bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factor IXa variants resistant to plasma inhibitors enhance clot formation in vivo
Authors: Ivanciu Lacramioara , Arruda Valder R. , Camire Rodney M. 
Published: February 2023

Abstract
Factor IXa (FIXa) plays a pivotal role in coagulation by contributing to FX activation via the intrinsic pathway. Although antithrombin (AT) and other plasma inhibitors are thought to regulate FIXa procoagulant function, the impact of FIXa inhibition on thrombin generation and clot formation in vivo remains unclear. Here, we generated FIXa variants with altered reactivity to plasma inhibitors that target the FIXa active site but maintain procoagulant function when bound to its cofactor, FVIIIa. We found that selected FIXa variants (eg, FIXa-V16L) have a prolonged activity half-life in the plasma due, in part, to AT resistance. Studies using hemophilia B mice have shown that delayed FIXa inhibition has a major impact on reducing the bleeding phenotype and promoting thrombus formation following administration of FIX protein. Overall, these results demonstrate that the regulation of FIXa inhibition contributes in a major way to the spatial and temporal control of coagulation at the site of vascular injury. Our findings provide novel insights into the physiological regulation of FIXa, enhance our understanding of thrombus formation in vivo via the intrinsic pathway, and suggest that altering FIXa inhibition could have therapeutic benefits.
Coronary artery disease in a patient with Addison’s disease: a case report and literature review
Authors: Zhao Ruohan , Luo Suxin , Wang Shuzhen , Wen Yi , Xiong Feng 
Published: January 2023

Abstract
Background
Addison’s disease which is due to dysfunction of the adrenal gland, with abnormal secretion of glucocorticoids and mineralocorticoids, is rare. By inducing inflammation and disorders of water and electrolyte metabolism, Addison’s disease may accelerate progression of co-existed cardiovascular diseases. Addison’s disease combined with cardiovascular disease is infrequent, only 10 cases in the literature.

Case presentation
We reported a 51-year-old male patient with unstable angina pectoris and hypotension. Changes on coronary angiography within 2 years suggested rapid progression of coronary artery disease in a patient with low cardiovascular risk. An additional clue of skin hyperpigmentation, fatigue and further examination confirmed the diagnosis of Addison’s disease caused by adrenal tuberculosis. After hormone replacement treatment, the frequency and severity of the angina pectoris were alleviated significantly, as were hypotension, hyperpigmentation and fatigue.

Conclusions
The combination of Addison’s disease and coronary artery disease in one patient is rare. Addison’s disease can induce inflammation and disorders of water and electrolyte metabolism, which may further accelerate the course of coronary artery disease. Meanwhile, the hypotension in Addison’s disease may affect the coronary blood flow, which may result in an increased susceptibility to unstable angina in the presence of coronary stenosis. So, we should analyze comprehensively if the coronary artery disease progress rapidly.
Empirical evaluation of internal validation methods for prediction in large-scale clinical data with rare-event outcomes: a case study in suicide risk prediction
Authors: Coley R Yates , Liao Qinqing , Simon Noah , Shortreed Susan M. 
Published: February 2023

