in vitro. We also established two experimental pulmonary fibrosis mouse models by a single intratracheal instillation with 50 mg/kg silica or 6 mg/kg bleomycin (BLM). ZNF416 siRNA-loaded liposomes and TGF-β1 receptor inhibitor SB431542 were administrated in vivo.

Results
Our study identified that ZNF416 could regulate fibroblast differentiation, proliferation, and contraction by promoting the nuclear accumulation of p-Smad2/3. Besides, ZNF416 siRNA-loaded liposome delivery by tail-vein could passively target the fibrotic area in the lung, and co-administration of ZNF416 siRNA-loaded liposomes and SB431542 significantly protects mice against silica or BLM-induced lung injury and fibrosis.

Conclusion
In this study, our results indicate that mechanosensitive ZNF416 is a potential molecular target for the treatment of pulmonary fibrosis. Strategies aimed at silencing ZNF416 could be a promising approach to fight against pulmonary fibrosis.
‘It is a hard decision’: a qualitative study of perinatal intimate partner violence disclosure
Authors: Amel Barez Malikeh , Mirzaii Najmabadi Khadijeh , Latifnejad Roudsari Robab , Mousavi Bazaz Mojtaba , Babazadeh Raheleh 
Published: November 2022

Abstract
Background
Perinatal intimate partner violence is a hidden under reported and difficult to identify problem which has negative effects on mother and child. The present study aimed to explore barriers and facilitators of perinatal intimate partner violence disclosure.

Methods
This qualitative study was carried out from October 2019 to January 2021 in Mashhad, Iran. Participants included 23 abused women (11 pregnant and 12 after birth) which were selected via purposive sampling. Semi-structured in-depth interviews and focus group discussion were conducted until the data saturation was achieved. The data analysis was performed based on conventional content analysis adopted by Graneheim & Lundman.

Results
The main themes “barriers to disclosure” and “facilitators of disclosure” were emerged as the result of data analysis. Barriers to disclosure included negative disclosure consequences and protection of family privacy. Facilitators of disclosure included maternal self-efficacy, threats to security, and formal and informal supportive networks.

Conclusions
Most abused women did not disclose violence despite routine screening for perinatal intimate partner violence in antenatal care. Recognizing the barriers to and facilitators of violence disclosure play an important role in eliminating barriers, strengthening facilitators, providing effective supportive services for abused women, and reducing perinatal violence. Focus on the barriers to and the facilitators of disclosure will be useful to policymakers, health program planners, and health care providers to identify and manage intimate partner violence, appropriately.
Can you be a manual therapist without using your hands?
Authors: Saragiotto Bruno T. , Sandal Louise F. , Hartvigsen Jan 
Published: November 2022

Abstract
Background
To align with current best practices, manual therapists have refined their treatment options to include exercise and pain education for people with chronic musculoskeletal pain. In this commentary, we suggest that manual therapists should also add telehealth to their toolbox. Thus, we aim to discuss the use of telehealth by manual therapists caring for patients with musculoskeletal disorders.

Main body
Telehealth can be delivered to the patient in different modes, such as real-time clinical contact or asynchronously. Platforms vary from websites and smartphone apps to virtual reality systems. Telehealth may be an effective approach, especially for improving pain and function in people with musculoskeletal pain, and it has the potential to reduce the individual and socioeconomic burden of musculoskeletal conditions. However, the certainty of evidence reported in systematic reviews is often low. Factors such as convenience, flexibility, undivided attention from the clinician, user-friendly platforms, goal setting, and use of evidence-based information are all enablers for telehealth use and improving patients’ knowledge, self-efficacy, and self-management. Barriers to widening the use of telehealth in musculoskeletal care include the reliability of technology, data privacy issues, difficult to build therapeutic alliance, one-size-fits-all approaches, digital health literacy, and payment models.

Conclusion
We suggest that practitioners of manual medicine make telehealth part of their clinical toolbox where it makes sense and where there is evidence that it is beneficial for people who seek their care.
A novel missense mutation in GREB1L identified in a three-generation family with renal hypodysplasia/aplasia-3
Authors: Wu Sixian , Wang Xiang , Dai Siyu , Zhang Guohui , Zhou Jiaojiao , Shen Ying 
Published: November 2022

Abstract
Background
Renal hypodysplasia/aplasia-3 (RHDA3), as the most severe end of the spectrum of congenital anomalies of the kidney and urinary tract, is mainly caused by mutations in GREB1L. However, the mutations in GREB1L identified to date only explain a limited proportion of RHDA3 cases, and the mechanism of GREB1L mutations causing RHDA3 is unclear.

Results
According to whole-exome sequencing, a three-generation family suffering from RHDA3 was investigated with a novel missense mutation in GREB1L, c.4507C>T. All three-generation patients suffered from unilateral absent kidney. This missense mutation resulted in sharp downregulation of mRNA and protein expression, which might lead to RHDA3. Mechanistically, through RNA-sequencing, it was found that the mRNA levels of PAX2 and PTH1R, which are key molecules involved in the development of the kidney, were significantly downregulated by knocking out GREB1L in vitro.

Conclusions
This novel missense mutation in GREB1L can be helpful in the genetic diagnosis of RHDA3, and the discovery of the potential mechanism that GREB1L mutations involved in RHDA3 pathogenesis can promote the adoption of optimal treatment measures and the development of personalized medicine directly targeting these effects.
Fetal umbilical artery thrombosis: prenatal diagnosis, treatment and follow-up
Authors: Wu Xiafang , Wei Chenchen , Chen Ruifeng , Yang Linxian , Huang Weifei , Huang Liang , Yan XinXin , Deng Xuedong , Gou Zhongshan 
Published: November 2022

Abstract
Background
To analyze the ultrasound imaging and clinical characteristics of fetuses with umbilical artery thrombosis (UAT), explore the potential causes of UAT and construct a prognostic prediction model to guide clinical practice.

