bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic alterations and their therapeutic implications in epithelial ovarian cancer
Authors: Lapke Nina , Chen Chien-Hung , Chang Ting-Chang , Chao Angel , Lu Yen-Jung , Lai Chyong-Huey , Tan Kien Thiam , Chen Hua-Chien , Lu Hsiao-Yun , Chen Shu-Jen 
Published: May 2021

Abstract
Background
Genetic alterations for epithelial ovarian cancer are insufficiently characterized. Previous studies are limited regarding included histologies, gene numbers, copy number variant (CNV) detection, and interpretation of pathway alteration patterns of individual patients.

Methods
We sequenced 410 genes to analyze mutations and CNV of 82 ovarian carcinomas, including high-grade serous (n = 37), endometrioid (n = 22) and clear cell (n = 23) histologies. Eligibility for targeted therapy was determined for each patient by a pathway-based approach. The analysis covered DNA repair, receptor tyrosine kinase, PI3K/AKT/MTOR, RAS/MAPK, cell cycle, and hedgehog pathways, and included 14 drug targets.

Results
Postulated PARP, MTOR, and CDK4/6 inhibition sensitivity were most common. BRCA1/2 alterations, PTEN loss, and gain of PIK3CA and CCND1 were characteristic for high-grade serous carcinomas. Mutations of ARID1A, PIK3CA, and KRAS, and ERBB2 gain were enriched in the other histologies. PTEN mutations and high tumor mutational burden were characteristic for endometrioid carcinomas. Drug target downstream alterations impaired actionability in all histologies, and many alterations would not have been discovered by key gene mutational analysis. Individual patients often had more than one actionable drug target.

Conclusions
Genetic alterations in ovarian carcinomas are complex and differ among histologies. Our results aid the personalization of therapy and biomarker analysis for clinical studies, and indicate a high potential for combinations of targeted therapies.
The D*Phase-study: study protocol for a pragmatic two-phased, randomised controlled (non-inferiority) trial that addresses treatment non-response and compares cognitive behavioural therapy and short-term psychodynamic supportive psychotherapy for major depression
Authors: Miggiels M. F. , ten Klooster P. M. , Bremer-Hoeve S. , Dekker J. J. M. , Huibers M. J. H. , Reefhuis E. , Van H. L. , van Dijk M. K. 
Published: May 2021

AbstractBackgroundSeveral evidence-based psychotherapeutic treatment options are available for depression, but the treatment results could be improved. The D*Phase study directly compares short-term psychodynamic supportive psychotherapy (SPSP) and cognitive behavioural therapy (CBT) for Major Depressive Disorder (MDD). The objectives are 1. to investigate if, from a group level perspective, SPSP is not inferior to CBT in the treatment of major depressive disorder, 2. to build a model that may help predict the optimal type of treatment for a specific individual; and 3. to determine whether a change of therapist or a change of therapist and treatment method are effective strategies to deal with non-response. Furthermore (4.), the effect of the therapeutic alliance, treatment integrity and therapist allegiance on treatment outcome will be investigated.MethodIn this pragmatic randomised controlled trial, 308 patients with a primary diagnosis of MDD are being recruited from a specialised mental health care institution in the Netherlands. In the first phase, patients are randomised 1:1 to either SPSP or CBT. In case of treatment non-response, a second phase follows in which non-responders from treatment phase one are randomised 1:1:1 to one of three groups: continuing the initial treatment with the same therapist, continuing the initial treatment with another therapist or continuing the other type of treatment with another therapist. In both treatment phases, patients are offered sixteen twice-weekly psychotherapy sessions. The primary outcome is an improvement in depressive symptoms. Process variables, working alliance and depressive symptoms, are frequently measured. Comprehensive assessments take place before the start of the first phase (at baseline), in week one, two and four during the treatment, and directly after the treatment (week eight).DiscussionWhile the naturalistic setting of the study involves several challenges, we expect, by focusing on a large and diverse number of research variables, to generate important knowledge that may help enhance the effect of psychotherapeutic treatment for MDD.Trial registrationThe study was registered on 26 August 2016 with the Netherlands Trial Register, part of the Dutch Cochrane Centre (NL5753),https://www.trialregister.nl/trial/5753
The Eating Disorders Genetics Initiative (EDGI): study protocol
Authors: Bulik Cynthia M. , Thornton Laura M. , Parker Richard , Kennedy Hannah , Baker Jessica H. , MacDermod Casey , Guintivano Jerry , Cleland Lana , Miller Allison L. , Harper Lauren , Larsen Janne T. , Yilmaz Zeynep , Grove Jakob , Sullivan Patrick F. , Petersen Liselotte V. , Jordan Jennifer , Kennedy Martin A. , Martin Nicholas G. 
Published: May 2021

