bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics, Pharmacodynamics and Antiviral Efficacy of the MEK Inhibitor Zapnometinib in Animal Models and in Humans
Authors: Koch-Heier Julia , Schönsiegel Annika , Waidele Lara Maria , Volk Julian , Füll Yvonne , Wallasch Christian , Canisius Sebastian , Burnet Michael , Planz Oliver 
Published: June 2022

The mitogen-activated protein kinase (MEK) inhibitor zapnometinib is in development to treat acute viral infections like COVID-19 and influenza. While the antiviral efficacy of zapnometinib is well documented, further data on target engagement/pharmacodynamics (PD) and pharmacokinetics (PK) are needed. Here, we report zapnometinib PK and PD parameters in mice, hamsters, dogs, and healthy human volunteers. Mice received 25 mg/kg/day zapnometinib (12.5 mg/kg p. o. twice daily, 8 h interval). Syrian hamsters received 30 mg/kg (15 mg/kg twice daily) or 60 mg/kg/day once daily. Beagle dogs were administered 300 mg/kg/day, and healthy human volunteers were administered 100, 300, 600 and 900 mg zapnometinib (once daily p. o.). Regardless of species or formulation, zapnometinib maximum plasma concentration (Cmax) was reached between 2–4 h after administration with an elimination half-life of 4–5 h in dogs, 8 h in mice or hamsters and 19 h in human subjects. Doses were sufficient to cause up to 80% MEK inhibition. Across all species approximately 10 μg/ml zapnometinib was appropriate to inhibit 50% of peripheral blood mononuclear cells (PBMC) MEK activity. In mice, a 50%–80% reduction of MEK activity was sufficient to reduce influenza virus titer in the lungs by more than 90%. In general, while &gt;50% MEK inhibition was reached in vivo at most doses, 80% inhibition in PBMCs required significantly higher doses and appeared to be the practical maximal level obtained in vivo. However, the period of reduced phosphorylated extracellular-signal regulated kinase (pERK), a measure of MEK inhibition, was maintained even after elimination of zapnometinib from plasma, suggesting a sustained effect on MEK consistent with regulatory effects or a slow off-rate. These data suggest a target plasma Cmax of at least 10 μg/ml zapnometinib in further clinical studies.
Potential Application of Pyroptosis in Kidney Renal Clear Cell Carcinoma Immunotherapy and Targeted Therapy
Authors: Qi Xiaochen , Che Xiangyu , Li Quanlin , Wang Qifei , Wu Guangzhen 
Published: June 2022

Renal cell carcinoma (RCC) is a type of cancer with an increasing rate of morbidity and mortality and is a serious threat to human health. The treatment of RCC, especially kidney renal clear cell carcinoma (KIRC), has always been the focus of clinical treatment. Using The Cancer Genome Atlas (TCGA) database as a starting point, we explored the feasibility of applying the pyroptosis mechanism to KIRC treatment by searching for cancer markers associated with pyroptosis and cancer treatment signatures. The obtained samples were clustered using unsupervised clustering analysis to define the different KIRC subtypes with different pyroptosis expression levels. Based on this, a gene expression analysis was performed to explore the carcinogenic mechanism that is markedly related to pyroptosis. The Genomics of Drug Sensitivity in Cancer database and single sample gene set enrichment analysis (ssGSEA) algorithm were used to analyze the different treatment methods of the current prominent KIRC to determine whether pyroptosis plays a role. Finally, LASSO regression was used to screen for related genes and construct a model to predict patient prognosis. The expression levels of GSDME, CASP3, CASP4, CASP5, CHMP3, and CHMP4C were incorporated into the model construction. After verification, the prediction accuracy of the 3-, 5-, 7- and 10 years survival rates of our prognostic model were 0.66, 0.701, 0.719, and 0.728, respectively. Through the above analysis, we demonstrated the feasibility of pyroptosis in the clinical treatment of KIRC and provided novel ideas and suggestions for the clinical treatment of KIRC.
Media Internalized Pressure and Restrained Eating Behavior in College Students: The Multiple Mediating Effects of Body Esteem and Social Physique Anxiety
Authors: Fu Tiantian , Wang Jun , Xu Shanshan , Yu Jinrong , Sun Guoxiao 
Published: June 2022