Methods
This was a retrospective cohort study of fetal UAT cases examined at two academic tertiary referral care centers from 2014 to 2020. The basic information of the participants was obtained by interview during follow-up, and data on clinical treatment, delivery conditions, diagnosis and confirmation were obtained through medical records. Probable causes of thrombosis were explored by comparative analysis of the UAT group to the control group and by further regression analysis. Multivariable logistic regression models were used to evaluate risk factors for adverse pregnancy outcomes. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic value of the prognostic prediction model.

Results
Thirty fetuses with UAT were included in this study. UAT occurred mostly in the third trimester of pregnancy, and there was an obvious predominance of right UAT. An abnormal pregnancy history (53.3%) was the most common comorbidity, followed by gestational diabetes mellitus (GDM) (20.0%). GDM and umbilical cord (UC) abnormalities were found to be independent risk factors for the development of UAT. After comprehensive decision-making, over two-thirds of the patients with UAT received urgent treatment, and less than one-third received expectant management. Surprisingly, there were no significant differences in fetal outcomes between the urgent treatment and expectant management groups. Multivariate logistic regression analysis showed that gestational age (GA) at clinical diagnosis and UC abnormalities were independent risk factors for adverse pregnancy outcomes (OR 0.781, p = 0.042; OR 16.779, p = 0.023, respectively). Based on this, we constructed a comprehensive prognostic prediction model. The area under the ROC curve (AUC) was 0.877 (95% CI 0.698–0.970; p < 0.001), which suggested that the combination of GA and UC abnormalities was a better predictor for fetal outcomes in our setting.

Conclusion
In summary, maternal GDM and fetal UC abnormalities are independent risk factors for UAT. UAT is more frequently observed on the right side. Moreover, poor clinical outcomes for fetuses with UAT are ascribed mainly to GA and UC abnormalities, which should be comprehensively evaluated to choose the appropriate treatment.
Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies
Authors: Kramer Kim , Pandit-Taskar Neeta , Kushner Brian H. , Zanzonico Pat , Humm John L. , Tomlinson Ursula , Donzelli Maria , Wolden Suzanne L. , Haque Sophia , Dunkel Ira , Souweidane Mark M. , Greenfield Jeffrey P. , Tickoo Satish , Lewis Jason S. , Lyashchenko Serge K. , Carrasquillo Jorge A. , Chu Bae , Horan Christopher , Larson Steven M. , Cheung Nai-Kong V. , Modak Shakeel 
Published: November 2022

Abstract
Background
The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies.

Patients and methods
We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease.

Results
Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data.

Conclusions
cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases.
Trial registration: clinicaltrials.gov NCT00089245, August 5, 2004.
Spontaneous pneumomediastinum: a surrogate of P-SILI in critically ill COVID-19 patients
Authors: Elabbadi Alexandre , Urbina Tomas , Berti Enora , Contou Damien , Plantefève Gaëtan , Soulier Quintana , Milon Audrey , Carteaux Guillaume , Voiriot Guillaume , Fartoukh Muriel , Gibelin Aude 
Published: November 2022

AbstractSpontaneous pneumomediastinum (SP) has been described early during the COVID-19 pandemic in large series of patients with severe pneumonia, but most patients were receiving invasive mechanical ventilation (IMV) at the time of SP diagnosis. In this retrospective multicenter observational study, we aimed at describing the prevalence and outcomes of SP during severe COVID-19 with pneumonia before any IMV, to rule out mechanisms induced by IMV in the development of pneumomediastinum.Among 549 patients, 21 patients (4%) developed a SP while receiving non-invasive respiratory support, after a median of 6 days [4–12] from ICU admission. The proportion of patients requiring IMV was similar. However, the time to tracheal intubation was longer in patients with SP (6 days [5–13] vs. 2 days [1–4]; P = 0.00002), with a higher first-line use of non-invasive ventilation (n = 11; 52% vs. n = 150; 28%; P = 0.02). The 21 patients who developed a SP had persisting signs of severe lung disease and respiratory failure with lower ROX index between ICU admission and occurrence of SP (3.94 [3.15–5.55] at admission vs. 3.25 [2.73–4.02] the day preceding SP; P = 0.1), which may underline potential indirect signals of Patient-self inflicted lung injury (P-SILI).In this series of critically ill COVID-19 patients, the prevalence of SP without IMV was not uncommon, affecting 4% of patients. They received more often vasopressors and had a longer ICU length of stay, as compared with their counterparts. One pathophysiological mechanism may potentially be carried out by P-SILI related to a prolonged respiratory failure, as underlined by a delayed use of IMV and the evolution of the ROX index between ICU admission and the day preceding SP.
MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution
Authors: Kaufmann Tom L. , Petkovic Marina , Watkins Thomas B. K. , Colliver Emma C. , Laskina Sofya , Thapa Nisha , Minussi Darlan C. , Navin Nicholas , Swanton Charles , Van Loo Peter , Haase Kerstin , Tarabichi Maxime , Schwarz Roland F. 
Published: November 2022

AbstractAneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as the infinite sites assumption, allowing multiple mutations and parallel evolution, and does not treat adjacent loci as independent, allowing overlapping copy-number events. Using simulations and multiple data types from 2780 tumors, we use MEDICC2 to demonstrate accurate inference of phylogenies, clonal and subclonal WGD, and ancestral copy-number states.