AbstractBackgroundThe Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder.MethodsA total of 14,500 individuals with eating disorders and 1500 controls will be included from the United States (US), Australia (AU), New Zealand (NZ), and Denmark (DK). In the US, AU, and NZ, participants will complete comprehensive online phenotyping and will submit a saliva sample for genotyping. In DK, individuals with eating disorders will be identified by the National Patient Register, and genotyping will occur using bloodspots archived from birth. A genome-wide association study will be conducted within EDGI and via meta-analysis with other data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED).DiscussionEDGI represents the largest genetic study of eating disorders ever to be conducted and is designed to rapidly advance the study of the genetics of the three major eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). We will explicate the genetic architecture of eating disorders relative to each other and to other psychiatric and metabolic disorders and traits. Our goal is for EDGI to deliver “actionable” findings that can be transformed into clinically meaningful insights.Trial registrationEDGI is a registered clinical trial: clinicaltrials.govNCT04378101.
Fluoride in the drinking water and dental caries experience by tooth surface susceptibility among adults
Authors: Stangvaltaite-Mouhat Lina , Puriene Alina , Stankeviciene Indre , Aleksejuniene Jolanta 
Published: May 2021

Abstract
Background
Dental caries is the most prevalent non-communicable health condition globally. The surface-based susceptibility hierarchy indicates that surfaces in the same group have similar susceptibility to caries, where the most susceptible group consists of occlusal surfaces of first molars and buccal surfaces of lower first molars, and the least susceptible surfaces are smooth and proximal surfaces of first premolars, canines and incisors. Therefore, fluoride in the drinking water could impact one group more than the other group. The present study examined the association between fluoride levels in the drinking water and dental caries experience in adults in the context of varying tooth surface susceptibility.

Methods
Data from the cross-sectional National Lithuanian Oral Health Survey conducted in 2017–2019 included a stratified random sample of 1398 35–74-year-olds (52% response rate). Dental caries experience in dentine was measured at a surface level. The surfaces were grouped according to their caries susceptibility (group 1 being the most and group 4 the least susceptible), and dental caries experience was calculated separately for each susceptibility group, creating four outcomes. Information about explanatory variable, fluoride levels in the drinking water, was provided by the water suppliers. The questionnaire inquired about potential determinants: sociodemographic characteristics and oral health-related behaviors. Chi-square, Mann–Whitney U and Kruskal Wallis tests were used for descriptive statistics, and linear regression analyses to examine the association between fluoride levels and four outcomes.

Results
The proportions of median decayed, missing, filled surfaces decreased following the surface-based susceptibility hierarchy (group 1–33%, group 2–28%, group 3–24%, group 4–15%). When adjusted for potential determinants, higher-level fluoride (≥ 0.7 ppm vs < 0.7 ppm) in the drinking water associated with lower dental caries experience in all surface-based susceptibility hierarchy groups; Group 1: β = − 0.23 (95 %CI − 0.44; − 0.001), Group 2: β = − 0.44 (95 %CI − 0.82; − 0.07), Group 3: β = − 1.14 (95 %CI − 1.88; − 0.41) and Group 4: β = − 6.28 (95 %CI − 9.29; − 3.30).

Conclusions
The higher-level fluoride in the drinking water associated with lower dental caries experience in adults and this was observed in all surface-based susceptibility groups. However, there is a need to validate the surface-based susceptibility hierarchy in longitudinal adult studies.
Student and educator perspectives on virtual institutional introductory pharmacy practice experience (IPPE)
Authors: Almohammed Omar A. , Alotaibi Lama H. , Ibn Malik Shatha A. 
Published: May 2021

Abstract
Background
The COVID-19 pandemic has required governments around the world to suspend face-to-face learning for school and university students. Colleges of pharmacy are faced with the challenge of training students in hospitals that are under considerable pressure at this time. The government of Saudi Arabia has moved all classes and training online to limit the spread of the virus. This study describes the experience of the Introductory and Advanced Pharmacy Practice Experience (IPPE and APPE) students and preceptors engaged in the virtual IPPE training.