BackgroundRestrained eating behavior has become the norm in college students' lives, and considering the harm it causes to college students, it is necessary to explore the factors associated with it. The aim of this study was to explore the association between media internalized pressure, body esteem, social physique anxiety, and restrained eating behavior.MethodsThe participants in this study were 1,032 Chinese college students (439 males and 593 females) and had a mean age of 20.22 years (SD = 1.277). They completed the Sociocultural Attitudes Toward Appearance Questionnaire-3, Body Esteem Scale (BES), Social Physique Anxiety Scale (SPAS), and Dutch Eating Behavior Questionnaire (DEBQ).ResultsThe results showed that media internalized pressure was significantly and positively associated with college students' restrained eating behavior, that body esteem and social physique anxiety played a mediating role between media internalized pressure and restrained eating behavior, respectively, and that body esteem and social physique anxiety can also play a chained mediating role.ConclusionThis study reveals the relationship between media internalized pressure and restrained eating behavior, and the important role played by body esteem and social physique anxiety. Future interventions targeting restrained eating should focus on the aspects of body esteem and social physique anxiety.
Analysing the Relationship Between Immigrant Status and the Severity of Offending Behaviour in Terms of Individual and Contextual Factors
Authors: Fernández-Pacheco Alises Gloria , Torres-Jiménez Mercedes , Martins Paula Cristina , Mendes Silvia María Vale 
Published: June 2022

BackgroundSocial inclusion is a context for both risk and protective factors of migrant youth delinquency. This study aims to shed light on the issue by comparing delinquency amongst native, first-generation, and second-generation immigrant youths in Portugal, a country located in the south of Europe, an area where research in this field is still scarce.MethodsThe research is based on the International Self-Reported Delinquency (ISRD-3) dataset, which includes information on over 4,000 adolescents, who self-reported on their socio-demographic status, leisure activities, school and neighbourhood environment, family bonds, and self-control.ResultsNested Logistic Regression analyses showed that a young first-generation immigrant is twice as likely to commit a crime, with or without violence, as a young native born in Portugal. However, no differences were found regarding the prevalence of delinquency amongst second-generation immigrants and natives, which is likely due to the integration and cultural assimilation of the immigrant over time. Regarding the analysed risk factors, it was found that both structural and individual factors, identified by the theories of control, stress, as well as situational action theory, have a direct effect on the commission of juvenile crimes (both non-violent and violent). Moreover, this effect is significant in adolescents living in Portugal in general, both immigrants and natives. The most influential variable for both types of delinquent behaviour, with and without violence, is peer delinquency, followed by low morality and self-control.ConclusionThese findings have relevant policy implications and are useful for evidence-based interventions aimed at promoting migrant adolescent well-being and targeting host countries’ performance.
Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Monocyte-to-Lymphocyte Ratio in Depression: An Updated Systematic Review and Meta-Analysis
Authors: Cheng Yanwei , Wang Yiwen , Wang Xiangyi , Jiang Zhuoya , Zhu Lijun , Fang Shaokuan 
Published: June 2022