AbstractBackgroundThere is increasing interest in clinical prediction models for rare outcomes such as suicide, psychiatric hospitalizations, and opioid overdose. Accurate model validation is needed to guide model selection and decisions about whether and how prediction models should be used. Split-sample estimation and validation of clinical prediction models, in which data are divided into training and testing sets, may reduce predictive accuracy and precision of validation. Using all data for estimation and validation increases sample size for both procedures, but validation must account for overfitting, oroptimism. Our study compared split-sample and entire-sample methods for estimating and validating a suicide prediction model.MethodsWe compared performance of random forest models estimated in a sample of 9,610,318 mental health visits (“entire-sample”) and in a 50% subset (“split-sample”) as evaluated in a prospective validation sample of 3,754,137 visits. We assessed optimism of three internal validation approaches: for the split-sample prediction model, validation in the held-out testing set and, for the entire-sample model, cross-validation and bootstrap optimism correction.ResultsThe split-sample and entire-sample prediction models showed similar prospective performance; the area under the curve, AUC, and 95% confidence interval was 0.81 (0.77–0.85) for both. Performance estimates evaluated in the testing set for the split-sample model (AUC = 0.85 [0.82–0.87]) and via cross-validation for the entire-sample model (AUC = 0.83 [0.81–0.85]) accurately reflected prospective performance. Validation of the entire-sample model with bootstrap optimism correction overestimated prospective performance (AUC = 0.88 [0.86–0.89]). Measures of classification accuracy, including sensitivity and positive predictive value at the 99th, 95th, 90th, and 75thpercentiles of the risk score distribution, indicated similar conclusions: bootstrap optimism correction overestimated classification accuracy in the prospective validation set.ConclusionsWhile previous literature demonstrated the validity of bootstrap optimism correction for parametric models in small samples, this approach did not accurately validate performance of a rare-event prediction model estimated with random forests in a large clinical dataset. Cross-validation of prediction models estimated with all available data provides accurate independent validation while maximizing sample size.
Characterisation of tumour-immune phenotypes and PD-L1 positivity in squamous bladder cancer
Authors: Jung Max , Rose Michael , Knuechel Ruth , Loeffler Chiara , Muti Hannah , Kather Jakob Nikolas , Gaisa Nadine T. ,   on behalf of the German Study Group of Bladder Cancer (DFBK e.V.)
Published: February 2023

Abstract
Aims
Immune checkpoint inhibitor (ICI) therapy has become a viable treatment strategy in bladder cancer. However, treatment responses vary, and improved biomarkers are needed. Crucially, the characteristics of immune cells remain understudied especially in squamous differentiated bladder cancer (sq-BLCA). Here, we quantitatively analysed the tumour-immune phenotypes of sq-BLCA and correlated them with PD-L1 expression and FGFR3 mutation status.

Methods
Tissue microarrays (TMA) of n = 68 non-schistosomiasis associated pure squamous cell carcinoma (SCC) and n = 46 mixed urothelial carcinoma with squamous differentiation (MIX) were subjected to immunohistochemistry for CD3, CD4, CD8, CD56, CD68, CD79A, CD163, Ki67, perforin and chloroacetate esterase staining. Quantitative image evaluation was performed via digital image analysis.

Results
Immune infiltration was generally higher in stroma than in tumour regions. B-cells (CD79A) were almost exclusively found in stromal areas (sTILs), T-lymphocytes and macrophages were also present in tumour cell areas (iTILs), while natural killer cells (CD56) were nearly missing in any area. Tumour-immune phenotype distribution differed depending on the immune cell subset, however, hot tumour-immune phenotypes (high density of immune cells in tumour areas) were frequently found for CD8 + T-cells (33%), especially perforin + lymphocytes (52.2%), and CD68 + macrophages (37.6%). Perforin + CD8 lymphocytes predicted improved overall survival in sq-BLCA while high PD-L1 expression (CPS ≥ 10) was significantly associated with higher CD3 + , CD8 + and CD163 + immune cell density and high Ki67 (density) of tumour cells. Furthermore, PD-L1 expression was positively associated with CD3 + /CD4 + , CD3 + /CD8 + and CD68 + /CD163 + hot tumour-immune phenotypes. FGFR3 mutation status was inversely associated with CD8 + , perforin + and CD79A + lymphocyte density.

Conclusions
Computer-based image analysis is an efficient tool to analyse immune topographies in squamous bladder cancer. Hot tumour-immune phenotypes with strong PD-L1 expression might pose a promising subgroup for clinically successful ICI therapy in squamous bladder cancer and warrant further investigation.
Physical activity and psychological adjustment among retirees: a systematic review
Authors: Sharifi Mehdi , Nodehi Davud , Bazgir Behzad 
Published: January 2023

Abstract
Background
Health-related behaviors may change after retirement and induce changes in the mental health. This systematic review aimed to investigate the nature of changes in physical activity and leisure activities, as well as the relationship between physical activity, leisure, and psychological adjustment among retirees.

