bluuebunny/crossref_metadata_2025_split huggingface dataset:
Porphyria cutanea tarda and patterns of long-term sick leave and disability pension: a 24-year nationwide matched-cohort study
Authors: Baravelli Carl Michael , Aarsand Aasne Karine , Sandberg Sverre , Tollånes Mette Christophersen 
Published: February 2022

AbstractBackgroundPorphyria cutanea tarda (PCT) is a skin disorder caused by a defect in the liver enzyme uroporphyrinogen decarboxylase and is associated with hepatitis C virus infection, high alcohol intake, smoking and iron overload. Data on the long-term morbidity of PCT is lacking.MethodsWe conducted a nationwide matched cohort study over a 24-year period. The study sample included 534 persons aged 18–67 years with a biochemically confirmed PCT diagnosis and a sample of 21,360 persons randomly selected from the working age population, matched on age, sex and educational attainment. We investigated if persons with sporadic and familial PCT had an increased risk of long-term sick leave (LTSL) or disability pension. We further assessed risk before (pre-PCT), during (during-PCT) and after (post-PCT) the typical period of first onset to diagnosis, treatment and remission.ResultsOverall, persons with PCT had a 40% increased risk (hazard ratio [HR] = 1.4, 95% confidence interval [CI] = 1.3, 1.5) of LTSL and a 50% increased risk (HR = 1.5, CI = 1.3, 1.7) of disability pension. Risk of disability pension was increased pre-PCT (HR = 1.3, CI 1.3 (1.0, 1.6), during-PCT (HR 1.5, CI 1.0, 2.2) and post-PCT (HR = 2.0, CI 1.5, 2.6). For LTSL, risk was increased pre-PCT (HR = 1.3, CI 1.1, 1.4) and during-PCT (HR = 1.5, CI 1.1, 2.1), but not post-PCT. Risk was greatest in persons with sporadic than familial PCT. Diagnostic reasons for disability pension that were increased compared to matched controls were PCT or skin disease in 11 of 199 cases (PCT: n = 7, incident rate ratios [IRR] = 49.2, CI = 38.8, 62.4; diseases of the skin and subcutaneous tissue, n = 4, IRR = 4.2, CI = 1.6, 11.0). The vast majority of diagnostic reasons for accessing disability pension were related to comorbidities, PCT susceptibility factors and more general health issues such as: malignant neoplasms (n = 12, IRR = 2.4, CI = 1.4, 4.2), substance and alcohol dependence (n = 7, IRR = 5.0, CI = 2.5, 10.1), neurotic and mood—disorders (n = 21, IRR = 1.7, CI = 1.1, 2.6), and diseases of the musculoskeletal system and connective tissue (n = 71, IRR = 2.5, CI = 1.9, 3.2).ConclusionsPersons with PCT have an increased risk of LTSL and disability pension indicating significant morbidity in this patient group. Appropriate long-term follow-up and monitoring for relapses and co-morbid diseases are recommended.
Collaborative research protocol to define patient-reported experience measures of the cystic fibrosis care pathway in France: the ExPaParM study
Authors: Pougheon Bertrand D. , Fanchini A. , Lombrail P. , Rault G. , Chansard A. , Le Breton N. , Frenod C. , Milon F. , Heymes-Royer C. , Segretain D. , Silber M. , Therouanne S. , Haesebaert J. , Llerena C. , Michel P. , Reynaud Q. 
Published: February 2022

Abstract
Introduction
In France, the cystic fibrosis (CF) care pathway is coordinated by multidisciplinary teams from specialised CF centres or transplant centres. It includes the care provided at home or out of hospital, risk prevention in daily life and adjustments to social life, which together contribute to the person’s quality of life. Patient experience is used to describe and evaluate the care and life of patients living with the disease.

Objectives
Our collaborative research aims to identify the most significant areas and criteria that characterise the CF pathway. It will lead to the development of a questionnaire to collect patients' experience, which can be administered to all patients or parents of children registered and followed in the centres. The article describes the protocol developed in partnership with patients and parents of children living with the disease.

Method
A multidisciplinary research group brings together researchers, patients, parents of children with CF and health care professionals. The patient partnership is involved in the 4 phases of the protocol: (1) setting up the study, recruiting patient and parent co-researchers, training them in qualitative research methods, defining the situations and profiles of patients in the study population, elaborating the protocol; (2) selecting the study sites, recruiting participants, carrying out semi-structured interviews, analysing verbatims using the grounded theory approach; (3) co-elaborating Patient-Reported Experience Measures (PREM) questionnaires adapted to the 4 types of participants: parents, adolescents, non-transplanted adults and transplanted adults; (4) validating the construct with participants and professionals from the study centres.

