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Introduction: Despite increased focus on development of mental health services worldwide, many adolescents still hesitate to reach out to the services when they need them. This might be linked to the lack of adolescent involvement in the development of services. This study aimed to explore adolescents' perspectives on the ideal healthcare services to meet their mental health needs. Methods: A two‐stage qualitative study was carried out to explore the perspectives of adolescents on the healthcare services to support their mental health. In the first stage, data from 295 adolescents attending a mental health seminar were analysed using qualitative content analysis. In the second stage, in‐depth perspectives of 10 adolescent coresearchers were gathered through self‐reflection and group discussions to further explore the categories developed in the first stage. Thematic analysis was used to develop the themes answering the research question. Ten adolescent coresearchers planned the study, collected and analysed data and authored the manuscript, with the support of a senior researcher. Results: Five themes describe adolescents' perspectives on the ideal healthcare services to meet their mental health needs: (1) Culturally Sensitive and Responsive; (2) Communication of Information; (3) Easy Access; (4) Variety of Support; and (5) Consistency. Culturally Sensitive and Responsive services influenced all other themes. The themes describe suggestions for mental health service improvement, including how to manage the barriers that adolescents face to receive help from the mental health services. Discussion: This study highlights the importance of culturally sensitive and responsive services. It raises the need for an expanded definition of culture going beyond nationality and ethnic background. Adolescents need flexible services that meet their individual mental health needs. This has implications for practitioners, educators, system organizers and researchers, who should also involve adolescents in planning, implementing and assessing the services. There is a need for a self‐learning system to continuously adapt to user feedback. Conclusion: This study provides insight into adolescents' perspectives on the ideal mental health services. It offers suggestions for ways to improve services to better meet the individual mental health needs of adolescents. Additional research is needed to further develop and implement service changes, as well as to assess their acceptability, effectiveness, cost‐effectiveness and safety. Patient or Public Contribution: This is a study lead by adolescents. Adolescent coresearchers have, with the support of a senior researcher, planned and carried out the study, collected and analysed data and authored the manuscript. [ABSTRACT FROM AUTHOR]

Background: Diffuse hemispheric glioma H3 G34-mutant (G34-DHG) is a new type of pediatric-type diffuse high-grade glioma in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The current treatment for G34-DHG involves a combination of surgery and conventional radiotherapy or chemotherapy; however, the therapeutic efficacy of this approach is not satisfactory. In recent years, molecular targeted therapy and immunotherapy have achieved significant benefits in a variety of tumors. In-depth understanding of molecular changes and immune infiltration in G34-DHGs will help to establish personalized tumor treatment strategies. Here, we report the clinicopathological, molecular and immune infiltration characteristics of G34-DHG cases from our center along with cases from the HERBY Trial and the Chinese Glioma Genome Atlas database (CGGA).Methods: Hematoxylin-eosin (HE) and immunohistochemistry (IHC) staining were used to present the clinicopathological characteristics of 10 Chinese G34-DHG patients treated at our institution. To address the molecular characteristics of G34-DHG, we performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analyses of 5 patients from our center and 3 Chinese patients from the Chinese Glioma Genome Atlas (CGGA) database. Additionally, 7 European G34-DHG patients from the HERBY Trail were also subjected to analyses, with 7 cases of WES data and 2 cases of RNA-seq data. Six G34-DHG patients from another organization were used as external validation.Results: WES showed a high frequency of PDGFRA mutation in G34-DHGs (12/15). We further identified frequent mutations in MUC family genes in G34-DHGs, including MUC16 (8/15) and MUC17 (8/15). Although no statistical difference was found, PDGFRA mutation tended to be an indicator for worse prognosis whereas MUC16/MUC17 mutation indicated a favorable prognosis in G34-DHGs. RNA sequencing results revealed that most G34-DHG are considered to be immune cold tumors. However, one patient in our cohort with MUC16 mutation showed significant immune infiltration, and the total overall survival of this patient reached 75 months.Conclusions: Our results demonstrate that G34-DHG is a new high-grade glioma with high frequency of PDGFRA and MUC gene family mutations. PDGFRA may serve as an indicator of poor prognosis and an effective therapeutic target. Moreover, MUC16 tends to be a favorable prognostic factor and indicates high immune infiltration in certain patients, and these findings may provide a new direction for targeted therapy and immunotherapy of patients with G34-DHGs. [ABSTRACT FROM AUTHOR]