BackgroundResearch on neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in depression is still emerging and has increased 3-fold since the first meta-analysis. An updated meta-analysis with sufficient studies can provide more evidence for a potential relationship between NLR, PLR, MLR, and depression.MethodsWe identified 18 studies from the PubMed, EMBASE, Cochrane library, and Web of Science databases. Meta-analyses were performed to generate pooled standardized mean differences (SMDs) and 95% confidence intervals (CIs) between patients with depression and controls. Sensitivity analysis, subgroup analysis, meta-regression, and publication bias were conducted.ResultsA total of 18 studies including 2,264 depressed patients and 2,415 controls were included. Depressed patients had significantly higher NLR and PLR compared with controls (SMD = 0.33, 95% CI: 0.15–0.52, p &lt; 0.001 and SMD = 0.24, 95% CI: 0.02–0.46, p &lt; 0.05, respectively). MLR was slightly higher in depressed individuals compared to controls (SMD = 0.15, 95% CI: −0.26 to 0.55, p &gt; 0.05), despite the absence of significance. Sensitivity analysis removing one study responsible for heterogeneity showed a higher and significant effect (SMD = 0.32, 95% CI: 0.20–0.44) of MLR. Three subgroup analyses of NLR, PLR, MLR, and depression revealed obvious differences in the inflammatory ratios between depressed patients and controls in China and the matched age and gender subgroup. Individuals with post-stroke depression (PSD) had higher NLR and MLR values as compared to non-PSD patients (SMD = 0.51, 95% CI: 0.36–0.67, p &lt; 0.001 and SMD = 0.46, 95% CI: 0.12–0.79, p &lt; 0.01, respectively). Meta-regression analyses showed that male proportion in the case group influenced the heterogeneity among studies that measured NLR values (p &lt; 0.05).ConclusionsHigher inflammatory ratios, especially NLR, were significantly associated with an increased risk of depression. In the subgroup of China and matched age and gender, NLR, PLR, and MLR were all elevated in depressed patients vs. controls. Individuals with PSD had higher NLR and MLR values as compared to non-PSD patients. Gender differences may have an effect on NLR values in patients with depression.
The Association Between Emotion Recognition, Affective Empathy, and Structural Connectivity in Schizophrenia Patients
Authors: Koevoets Martijn G. J. C. , Prikken Merel , Hagenaar Doesjka A. , Kahn René S. , van Haren Neeltje E. M. 
Published: June 2022

IntroductionEmotion processing deficits often occur in patients with schizophrenia. We investigate whether patients and controls differ in the association between facial emotion recognition and experience of affective empathy and whether performance on these emotion processing domains differently relates to white matter connectivity.Materials and MethodsForty-seven patients with schizophrenia and 47 controls performed an emotion recognition and affective empathy task. T1-weighted and diffusion-tensor images (DTI) of the brain were acquired. Using Tracula 5.3, ten fibers were reconstructed and fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were extracted. Groups were compared on task performance, white matter measures and their interactions using ANCOVAs. Correction for multiple comparisons was applied.ResultsPatients scored lower on emotion recognition (p = 0.037) and reported higher levels of affective empathy (p &lt; 0.001) than controls. Patients with poor emotion recognition (PT-low) experienced stronger affective empathy than patients with similar emotion recognition performance as controls (PT-normal; p = 0.011), who in turn reported stronger affective empathy than controls (p = 0.043). We found a significant interaction between emotion recognition, affective empathy and anterior thalamic radiation AD (p = 0.017, d = 0.43). Post hoc analyses revealed that the correlation between AD and empathy differed significantly between all groups (empathy/AD in PT-low &lt; empathy/AD in PT-normal &lt; empathy/AD in controls).DiscussionIn patients with poor emotion recognition, the negative association between anterior thalamic radiation AD and affective empathy was stronger than in patients with normal emotion recognition capacity. Possibly, axonal damage in fronto-thalamic structural connections, as part of a larger frontotemporal network, underlies the association between poor emotion recognition and higher levels of affective empathy in schizophrenia patients.
The Bilateral Precuneus as a Potential Neuroimaging Biomarker for Right Temporal Lobe Epilepsy: A Support Vector Machine Analysis
Authors: Huang Chunyan , Zhou Yang , Zhong Yi , Wang Xi , Zhang Yunhua 
Published: June 2022