Results
The protocol obtained a favourable opinion from the Ethics Evaluation Committee of INSERM (IRB00003888—no. 20-700). Training was provided to the 5 patients and 2 parent co-researchers to enable them to participate effectively in the research. Eleven centres participated in the recruitment of participants in mainland France and Reunion Island. Eighty hours of interviews were conducted.

Discussion
The PREM questionnaires to be elaborated will have to undergo psychometric validation before being used by the actors of the CF network to assess the impact on the care pathways of quality approaches or new therapies available in cystic fibrosis.
Trial Registration Registry: IRB00003888 – no. 20-700. Issue date: 06/09/2020.
Understanding disease symptoms and impacts and producing qualitatively-derived severity stages for MPS IIIA: a mixed methods approach
Authors: Lanar Sally , Parker Samantha , O’Neill Cara , Marrel Alexia , Arnould Benoit , Héron Bénédicte , Muschol Nicole , Wijburg Frits A. , Chakrapani Anupam , Olivier Sophie , Aiach Karen 
Published: February 2022

Abstract
Background
MPS IIIA is a rare, degenerative pediatric genetic disease characterized by symptoms impacting cognition, mobility and behavior; the mean age of death is around 15 years of age. Currently, there are no approved therapies for MPS IIIA.

Methods
A two-year, multi-center, prospective, descriptive cohort study was conducted to document the natural history course of MPS IIIA. In the context of this study, semi-structured interviews were performed with parents of children at study entry and one year later. Interview transcripts were analyzed using thematic analysis methods to identity concepts of interest to children and parents, identify what factors impacted parents’ burden the most, and develop qualitatively-derived disease severity stages. Children were sorted into these stages according to the symptoms their parents described at the entry interview. This sorting was compared quantitatively to the sorting of children at baseline according to the child’s calendar age and their BSID development quotient (DQ).

Results
22 parents in France, Germany, the Netherlands and the UK were interviewed. Children ranged in age from 28 to 105 months (mean 61.4 months). The conceptual models for children’s symptoms and impacts and parents’ impacts provided a detailed and comprehensive picture of what it is like for children of various ages and their parents to live with MPS IIIA. Four factors were identified as mediating the burden perceived by parents: state support, family support, time since diagnosis, and parent coping strategy. Four disease stages were developed, accounting for both the presence and the severity of MPS IIIA symptoms. The comparison of children’s sorting into these stages with the BSID DQ and the child’s calendar age showed strong statistical associations.

Conclusions
The findings of this qualitative research embedded in a natural history study add to the current understanding of MPS IIIA as a complex disease that impacts every aspect of the lives of children and their families. This study demonstrates the unique potential of mixed methods research in rare diseases to address some of the current limitations of more traditional quantitative approaches by providing an individualized, detailed understanding of the patient experience.
Craniofacial and dentoalveolar morphology in individuals with Prader–Willi syndrome: a case-control study
Authors: Vasconcelos Gisela , Stenehjem Jo S. , Axelsson Stefan , Saeves Ronnaug 
Published: February 2022

Abstract
Background
Prader–Willi syndrome (PWS) is a complex multisystem genetic disorder with distinct genetic and clinical features. Among other clinical symptoms, PWS is characterized by severe infantile hypotonia with feeding problems, childhood onset hyperphagia, obesity, scoliosis, short stature combined with growth hormone deficiency and developmental delay. PWS is associated with facial dysmorphology, orofacial dysfunction, oral abnormalities, low salivary flow and subsequent severe tooth wear. Little is known about the craniofacial growth direction or dental and skeletal relationships in individuals with PWS in different ages. The purpose of this study was to assess the craniofacial and dentoalveolar characteristics and to investigate the craniofacial growth direction separately in children, young adults and adults with PWS, using a cephalometric analysis of lateral cephalograms.