Methods
Search of papers was done in three electronic databases of PubMed, ISI Web of Science, and Scopus without constraints on time, geographical regions, or languages in February 2022. The papers that had examined the relationship between physical activity and adjustment among retirees using observational design (cross-sectional or longitudinal) were included in the present study. To evaluate the methodological quality of cross-sectional studies, Joanna Briggs Institute (JBI) Critical Appraisal Checklist, and for longitudinal studies, Newcastle-Ottawa Scale (NOS) were used.

Results
The search results identified 1458 records. Twenty-six papers were included in this review based on the inclusion and exclusion criteria. The findings of most of these studies indicated a significant positive correlation between physical activity, leisure, and psychological adjustment in retirees. Retirees were mostly engaged in passive leisure activities such as reading, watching TV and movies, and less engaged in physical activities, sport, or physical exercise. General organized assessment of the total physical activity among retirees was not possible.

Conclusions
Based on the study findings, it can be stated that there is a positive correlation between physical activity, leisure, and the retirees’ adjustment. Usage of the same and valid measurement method specific to old age and retirement period can be useful in more precise assessment of physical activity and its association with adjustment among retirees.
A decade of child pedestrian safety in England: a bayesian spatio-temporal analysis
Authors: Shoari Niloofar , Heydari Shahram , Blangiardo Marta 
Published: February 2023

AbstractBackgroundChild pedestrian injury is a public health and health equality challenge worldwide, including in high-income countries. However, child pedestrian safety is less-understood, especially over long time spans. The intent of this study is to understand factors affecting child pedestrian safety in England over the period 2011–2020.MethodsWe conducted an area-level study using a Bayesian space-time interaction model to understand the association between the number of road crashes involving child pedestrians in English Local Authorities and a host of socio-economic, transport-related and built-environment variables. We investigated spatio-temporal trends in child pedestrian safety in England over the study period and identified high-crash local authorities.ResultsWe found that child pedestrian crash frequencies increase as child population, unemployment-related claimants, road density, and the number of schools increase. Nevertheless, as the number of licensed vehicles per capita and zonal-level walking/cycling increase, child pedestrian safety increases. Generally, child pedestrian safety has improved in England since 2011. However, the socio-economic inequality gap in child pedestrian safety has not narrowed down. In addition, we found that after adjusting for the effect of covariates, the rate of decline in crashes varies between local authorities. The presence of localised risk factors/mitigation measures contributes to variation in the spatio-temporal patterns of child pedestrian safety.ConclusionsOverall, southern England has experienced more improvement in child pedestrian safety over the last decade than the northern regions. Our study revealed socio-economic inequality in child pedestrian safety in England. To better inform safety and public health policy, our findings support the importance of a targeted system approach, considering the identification of high-crash areas while keeping track of how child pedestrian safety evolves over time.
Impact of pre-pandemic sick leave diagnoses on the length of COVID-19-related sick leave: a nationwide registry-based study
Authors: Abzhandadze Tamar , Westerlind Emma , Persson Hanna C. 
Published: January 2023

Abstract
Background
The COVID-19 pandemic has caused difficulties and changes in many aspects of people’s health and lives. Although infection affected work capacity, during the first wave policies for sick leave due to COVID-19 were unclear. The aim of this study was to investigate the impact of sick leave diagnoses in the year before the COVID-19 diagnosis on sick leave duration due to COVID-19 in a nationwide non-hospitalised population.

Methods
Data from three Swedish registries were analysed for sick leave commencing between 1 March and 31 August 2020, with a follow-up period of 4 months. Sick leave due to COVID-19 was considered the number of days that sickness benefits were used and included at least one registered COVID-19 diagnosis. Sick leave in the year before COVID-19 diagnosis were categorised into five diagnostic groups and one reference group (participants without prior sick leave).

Results
The study comprised 8935 individuals who received sickness benefits due to COVID-19 in Sweden during the first pandemic wave (mean age 46.7 years, 67% females, and 24% had diagnoses for sick leave in the year before COVID-19 diagnosis). The duration of sick leave due to COVID-19 was significantly higher in the groups with prior sick leave owing to musculoskeletal system diseases (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.01–1.15); respiratory system diseases (OR: 1.22, 95% CI: 1.14–1.31); all other isolated diagnoses (OR: 1.08, 95% CI: 1.03–1.14); and multiple diagnoses (OR: 1.32, 95% CI: 1.21–1.43).