Background and ObjectiveWhile evidence has demonstrated that the default-mode network (DMN) plays a key role in the broad-scale cognitive problems that occur in right temporal lobe epilepsy (rTLE), little is known about alterations in the network homogeneity (NH) of the DMN in TLE. In this study, we used the NH method to investigate the NH of the DMN in TLE at rest, and an support vector machine (SVM) method for the diagnosis of rTLE.MethodsA total of 43 rTLE cases and 42 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Imaging data were analyzed with the NH and SVM methods.ResultsrTLE patients have a decreased NH in the right inferior temporal gyrus (ITG) and left middle temporal gyrus (MTG), but increased NH in the bilateral precuneus (PCu) and right inferior parietal lobe (IPL), compared with HCs. We found that rTLE had a longer performance reaction time (RT). No significant correlation was found between abnormal NH values and clinical variables of the patients. The SVM results showed that increased NH in the bilateral PCu as a diagnostic biomarker distinguished rTLE from HCs with an accuracy of 74.12% (63/85), a sensitivity 72.01% (31/43), and a specificity 72.81% (31/42).ConclusionThese findings suggest that abnormal NH of the DMN exists in rTLE, and highlights the significance of the DMN in the pathophysiology of cognitive problems occurring in rTLE, and the bilateral PCu as a neuroimaging diagnostic biomarker for rTLE.
Epidemiology of Constipation in Elderly People in Parts of China: A Multicenter Study
Authors: Du Xiaoshan , Liu Shuai , Jia Peifei , Wang Xiaodan , Gan Jinghuan , Hu Wenzheng , Zhu Han , Song Yehua , Niu Jianping , Ji Yong 
Published: June 2022

PurposeTo investigate the epidemiological characteristics of constipation in people aged 65 years and older in several regions of China.Patients and MethodsA cross-sectional study based on a cluster sampling design was conducted in four cities of China: Tianjin, Xiamen, Cangzhou and Harbin. A total of 5,222 cases (age ≥ 65 years) were recruited, and the survey was conducted via centralized and household questionnaires that included the following: basic demographic characteristics such as sex, age, education, marital status, living status and occupation; social activities; duration of sleep at night; duration of menstruation and delivery times (in females); and if the participant had constipation symptoms, the severity of constipation. Constipation was diagnosed according to the Rome IV criteria.ResultsOf the 5,222 participants, 919 were diagnosed with constipation. The prevalence of constipation was 17.60% in elderly people ≥65 years old. Prevalence increased with age and was significantly higher in females than males (P &lt; 0.05). Prevalence was lower in the manual compared to the non-manual worker group, and significantly increased with decreasing duration of night sleep (P &lt; 0.05). Older age, female sex and shorter sleep duration at night were risk factors for constipation in elderly people.ConclusionThe prevalence of constipation in the elderly people in four cities of China was 17.60%, and was significantly affected by age, sex and sleep duration at night.
Sources of Conflict and Prevention Proposals in User Violence Toward Primary Care Staff: A Qualitative Study of the Perception of Professionals
Authors: Pina David , Peñalver-Monteagudo Carmen María , Ruiz-Hernández José Antonio , Rabadán-García José Antonio , López-Ros Paloma , Martínez-Jarreta Begoña 
Published: June 2022

BackgroundSome studies indicate that at least one in four cases of workplace violence occurs in the health sector, with a higher incidence in Emergency Departments, Mental Health Services or Primary Care. Unlike other professional groups, healthcare workers perceive this type of behavior mainly from users or patients. This is the reason why both the detection of conflict between users and professionals and the ways to face and reduce these conflicts has been and is one of the main fields of study in this population. The aim of this study was to delve into the sources of conflict between users and professionals in Primary Care from the perspective of the professionals themselves. In addition, the aim was to explore the proposals for intervention/prevention of this conflict that the professionals perceived as necessary to improve the work environment.MethodsThis study uses qualitative methodology conducting 8 focus groups with professionals related to Primary Health Care. The final sample was composed of 44 workers who were part of the regional management, labor unions, area coordinators, center coordinators and representatives of the professional groups of these centers (medicine, nursing and administration). Thematic analysis was used to extract topics and subtopics.ResultsThe results are divided into areas of conflict and intervention proposals. The professionals detect a lack of training or education in themselves, absence of functional multidisciplinary teams or competencies to improve the patient-professional relationship, among others. To address these shortcomings, they propose the creation of protocols for action in the face of aggression, the formation of spaces and channels of communication both among the center's own workers and between them and other organizations (e.g., hospitals), fostering a positive relationship with the user community and ongoing training in various topics such as self-safety, management of emotions, empathy or interpersonal communication.ConclusionsThis study allows to highlight specific areas of user-professional conflict in Primary Care. Furthermore, the inclusion of intervention proposals by the professionals allows to propose starting points for the development of complete plans.
Views of Pharmacists and Government Representatives Toward the Pilot Chief Pharmacist System in Chinese Hospitals: A Multicenter Exploratory Qualitative Study
Authors: Yang Ruomeng , Li Qian , Hayat Khezar , Zhai Panpan , Liu Wenchen , Chen Chen , Saeed Amna , Chang Jie , Li Pengchao , Du Qianqian , Xu Sen , Wen Jun , Fang Yu 
Published: June 2022