Results
Lateral cephalograms of 42 individuals with a confirmed genetic diagnosis of PWS were analysed and divided into three groups according to their age: Children (< 12 years), young adults (12–20 years) and adults (> 20 years). Cephalometric variables were compared between PWS patients and controls by age and sex. Significant deviations and distinct craniofacial patterns were found in children, young adults and adults with PWS compared with the control group. Children showed retrognatic mandible with a skeletal class II relationship, posterior growth direction and longer anterior face height. The young adults had smaller cranial base angle, a skeletal class II pattern and a higher anterior lower face than the control group. Adults with PWS had a prognathic mandible, skeletal class III relationship with anterior growth direction, more retroclined lower incisors and proclined upper incisors than the controls. Similar results were found when comparing the three groups with PWS; the adults had a prognathic mandible, skeletal class III pattern and anterior growth direction. Children had a retropositioned mandibula, skeletal class II relationship and posterior growth direction.

Conclusion
This study may contribute to a better understanding of the craniofacial growth pattern in children, young adults and adults with PWS and may have a clinical importance when planning dental treatment, such as prosthodontics and/or orthodontics.
Application of a next-generation sequencing (NGS) panel in newborn screening efficiently identifies inborn disorders of neonates
Authors: Huang Xinwen , Wu Dingwen , Zhu Lin , Wang Wenjun , Yang Rulai , Yang Jianbin , He Qunyan , Zhu Bingquan , You Ying , Xiao Rui , Zhao Zhengyan 
Published: February 2022

Abstract
Background
Newborn screening (NBS) has been implemented for neonatal inborn disorders using various technology platforms, but false-positive and false-negative results are still common. In addition, target diseases of NBS are limited by suitable biomarkers. Here we sought to assess the feasibility of further improving the screening using next-generation sequencing technology.

Methods
We designed a newborn genetic sequencing (NBGS) panel based on multiplex PCR and next generation sequencing to analyze 134 genes of 74 inborn disorders, that were validated in 287 samples with previously known mutations. A retrospective cohort of 4986 newborns was analyzed and compared with the biochemical results to evaluate the performance of this panel.

Results
The accuracy of the panel was 99.65% with all samples, and 154 mutations from 287 samples were 100% detected. In 4986 newborns, a total of 113 newborns were detected with biallelic or hemizygous mutations, of which 36 newborns were positive for the same disorder by both NBGS and conventional NBS (C-NBS) and 77 individuals were NBGS positive/C-NBS negative. Importantly, 4 of the 77 newborns were diagnosed currently including 1 newborn with methylmalonic acidemia, 1 newborn with primary systemic carnitine deficiency and 2 newborns with Wilson’s disease. A total of 1326 newborns were found to be carriers with an overall carrier rate of 26.6%.

Conclusion
Analysis based on next generation sequencing could effectively identify neonates affected with more congenital disorders. Combined with C-NBS, this approach may improve the early and accurate identification of neonates with inborn disorders. Our study lays the foundation for prospective studies and for implementing NGS-based analysis in NBS.
Profiles of positive changes in life outcomes over the COVID-19 pandemic in Chinese adolescents: the role of resilience and mental health consequence
Authors: Li Jian-Bin , Dou Kai , Liu Zi-Hao 
Published: February 2022

AbstractBackgroundThe 2019 coronavirus (COVID-19) has caused enormous negative impacts on adolescents’ routines, social interaction, interpersonal relationships, psychosocial well-being, and physical health. Nevertheless, theories suggest that individuals also often seek out solutions that may facilitate positive changes when they are faced with uncertainty and crisis. However, the existing literature has disproportionately focused on the negative effect of COVID-19 on adolescents, and scant research has examined to what extent and in what aspects adolescents would experience positive changes in times of the pandemic. This pre-registered research aims to bridge said gaps by: (1) exploring different profiles of positive changes in various life outcomes in Chinese adolescents over the COVID-19 pandemic; (2) examining the role of resilience in differentiating different profiles; (3) comparing adolescents’ mental health across profiles.MethodParticipants were 2,567 adolescents aged 12 to 24 recruited from 32 provinces in mainland China (66.89% females; Mage = 19.87 years, SD = 2.02). Through an online survey, participants rated how much their lives of different domains had experienced positive changes since the outbreak of the pandemic. They also answered standardized questionnaires that measured their resilience and mental health.ResultsResults of latent profile analysis revealed three profiles:limited positive changes(33.3%),partial positive changes(49.5%), andoverall strong positive changes(17.2%). Moreover, adolescents with a higher level of resilience were more likely to be categorized into thepartial positive changesprofile compared to thelimited positive changesprofile and categorized into theoverall strong positive changesprofile compared to the other two profiles, after controlling for multiple covariates. Adolescents in theoverall strong positive changesprofile had better mental health than their counterparts of the other two profiles.ConclusionChinese adolescents appear to experience positive changes in various life outcomes during the COVID-19 pandemic, especially for those with high levels of resilience. Such positive changes have important implications on adolescents’ mental health.
Structural insights into inhibition of PRRSV Nsp4 revealed by structure-based virtual screening, molecular dynamics, and MM-PBSA studies
Authors: Pathak Rajesh Kumar , Seo Young-Jun , Kim Jun-Mo 
Published: February 2022