Conclusions
The results of this nationwide registry-based study indicate that individuals with premorbid conditions are more prone to longer sick leave durations due to COVID-19. Prediction of sick leave duration during the first wave of the COVID-19 pandemic is complex and several factors played a role.
In vitro evaluation of dental color stability using various aesthetic restorative materials after immersion in different drinks
Authors: Faris Tavga Mustafa , Abdulrahim Rukhosh Hasan , Mahmood Mohammed Abdalla , Mhammed Dalloo Gollshang Ahmad , Gul Sarhang Sarwat 
Published: January 2023

AbstractBackgroundCurrently, the demands for restorations have increased considerably; thus, improvements and modifications have been made in dental composite technologies especially using materials that have been claimed to improve color stability.ObjectiveThis study aimed to determine the effect of various solutions on the color stability of different restorative materials in vitro study.MethodsThis study used three types of esthetic restorative materials. The samples comprised 45 discs, including 15 micro-hybrids, 15 nano-hybrids, and 15 glass ionomers). These discs were immersed in various beverages an hour a day for one month at room temperature. The color stability was measured using a spectrophotometer before/after immersion (days 7 and 30).ResultsWe realized a significant difference in color change with Coca-Cola and tea-milk solution after seven days and 30 days (p < 0.05). However, no significant difference was found in the samples immersed in DM after seven days and 30 days (p > 0.05). The highest value of lightness (∆L) and stainability (∆a) was seen in micro-hybrid after 30 days of immersion in tea-milk solution (− 12.16 ± 1.74 and 11.4 ± 3.82, respectively), while most samples had a positive ∆b value.ConclusionAfter one month, the tea-milk solution affected the color stability of all used restorative materials. In addition, micro-hybrid had higher color stability than nano-hybrid and glass ionomer.
Intimate partner violence and associated factors among HIV positive women attending antiretroviral therapy clinics in Gondar city, Northwest Ethiopia
Authors: Alemie Amsal Seraw , Yeshita Hedija Yenus , Zeleke Ejigu Gebeye , Mekonnen Birye Dessalegn 
Published: February 2023

Abstract
Introduction
Intimate partner violence against women is a behavior within an intimate relationship that causes sexual, physical, or psychological harm to the women. It occurs among all socioeconomic, religious, and cultural groups in all settings, and affects the health of women, families, and the community at large. Determining the magnitude and determinants of intimate partner violence against HIV positive women could help to design preventive and control strategies. However, there is a dearth of information regarding the magnitude and determinants of intimate partner violence against HIV positive women in Ethiopia. Thus, this study aimed to assess the magnitude and associated factors of intimate partner violence against HIV positive women in Gondar city, Northwest Ethiopia.

Method
A facility-based cross-sectional study was carried out from February to May 2021 in selected public health facilities of Gondar city among 626 HIV positive women. A systematic random sampling technique was used to select study participants. Data were analyzed using Statistical Package of Social Science (SPSS) version 20 software. Bivariable and Multivariable logistic regression models were done. Adjusted odds ratio (AOR) with a 95% confidence interval (CI) was used to identify determinants of intimate partner violence. Statistical significance was considered at a p value < 0.05.

Results
The overall prevalence of intimate partner violence against HIV positive women within the last 12 months was 64.2% (95% CI 60.4, 68.2). Physical violence was the most common type (54.8%), followed by sexual (51.1%) and emotional (48.9%) violence. Intimate partner violence among HIV positive women was associated with women’s age 19–24 (AOR = 0.13, 95% CI 0.02, 0.79), monthly income of 500–2500 (AOR = 6.5, 95% CI 1.72, 25.0), urban residence (AOR = 0.35, 95% CI 0.13, 0.91), partner drink alcohol (AOR = 2.14, 95% CI 1.42, 4.06), and a husband with no multiple sexual partners (AOR = 0.75, 95% CI 0.34, 0.94).