Objective: To develop a model for identifying clinic performance at fulfilling next-day and walk-in requests after adjusting for patient demographics and risk.Data Source: Using Department of Veterans Affairs (VA) administrative data from 160 VA primary care clinics from 2014 to 2017.Study Design: Using a retrospective cohort design, we applied Bayesian hierarchical regression models to predict provision of timely care, with clinic-level random intercept and slope while adjusting for patient demographics and risk status. Timely care was defined as the provision of an appointment within 48 hours of any patient requesting the clinic's next available appointment or walking in to receive care.Data Collection/extraction Methods: We extracted 1 841 210 timely care requests from 613 263 patients.Principal Findings: Across 160 primary care clinics, requests for timely care were fulfilled 86 percent of the time (range 83 percent-88 percent). Our model of timely care fit the data well, with a Bayesian R2 of .8. Over the four years of observation, we identified 25 clinics (16 percent) that were either struggling or excelling at providing timely care.Conclusion: Statistical models of timely care allow for identification of clinics in need of improvement after adjusting for patient demographics and risk status. VA primary care clinics fulfilled 86 percent of timely care requests. [ABSTRACT FROM AUTHOR]

MUC4 is a large, heavily glycosylated transmembrane mucin, that is implicated in the pathogenesis of various types of cancers. To date, no extensive study has been done to check the expression and functional significance of MUC4 in different types of gastric adenocarcinomas. Here, we report the expression profile of MUC4 in gastric adenocarcinomas and its function in poorly differentiated gastric non-signet ring cell carcinoma (non-SRCC) type cells. Immunohistochemical analysis using tissue microarray (TMA) showed a significant difference in MUC4 expression between normal adjacent (n = 45) and gastric adenocarcinoma (n = 83; P < 0.001). MUC4 expression was not associated with tumour type, stage or with the degree of differentiation. To gain further insight into the significance of MUC4 expression in gastric non-SRCC cells, MUC4 was ectopically expressed in AGS, a poorly differentiated gastric non-signet ring cell line. The MUC4 overexpressing cells (AGS-MUC4) showed a significant increase (P < 0.005) in cell motility and a decrease in cellular aggregation as compared with the vector-transfected cells. Furthermore, in vivo tumorigenicity analysis revealed that animals transplanted with the MUC4 overexpressing cells (AGS-MUC4) had a greater incidence of tumours (83%) in comparison to empty vector control (17%). In addition, the expression of MUC4 resulted in enhanced expression of total cellular ErbB2 and phosphorylated ErbB2. In conclusion, our results showed that MUC4 is overexpressed in gastric adenocarcinoma tissues, and that it has a role in promoting aggressive properties in poorly differentiated gastric non-SRCC cells through the activation of the ErbB2 oncoprotein. [ABSTRACT FROM AUTHOR]

The mucin MUC4 is a high molecular weight transmembrane glycoprotein. It consists of a mucin-type subunit (MUC4alpha) and a transmembrane growth factor-like subunit (MUC4beta). The mucin MUC4 is overexpressed in many epithelial malignancies including ovarian cancer, suggesting a possible role in the pathogenesis of these cancers. In this study, we investigated the functional role of MUC4 in the human ovarian cancer cell line SKOV3. The mucin MUC4 was ectopically expressed by stable transfection, and its expression was examined by western blot and confocal microscopy analyses. The in vitro studies demonstrated an enhanced motility of MUC4-expressing SKOV3 cells compared with the vector-transfected cells. The mucin MUC4 expression was associated with apparent changes in actin organisation, leading to the formation of microspike, lammelopodia and filopodia-like cellular projections. An enhanced protein expression and activation of HER2, a receptor tyrosine kinase, was also seen, although no significant change was observed in HER-2 transcript levels in the MUC4-transfected SKOV3 cells. Reciprocal co-immunoprecipitation revealed an interaction of MUC4 with HER2. Further, the MUC4-overexpressing SKOV3 cells exhibited an increase in the phosphorylation of focal adhesion kinase (FAK), Akt and ERK, downstream effectors of HER2. Taken together, our findings demonstrate that MUC4 plays a role in ovarian cancer cell motility, in part, by altering actin arrangement and potentiating HER2 downstream signalling in these cells. [ABSTRACT FROM AUTHOR]