Methods
A cross-sectional study was conducted to describe and appraise the implemented virtual IPPE training from the experiences of IPPE and APPE students, and their preceptor. The IPPE students described their experiences in close-ended questionnaires, while APPE students in open-ended questionnaires, and the preceptor described the experiences in narrative. The study focused on highlighting the advantages, opportunities, challenges, and shortcomings of the virtual training.

Results
Two preceptors and seven APPE students participated in the preparation and administration of the virtual training. The IPPE students’ experiences, based on 87 respondents, were mostly positive. Although IPPE students enjoyed the time flexibility that allowed the learning of new skills and reflection on previous experiences, 15% experienced difficulty finding quiet places with a reliable internet connection or had difficulty working on team-based activities. Moreover, some were anxious about the lack of adequate patient-care experience. On the other hand, the APPE students found the experience enriching as they gained experience and understanding of academic workflow, gained skills, and overcame the challenges they faced during this virtual training experience.

Conclusions
Future training programs should be organized to overcome the challenges and to maximize the benefits of training experiences. Schools of pharmacy may benefit from the training materials constructed, prepared, and administered by APPE students to improve IPPE students’ learning experiences and outcomes.
The alveolar epithelial cells are involved in pulmonary vascular remodeling and constriction of hypoxic pulmonary hypertension
Authors: Wang Yanxia , Li Xiaoming , Niu Wen , Chen Jian , Zhang Bo , Zhang Xiumin , Wang Yingmei , Dang Shaokang , Li Zhichao 
Published: May 2021

AbstractBackgroundHypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. Alveolar epithelial cells (AECs) primarily sense alveolar hypoxia, but the role of AECs in HPH remains unclear. In this study, we explored whether AECs are involved in pulmonary vascular remodeling and constriction.MethodsIn the constructed rat HPH model, hemodynamic and morphological characteristics were measured. By treating AECs with hypoxia, we further detected the levels of superoxide dismutase 2 (SOD2), catalase (CAT), reactive oxygen species (ROS) and hydrogen peroxide (H2O2), respectively. To detect the effects of AECs on pulmonary vascular remodeling and constriction, AECs and pulmonary artery smooth cells (PASMCs) were co-cultured under hypoxia, and PASMCs and isolated pulmonary artery (PA) were treated with AECs hypoxic culture medium. In addition, to explore the mechanism of AECs on pulmonary vascular remodeling and constriction, ROS inhibitor N-acetylcysteine (NAC) was used.ResultsHypoxia caused pulmonary vascular remodeling and increased pulmonary artery pressure, but had little effect on non-pulmonary vessels in vivo. Meanwhile, in vitro, hypoxia promoted the imbalance of SOD2 and CAT in AECs, leading to increased ROS and hydrogen peroxide (H2O2) production in the AECs culture medium. In addition, AECs caused the proliferation of co-cultured PASMCs under hypoxia, and the hypoxic culture medium of AECs enhanced the constriction of isolated PA. However, treatment with ROS inhibitor NAC effectively alleviated the above effects.ConclusionThe findings of present study demonstrated that AECs were involved in pulmonary vascular remodeling and constriction under hypoxia by paracrine H2O2into the pulmonary vascular microenvironment.
Comparative outcomes in patients receiving pirfenidone or nintedanib for idiopathic pulmonary fibrosis
Authors: Belhassen Manon , Dalon Faustine , Nolin Maëva , Van Ganse Eric 
Published: May 2021

Abstract
Background
Real-world data regarding outcomes of idiopathic pulmonary fibrosis (IPF) are scarce, outside of registries. In France, pirfenidone and nintedanib are only reimbursed for documented IPF, with similar reimbursement criteria with respect to disease characteristics, prescription through a dedicated form, and IPF diagnosis established in multidisciplinary discussion.

Research question
The data of the comprehensive French National Health System were used to evaluate outcomes in patients newly treated with pirfenidone or nintedanib in 2015–2016.

Study design and methods
Patients aged < 50 years or who had pulmonary fibrosis secondary to an identified cause were excluded. All-cause mortality, acute respiratory-related hospitalisations and treatment discontinuations up to 31 December 2017 were compared using a Cox proportional hazards model adjusted for age, sex, year of treatment initiation, time to treatment initiation and proxies of disease severity identified during a pre-treatment period.