Abstract
Background
Porcine reproductive and respiratory syndrome respiratory sickness in weaned and growing pigs, as well as sow reproductive failure, and its infection is regarded as one of the most serious swine illnesses worldwide. Given the current lack of an effective treatment, in this study, we identified natural compounds capable of inhibiting non-structural protein 4 (Nsp4) of the virus, which is involved in their replication and pathogenesis.

Results
We screened natural compounds (n = 97,999) obtained from the ZINC database against Nsp4 and selected the top 10 compounds for analysing protein–ligand interactions and physicochemical properties. The five compounds demonstrating strong binding affinity were then subjected to molecular dynamics simulations (100 ns) and binding free energy calculations. Based on analysis, we identified four possible lead compounds that represent potentially effective drug-like inhibitors.

Conclusions
These methods identified that these natural compounds are capable of inhibiting Nsp4 and possibly effective as antiviral therapeutics against PRRSV.
Overexpressed integrin alpha 2 inhibits the activation of the transforming growth factor β pathway in pancreatic cancer via the TFCP2-SMAD2 axis
Authors: Cai Hongkun , Guo Feng , Wen Shuang , Jin Xin , Wu Heshui , Ren Dianyun 
Published: February 2022

AbstractBackgroundIntegrin alpha 2 (ITGA2) has been recently reported to be an oncogene and to play crucial roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study showed that ITGA2 was overexpressed in pancreatic cancer and promoted its progression. However, the mechanism of ITGA2 overexpression and other mechanisms for promoting the progression of pancreatic cancer are still unclear.MethodsThe GEPIA database was used to confirm the expression of ITGA2 in pancreatic cancer. To verify the influence of ITGA2 and TGF-β on the morphological changes of pancreatic cancer and tumor cell progression, we conduct CCK8 test, plate cloning, flow cytometry experiments and animal experiments. Then we conduct Western blot, RT-qPCR to explore the relationship between ITGA2 and TGF-β, and then find the key molecules which can regulate them by immunoprecipitation, Western blot, RT-qPCR, CHIP, nuclear and cytoplasmic separation test.ResultsThe results of the present study show that the abnormal activation of KRAS induced the overexpression of ITGA2 in pancreatic cancer. Moreover, ITGA2 expression significantly suppressed the activation of the TGF-β pathway. ITGA2 silencing enhanced the anti-pancreatic cancer proliferation and tumor growth effects of TGF-β. Mechanistically, ITGA2 expression suppressed the activation of the TGF-β pathway by inhibiting the SMAD2 expression transcriptionally. In addition, it interacted with and inhibited the nuclear translocation of TFCP2, which induced the SMAD2 expression as a transcription factor. Furthermore, TFCP2 also induced ITGA2 expression as a transcription factor, and the TFCP2 feedback regulated the ITGA2-TFCP2-SMAD2 pathway.ConclusionsTaken together, these results indicated that ITGA2 expression could inhibit the activation of the TGF-β signaling pathway in pancreatic cancer via the TFCP2-SMAD2 axis. Therefore, ITGA2, by effectively enhancing the anti-cancer effects of TGF- β, might be a potential clinical therapeutic target for pancreatic cancer.
Autophagy-based unconventional secretion of HMGB1 in glioblastoma promotes chemosensitivity to temozolomide through macrophage M1-like polarization
Authors: Li Zhuang , Fu Wen-Juan , Chen Xiao-Qing , Wang Shuai , Deng Ru-Song , Tang Xiao-Peng , Yang Kai-Di , Niu Qin , Zhou Hong , Li Qing-Rui , Lin Yong , Liang Mei , Li Si-Si , Ping Yi-Fang , Liu Xin-Dong , Bian Xiu-Wu , Yao Xiao-Hong 
Published: February 2022

Abstract
Background
Glioblastoma (GB) is the most common and highly malignant brain tumor characterized by aggressive growth and resistance to alkylating chemotherapy. Autophagy induction is one of the hallmark effects of anti-GB therapies with temozolomide (TMZ). However, the non-classical form of autophagy, autophagy-based unconventional secretion, also called secretory autophagy and its role in regulating the sensitivity of GB to TMZ remains unclear. There is an urgent need to illuminate the mechanism and to develop novel therapeutic targets for GB.