BackgroundIn China, the pharmacy departments of most hospitals have changed their main focus from drug procurement and distribution to providing pharmaceutical care services. Various regions of China have successively implemented the pilot Chief Pharmacist System (CPS) to help improve pharmaceutical care services and rational drug use in hospitals. This study was designed to explore the perspectives of pharmacists and government officials on CPS, including the advantages and barriers to the successful implementation of CPS.MethodsA qualitative study, based on semi-structured interviews, was conducted from October 1, 2018 to March 1, 2019. The interview data were gathered from 18 pharmacy staff and government representatives working in five distinct regions of China using purposive sampling. A thematic analysis approach and NVivo version 12 Plus was utilized to code and analysis of all interviews.ResultsFive broad themes were identified: the role of the chief pharmacist; their attitudes toward the CPS; the advantages and results of the CPS; the barriers toward CPS; and their suggestions toward CPS. Most of the participants believed that the chief pharmacist played a vital role in a hospital. Under CPS, the hospital pharmacy department pays more attention to prescription review, medication monitoring, and pharmaceutical consultation. However, an insufficient number of pharmacy personnel, unclear authority, and inadequate salaries were the main barriers to the implementation of the CPS.ConclusionThe attitudes of most of the participants were found to be positive toward CPS in China. The CPS can enhance the prestige of the hospital pharmacy department, improve the quality of hospital pharmaceutical care services, and promote rational drug use. Nevertheless, certain barriers highlighted in this study should be addressed promptly.
The Association Between Cognitive Impairment and Subsequent Falls Among Older Adults: Evidence From the China Health and Retirement Longitudinal Study
Authors: Zhou Rong , Li Jiayu , Chen Meiling 
Published: June 2022

IntroductionPrevious studies have suggested that cognitive impairment is associated with falls in older adults. However, the consistency of results among different subgroups defined by multiple characteristics of the elderly has not yet been tested. Additionally, results are inconsistent regarding the effects of different cognitive domains on falls. Therefore, this study sought to use representative data from a nationwide study to better understand the longitudinal association between cognitive impairment and subsequent falls in older adults.MethodsThe current study was conducted based on the China Health and Retirement Longitudinal Study (CHARLS) data of respondents aged ≥60 years in 2015 and the fall data in 2018. The respondents were divided into subgroups according to different demographic characteristics. Multiple logistic regression analysis was conducted to adjust for various confounding factors and evaluate the association between cognitive impairment and falls.ResultsOf the 5,110 respondents included in this study, 1,093 (21.39%) had falls within the last 2 years. A significant association was found between cognitive impairment and subsequent falls (OR = 0.97, 95% CI 0.95–0.99, P = 0.001) after adjusting for all of the covariates related to falls. Analysis of different cognitive domains showed that orientation (OR = 0.94, 95% CI 0.90–0.99, P = 0.013) and memory (OR = 0.93, 95% CI 0.90–0.97, P = 0.001) were significantly associated with falls. In subgroup analysis, the ORs of people aged 60–74 years, male, with lower education level were 0.97 (95% CI 0.95–0.99, P = 0.008), 0.96 (95% CI 0.93–0.98, P = 0.001), and 0.97 (95% CI 0.95–0.99, P = 0.001), respectively, suggesting that the associations were also statistically significant in these subgroups. There was also a significant association both in urban (OR = 0.97, 95% CI 0.95–0.99, P = 0.001) and in rural residents (OR = 0.97, 95% CI 0.95–0.99, P = 0.003).ConclusionsOur results suggest that the associations between cognition and falls vary depending on the different demographic characteristics of older adults. These findings may be useful for designing more accurate identification and intervention for the fall risk for specific high-risk groups.