Results
During the study period, a treatment with pirfenidone or nintedanib was newly initiated in 804 and 509 patients, respectively. No difference was found between groups for age, sex, time to treatment initiation, Charlson comorbidity score, and number of hospitalisations or medical contacts prior to treatment initiation. As compared to pirfenidone, nintedanib was associated with a greater risk of all-cause mortality (hazard ratio [HR], 1.8; 95% confidence interval [CI] 1.3–2.6), a greater risk of acute respiratory-related hospitalisations (HR 1.3; 95% CI 1.0–1.7) and a lower risk of treatment discontinuation at 12 months (HR 0.7; 95% CI 0.6–0.9).

Interpretation
This observational study identified potential differences in outcome under newly prescribed antifibrotic drugs, deserving further explorations.
Pals1 prevents Rac1-dependent colorectal cancer cell metastasis by inhibiting Arf6
Authors: Lüttgenau Simona Mareike , Emming Christin , Wagner Thomas , Harms Julia , Guske Justine , Weber Katrin , Neugebauer Ute , Schröter Rita , Panichkina Olga , Pethő Zoltán , Weber Florian , Schwab Albrecht , Wege Anja Kathrin , Nedvetsky Pavel , Krahn Michael P. 
Published: May 2021

AbstractLoss of apical-basal polarity and downregulation of cell-cell contacts is a critical step during the pathogenesis of cancer. Both processes are regulated by the scaffolding protein Pals1, however, it is unclear whether the expression of Pals1 is affected in cancer cells and whether Pals1 is implicated in the pathogenesis of the disease.Using mRNA expression data and immunostainings of cancer specimen, we show that Pals1 is frequently downregulated in colorectal cancer, correlating with poorer survival of patients. We further found that Pals1 prevents cancer cell metastasis by controlling Rac1-dependent cell migration through inhibition of Arf6, which is independent of the canonical binding partners of Pals1. Loss of Pals1 in colorectal cancer cells results in increased Arf6 and Rac1 activity, enhanced cell migration and invasion in vitro and increased metastasis of transplanted tumor cells in mice. Thus, our data reveal a new function of Pals1 as a key inhibitor of cell migration and metastasis of colorectal cancer cells. Notably, this new function is independent of the known role of Pals1 in tight junction formation and apical-basal polarity.
Inequality of weight status in urban Cuba: 2001–2010
Authors: Nie Peng , Ding Lanlin , Sousa-Poza Alfonso , Leon Alina Alfonso , Xue Hong , Jia Peng , Wang Liang , Wang Youfa 
Published: May 2021

Abstract
Background
Although understanding changes in the body weight distribution and trends in obesity inequality plays a key role in assessing the causes and persistence of obesity, limited research on this topic is available for Cuba. This study thus analyzed changes in body mass index (BMI) and waist circumference (WC) distributions and obesity inequality over a 9-year period among urban Cuban adults.

Methods
Kolmogorov-Smirnov tests were first applied to the data from the 2001 and 2010 National Survey on Risk Factors and Chronic Diseases to identify a rightward shift in both the BMI and WC distributions over the 2001–2010 period. A Shapley technique decomposed the increase in obesity prevalence into a mean-growth effect and a (re)distributional component. A univariate assessment of obesity inequality was then derived by calculating both the Gini and generalized entropy (GE) measures. Lastly, a GE-based decomposition partitioned overall obesity inequality into within-group and between-group values.

Results
Despite some relatively pronounced left-skewing, both the BMI and WC distributions exhibited a clear rightward shift to which the increases in general and central obesity can be mostly attributed. According to the Gini coefficients, both general and central obesity inequality increased over the 2001–2010 period, from 0.105 [95% confidence interval (CI) = 0.103–0.106] to 0.110 [95% CI = 0.107–0.112] and from 0.083 [95% CI = 0.082–0.084] to 0.085 [95% CI = 0.084–0.087], respectively. The GE-based decomposition further revealed that both types of inequality were accounted for primarily by within-group inequality (93.3%/89.6% and 87.5%/84.8% in 2001/2010 for general/central obesity, respectively).