Background: Children with emotional and behavioural disorders should be able to count on receiving care that meets their needs and is based on the best scientific evidence available, however, many do not receive these services. Implementation of evidence-based practice (EBP) relies, in part, on the research utilization practices of mental health care providers. This study reports on a survey of research utilization practices among 80 children's mental health (CMH) service provider organizations in Ontario, Canada. Methods: A web-based survey was distributed to 80 CMH service provider organizations, to which 51 executive directors and 483 children's mental health practitioners responded. Research utilization was assessed using questions with Likert-type responses based on the Canadian Health Services Research Foundation's Four-A's approach: access, assess, adapt, apply. Results: There was general agreement among executive directors and practitioners regarding the capacity of their organizations to use -- access, assess, adapt, and apply -- research evidence. Overall, both groups rated their organizations as using research information 'somewhat well.' The low response rate to the practitioner survey should be noted. Conclusion: These findings provide a useful benchmark from which changes in reported research utilization in the Ontario CMH sector can be tracked over time, as a function of EBP training and implementation initiatives, for instance. The need to improve access to research evidence should be addressed because it relates to the eventual implementation and uptake of evidence-based practices. Communities of practice are recommended as a strategy that would enable practitioners to build capacity in their adaptation and application of research evidence. [ABSTRACT FROM AUTHOR]

Several lines of evidence, including familial aggregation, suggest that allelic variation contributes to risk of diabetic nephropathy. To assess the evidence for specific susceptibility genes, we used the transmission/disequilibrium test (TDT) to analyze 115 candidate genes for linkage and association with diabetic nephropathy. A comprehensive survey of this sort has not been undertaken before. Single nucleotide polymorphisms and simple tandem repeat polymorphisms located within 10 kb of the candidate genes were genotyped in a total of 72 type 1 diabetic families of European descent. All families had at least one offspring with diabetes and end-stage renal disease or proteinuria. As a consequence of the large number of statistical tests and modest P values, findings for some genes may be false-positives. Furthermore, the small sample size resulted in limited power, so the effects of some tested genes may not be detectable, even if they contribute to susceptibility. Nevertheless, nominally significant TDT results (P < 0.05) were obtained with polymorphisms in 20 genes, including 12 that have not been studied previously: aquaporin 1; B-cell leukemia/lymphoma 2 (bcl-2) proto-oncogene; catalase; glutathione peroxidase 1; IGF1; laminin alpha 4; laminin, gamma 1; SMAD, mothers against DPP homolog 3; transforming growth factor, beta receptor II; transforming growth factor, beta receptor III; tissue inhibitor of metalloproteinase 3; and upstream transcription factor 1. In addition, our results provide modest support for a number of candidate genes previously studied by others. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate whether diabetic patients carrying the Arg(972) insulin receptor substrate-1 (IRS-1) variant are at increased risk for secondary failure to sulfonylurea.Research Design and Methods: A total of 477 unrelated Caucasian type 2 diabetic patients were recruited according to the following criteria: onset of diabetes after age 35 years, absence of ketonuria at diagnosis, and anti-GAD(-) antibody. Type 2 diabetes was diagnosed according to the American Diabetes Association criteria. Patients with secondary sulfonylurea failure were defined as those requiring insulin due to uncontrolled hyperglycemia (fasting plasma glucose >300 mg/dl) despite sulfonylurea-metformin combined therapy, appropriate diet, and absence of any conditions causing hyperglycemia.Results: Of the total patients, 53 (11.1%) were heterozygous for the Arg(972) IRS-1 variant, 1 (0.2%) was homozygous, and the remainder (88.7%) were homozygous for the wild-type allele. The genotype frequency of the Arg(972) IRS-1 variant was 8.7% among diabetic patients well controlled with oral therapy and 16.7% among patients with secondary failure to sulfonylurea (odds ratio 2.1 [95% CI 1.18-3.70], P = 0.01). Adjustment for age, sex, BMI, metabolic control, age at diagnosis, duration of diabetes, and Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma2 gene in a logistic regression analysis with secondary failure to sulfonylurea as a dependent variable did not change this association (2.0 [1.38-3.86], P = 0.038).Conclusions: These data demonstrate that the Arg(972) IRS-1 variant is associated with increased risk for secondary failure to sulfonylurea, thus representing a potential example of pharmacogenetics in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Apoptosis and necroptosis are major forms of regulated cell death (10). Necroptosis involves in part molecules also found to regulate apoptosis but depends on the formation of the necrosome, consisting [...], Metastasis is the leading cause of cancer-related death in humans. It is a complex multistep process during which individual tumour cells spread primarily through the circulatory system to colonize distant organs (1-3). Once in the circulation, tumour cells remain vulnerable, and their metastatic potential largely depends on a rapid and efficient way to escape from the blood stream by passing the endothelial barrier (4-9). Evidence has been provided that tumour cell extravasation resembles leukocyte transendothelial migration (7-9). However, it remains unclear how tumour cells interact with endothelial cells during extravasation and how these processes are regulated on a molecular level. Here we show that human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonineprotein kinase 1 (RIPKl)-inhibitor necrostatin-1 or endothelial-cell-specific deletion of RIPK3 reduced tumour-cell-induced endothelial necroptosis, tumour cell extravasation and metastasis. In contrast, pharmacological caspase inhibition or endothelial-cell-specific loss of caspase-8 promoted these processes. We furthermore show in vitro and in vivo that tumour-cell-induced endothelial necroptosis leading to extravasation and metastasis requires amyloid precursor protein expressed by tumour cells and its receptor, death receptor 6 (DR6), on endothelial cells as the primary mediators of these effects. Our data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies.