Conclusion
The result of this study revealed that intimate partner violence against HIV positive women was found to be high. Thus, protective measures that could increase the community’s and women’s awareness about the consequences of various forms of violence, and women empowerment are paramount. Priorities in programs of gender-based violence prevention should involve women from rural residences, older age, and males who consume alcohol.
Platelet P2Y1 receptor exhibits constitutive G protein signaling and β-arrestin 2 recruitment
Authors: Ribes Agnès , Garcia Cédric , Gratacap Marie-Pierre , Kostenis Evi , Martinez Laurent O. , Payrastre Bernard , Sénard Jean-Michel , Galés Céline , Pons Véronique 
Published: February 2023

Abstract
Background
Purinergic P2Y1 and P2Y12 receptors (P2Y1-R and P2Y12-R) are G protein-coupled receptors (GPCR) activated by adenosine diphosphate (ADP) to mediate platelet activation, thereby playing a pivotal role in hemostasis and thrombosis. While P2Y12-R is the major target of antiplatelet drugs, no P2Y1-R antagonist has yet been developed for clinical use. However, accumulating data suggest that P2Y1-R inhibition would ensure efficient platelet inhibition with minimal effects on bleeding. In this context, an accurate characterization of P2Y1-R antagonists constitutes an important preliminary step.

Results
Here, we investigated the pharmacology of P2Y1-R signaling through Gq and β-arrestin pathways in HEK293T cells and in mouse and human platelets using highly sensitive resonance energy transfer-based technologies (BRET/HTRF). We demonstrated that at basal state, in the absence of agonist ligand, P2Y1-R activates Gq protein signaling in HEK293T cells and in mouse and human platelets, indicating that P2Y1-R is constitutively active in physiological conditions. We showed that P2Y1-R also promotes constitutive recruitment of β-arrestin 2 in HEK293T cells. Moreover, the P2Y1-R antagonists MRS2179, MRS2279 and MRS2500 abolished the receptor dependent-constitutive activation, thus behaving as inverse agonists.

Conclusions
This study sheds new light on P2Y1-R pharmacology, highlighting for the first time the existence of a constitutively active P2Y1-R population in human platelets. Given the recent interest of P2Y12-R constitutive activity in patients with diabetes, this study suggests that modification of constitutive P2Y1-R signaling might be involved in pathological conditions, including bleeding syndrome or high susceptibility to thrombotic risk. Thus, targeting platelet P2Y1-R constitutive activation might be a promising and powerful strategy for future antiplatelet therapy.
PMCA inhibition reverses drug resistance in clinically refractory cancer patient-derived models
Authors: Park Ki Cheong , Kim Jung Min , Kim Sang Yong , Kim Seok-Mo , Lim Jin Hong , Kim Min Ki , Fang Sungsoon , Kim Yonjung , Mills Gordon B. , Noh Sung Hoon , Cheong Jae-Ho 
Published: February 2023

Abstract
Background
Cancer cells have developed molecular strategies to cope with evolutionary stressors in the dynamic tumor microenvironment. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a metabolic rheostat that regulates diverse cellular adaptive behaviors, including growth and survival. However, the mechanistic role of PGC1α in regulating cancer cell viability under metabolic and genotoxic stress remains elusive.

Methods
We investigated the PGC1α-mediated survival mechanisms in metabolic stress (i.e., glucose deprivation-induced metabolic stress condition)-resistant cancer cells. We established glucose deprivation-induced metabolic stress-resistant cells (selected cells) from parental tumor cells and silenced or overexpressed PGC1α in selected and parental tumor cells.

Results
Several in vitro and in vivo mouse experiments were conducted to elucidate the contribution of PGC1α to cell viability in metabolic stress conditions. Interestingly, in the mouse xenograft model of patient-derived drug-resistant cancer cells, each group treated with an anti-cancer drug alone showed no drastic effects, whereas a group that was co-administered an anti-cancer drug and a specific PMCA inhibitor (caloxin or candidate 13) showed marked tumor shrinkage.

Conclusions
Our results suggest that PGC1α is a key regulator of anti-apoptosis in metabolic and genotoxic stress-resistant cells, inducing PMCA expression and allowing survival in glucose-deprived conditions. We have discovered a novel therapeutic target candidate that could be employed for the treatment of patients with refractory cancers.