Conclusions
Obesity inequality in urban Cuba worsened over the 2001–2010 time period, with within-group inequality in overall obesity dominant over between-group inequality. In general, the results also imply that the rise in obesity inequality is immune to health care system characteristics.
Estimating causes of out-of-hospital deaths in China: application of SmartVA methods
Authors: Qi Jinlei , Adair Tim , Chowdhury Hafizur R. , Li Hang , McLaughlin Deirdre , Liu Yunning , Liu Jiangmei , Zeng Xinying , You Jinling , Firth Sonja , Sorchik Renee , Yin Peng , Wang Lijun , Zhou Maigeng , Lopez Alan D. 
Published: May 2021

Abstract
Background
Most deaths in China occur at home, making it difficult to collect reliable cause of death (CoD) information. Verbal autopsy (VA) was applied using the SmartVA tool to a sample of home deaths in China to explore its feasibility as a means of improving the quality of CoD data.

Methods
The study was carried out in 22 districts in 9 provinces, located in north-east, central, and western areas of China during 2017 and 2018. Trained interviewers selected suitable respondents in each household to collect information using the Population Health Metrics Research Consortium (PHMRC) shortened and validated electronic VA questionnaire on tablets. The CoD was diagnosed from the interview data using the SmartVA-Analyze 2.0 software (Tariff 2.0).

Results
Non-communicable diseases (NCDs) dominated the leading causes of death in all age groups and for both sexes. After redistribution of undetermined causes, stroke (24%), ischemic heart diseases (IHD) (21%), chronic respiratory diseases (11%), and lung cancer (6%) were the leading causes of death. The cause fractions for level-one cause categories and ranking of specific causes were similar between SmartVA and results from the Global Burden of Disease (GBD) study.

Conclusion
Evidence from this large pilot study suggests that SmartVA is a feasible and plausible tool and could be a valuable tool to improve the quality and standardization of CoD information across China.
Impact of mixed meal tolerance test composition on measures of beta-cell function in type 2 diabetes
Authors: Kössler Theresa , Bobrov Pavel , Strassburger Klaus , Kuss Oliver , Zaharia Oana-Patricia , Karusheva Yanislava , Möser Clara , Bódis Kálmán , Burkart Volker , Roden Michael , Szendroedi Julia ,   for the GDS Group, Roden M. , Al-Hasani H. , Belgardt B. , Burkart V. , Buyken A. E. , Geerling G. , Herder C. , Hwang J. H. , Icks A. , Jandeleit-Dahm K. , Kahl S. , Kotzka J. , Kuß O. , Lammert E. , Rathmann W. , Szendroedi J. , Trenkamp S. , Ziegler D. 
Published: May 2021

Abstract
Background
Application of mixed meal tolerance tests (MMTT) to measure beta-cell function in long-term studies is limited by modification of the commercial products occurring over time. This study assessed the intra-individual reliability of MMTTs and compared the effects of liquid meals differing in macronutrient composition on the estimation of beta-cell function in type 2 diabetes (T2DM).

Methods
To test the reliability of MMTTs, 10 people with T2DM (age 58 ± 11 years, body mass index 30.0 ± 4.9 kg/m2) received Boost®high Protein 20 g protein three times. For comparing different meals, another 10 persons with T2DM (58 ± 5 years, 31.9 ± 5.3 kg/m2) ingested either Boost®high Protein 20 g protein or the isocaloric Boost®high Protein 15 g protein containing 35% less protein and 18% more carbohydrates. C-peptide, insulin and glucose release were assessed from the incremental area under the concentration time curve (iAUC) and the intra- and inter-individual variation of these parameters from the coefficients of variations (CV).

Results
Repetitive ingestion of one meal revealed intra-individual CVs for the iAUCs of C-peptide, insulin and glucose, which were at least 3-times lower than the inter-individual variation of these parameters (18.2%, 19.7% and 18.9% vs. 74.2%, 70.5% and 207.7%) indicating a good reliability. Ingestion of two different meals resulted in comparable intra-individual CVs of the iAUCs of C-peptide and insulin (16.9%, 20.5%).

Conclusion
MMTTs provide reliable estimation of beta-cell function in people with T2DM. Furthermore, moderate differences in the protein and carbohydrate contents in a standardized liquid meal do not result in relevant changes of C-peptide and insulin responses.
Trial registration: Clinicaltrials.gov, Identifier number: NCT01055093. Registered 22 January 2010 – Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT01055093