Methods
Cancer genome databases and paired-GB patient samples with or without TMZ treatment were used to assess the relationship between HMGB1 mRNA levels and overall patient survival. The relationship between HMGB1 protein level and TMZ sensitivity was measured by immunohistochemistry, ELISA, Western blot and qRT-PCR. GB cells were engineered to express a chimeric autophagic flux reporter protein consisting of mCherry, GFP and LC3B. The role of secretory autophagy in tumor microenvironment (TME) was analyzed by intracranial implantation of GL261 cells. Coimmunoprecipitation (Co-IP) and Western blotting were performed to test the RAGE-NFκB-NLRP3 inflammasome pathway.

Results
The exocytosis of HMGB1 induced by TMZ in GB is dependent on the secretory autophagy. HMGB1 contributed to M1-like polarization of tumor associated macrophages (TAMs) and enhanced the sensitivity of GB cells to TMZ. Mechanistically, RAGE acted as a receptor for HMGB1 in TAMs and through RAGE-NFκB-NLRP3 inflammasome pathway, HMGB1 enhanced M1-like polarization of TAMs. Clinically, the elevated level of HMGB1 in sera may serve as a beneficial therapeutic-predictor for GB patients under TMZ treatment.

Conclusions
We demonstrated that enhanced secretory autophagy in GB facilitates M1-like polarization of TAMs to enhance TMZ sensitivity of GB cells. HMGB1 acts as a key regulator in the crosstalk between GB cells and tumor-suppressive M1-like TAMs in GB microenvironment and may be considered as an adjuvant for the chemotherapeutic agent TMZ.
Prospective, randomized, controlled, double-blind, multi-center, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) sOlution versus an Electrolyte solutioN In patients undergoing eleCtive abdominal Surgery: study protocol for the PHOENICS study
Authors: Buhre Wolfgang , de Korte-de Boer Dianne , de Abreu Marcelo Gama , Scheeren Thomas , Gruenewald Matthias , Hoeft Andreas , Spahn Donat R. , Zarbock Alexander , Daamen Sylvia , Westphal Martin , Brauer Ute , Dehnhardt Tamara , Schmier Sonja , Baron Jean-Francois , De Hert Stefan , Gavranović Željka , Cholley Bernard , Vymazal Tomas , Szczeklik Wojciech , Bornemann-Cimenti Helmar , Soro Domingo Marina Blanca , Grintescu Ioana , Jankovic Radmilo , Belda Javier 
Published: February 2022

Abstract
Background
Hydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss and to maintain hemodynamic stability. This study was requested by the European Medicines Agency (EMA) to provide more evidence on the long-term safety and efficacy of HES solutions in the perioperative setting.

Methods
PHOENICS is a randomized, controlled, double-blind, multi-center, multinational phase IV (IIIb) study with two parallel groups to investigate non-inferiority regarding the safety of a 6% HES 130 solution (Volulyte 6%, Fresenius Kabi, Germany) compared with a crystalloid solution (Ionolyte, Fresenius Kabi, Germany) for infusion in patients with acute blood loss during elective abdominal surgery. A total of 2280 eligible patients (male and female patients willing to participate, with expected blood loss ≥ 500 ml, aged > 40 and ≤ 85 years, and ASA Physical status II–III) are randomly assigned to receive either HES or crystalloid solution for the treatment of hypovolemia due to surgery-induced acute blood loss in hospitals in up to 11 European countries. The dosing of investigational products (IP) is individualized to patients’ volume needs and guided by a volume algorithm. Patients are treated with IP for maximally 24 h or until the maximum daily dose of 30 ml/kg body weight is reached.
The primary endpoint is the treatment group mean difference in the change from the pre-operative baseline value in cystatin-C-based estimated glomerular filtration rate (eGFR), to the eGFR value calculated from the highest cystatin-C level measured during post-operative days 1-3. Further safety and efficacy parameters include, e.g., combined mortality/major post-operative complications until day 90, renal function, coagulation, inflammation, hemodynamic variables, hospital length of stay, major post-operative complications, and 28-day, 90-day, and 1-year mortality.

Discussion
The study will provide important information on the long-term safety and efficacy of HES 130/0.4 when administered according to the approved European product information. The results will be relevant for volume therapy of surgical patients.

Trial registration
EudraCT 2016-002162-30. ClinicalTrials.govNCT03278548