Rates of alcohol use and alcohol use disorder (AUD) vary with geographic location. Research on risks for AUD associated with living in a rural versus urban setting is complicated by [...]

Alcohol use and misuse account for 3.3 million deaths every year, or 6 percent of all deaths worldwide. The harmful effects of alcohol misuse are far reaching and range from [...]

In addition to increasing beverage taxes or prices as a means to reduce alcohol accessibility, policymakers also may limit alcohol availability through laws and regulations that (1) proscribe sales to [...]

It has been widely recognized that an epidemiological study limited to individual risk factors will not be adequate to address the current public health challenges of human immunodeficiency virus (HIV)/acquired [...]

Hypertensive disease can lead to cardiac hypertrophy and heart failure and is a major cause of death in developed countries. The heart failure that follows prolonged hypertension is characterized by [...], Cardiac hypertrophy and heart failure caused by high blood pressure were studied in single myocytes taken from hypertensive rats (Dahl SS/Jr) and SH-HF rats in heart failure. Confocal microscopy and patch-clamp methods were used to examine excitation-contraction (EC) coupling, and the relation between the plasma membrane calcium current ([I.sub.Ca]) and evoked calcium release from the sarcoplasmic reticulum (SR), which was visualized as 'calcium sparks.' The ability of [I.sub.Ca] to trigger calcium release from the SR in both hypertrophied and failing hearts was reduced. Because [I.sub.Ca] density and SR calcium-release channels were normal, the defect appears to reside in a change in the relation between SR calcium-release channels and sarcolemmal calcium channels. Β-adrenergic stimulation largely overcame the defect in hypertrophic but not failing heart cells. Thus, the same defect in EC coupling that develops during hypertrophy may contribute to heart failure when compensatory mechanisms fail.

1. Introduction Peroxisome proliferator-activated receptor gamma (PPARG) gene is a member of nuclear hormone receptor superfamily, and it regulates the transcription of several genes involved in glucose metabolism, adipocyte differentiation, [...], Peroxisome proliferator-activated receptor gamma polymorphisms have been widely associated with type 2 diabetes, although their role in the pathogenesis of vascular complications is not yet demonstrated. In this study, a cohort of 211 type 2 diabetes, 205 obese, and 254 control individuals was genotyped for Pro12Ala, C1431T, C-2821T polymorphisms, and for a newly identified polymorphism (A-2819G). The above-mentioned polymorphisms were analyzed by gene-specific PCR and direct sequencing of all samples. A significant difference was found for -2819G frequency when patients with type 2 diabetes--particularly diabetic women with the proliferative retinopathy--were compared with healthy control individuals. In conclusion, we identified a novel polymorphism, A-2819G, in PPARG gene, and we found it to be associated with type 2 diabetes and proliferative retinopathy in diabetic females. In the analyzed population, this variant represents a genetic risk factor for developing the diabetic retinopathy, whereas Pro12Ala and C1431T do not. Copyright [C] 2009 Valerio Costa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How do you get a perfect sphere to acquire a front and back, right-hand and left-hand sides? Such is the challenge addressed during oogenesis, when the molecular signals that initiate [...]