Mcgeeshore1351

Histological study revealed reduced AMPK activity and major cardiac channels in the heart tissue with K485E mutation. Computational modelling suggests that K485E disrupts the salt bridge connecting the β and γ subunits of AMPK, R302Q/P decreases the binding affinity for ATP, T400N and H401D alter the orientation of H383 and R531 residues, thus altering nucleotide binding, and N488I and L341S lead to structural instability in the Bateman domain, which disrupts the intramolecular regulation. INTERPRETATION Including 4 families with 3 new mutations, we describe a cohort of 12 kindreds with PRKAG2 syndrome with novel pathogenic mechanisms by computational modelling. Severe clinical cardiac phenotypes may be developed, including HF, requiring close follow-up. BACKGROUND Bipolar disorder (BD) is a mental disorder characterized by mood fluctuations between an acute episodic state of either mania or depression and a clinically remitted state. Dysfunction of large-scale intrinsic brain networks has been demonstrated in this disorder, but it remains unknown whether those network alterations are related to different states. METHODS In the present study, we performed a meta-analysis of whole-brain seed-based resting-state functional connectivity (rsFC) studies in BD patients to compare the intrinsic function of brain networks between episodic and remitted states. Thirty-nine seed-based voxel-wise rsFC datasets from thirty publications (1047 BD patients vs 1081 controls) were included in the meta-analysis. Seeds were categorized into networks by their locations within a priori functional networks. Seed-based d mapping analysis of between-state effects identified brain systems in which different states were associated with increased connectivity or decreased connectivity won. FUNDING This study was supported by grants from the National Natural Science Foundation of China (81171488, 81671669 and 81820108018) and by a Sichuan Provincial Youth Grant (2017JQ0001). BACKGROUND Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer, which is characterized by an immunosuppressive microenvironment. VcMMAE chemical structure Yet, the spatial distribution of the immune infiltrate and how it changes during IPMN progression is just beginning to be understood. METHODS We obtained tissue samples from patients who underwent pancreatic surgery for IPMN, and performed comprehensive immunohistochemical analyses to investigate the clinical significance, composition and spatial organization of the immune microenvironment during progression of IPMNs. Survival analysis of pancreatic cancer patients was stratified by tumour infiltrating immune cell subtypes. FINDINGS The immune microenvironment evolves from a diverse T cell mixture, comprising CD8+ T cells, Th/c1 and Th/c2 as major players combined with Th9, Th/c17, Th22, and Treg cells in low-grade IPMN, to a Treg dominated immunosuppressive state in invasive pancreatic cancer. Organized lymphoid clusters formed in IPMN surrounding stroma and accumulated immunosuppressive cell types during tumour progression. Survival of pancreatic cancer patients correlated with Th2 signatures in the tumour microenvironment. INTERPRETATION The major change with regards to T cell composition during IPMN progression occurs at the step of tissue invasion, indicating that malignant transformation only occurs when tumour immune surveillance is overcome. This suggests that novel immunotherapies that would boost spontaneous antitumor immunity at premalignant states could prevent pancreatic cancer development. FUNDING The present work was supported by German Cancer Aid grants (70,112,720 and 70,113,167) to S. R., and the Olympia Morata Programme of the Medical Faculty of Heidelberg University to S. R. BACKGROUND Disparities in decision-making are a recognized concern within child protection systems and imply that marginalized groups are being treated unequally compared to majoritized groups. Previous studies reported that both ethnicity and the gender of the parent that maltreated the child seem associated with an increased likelihood that child protection agencies provide services after an investigation or that children are placed out of their homes. OBJECTIVE We investigated whether migration background and the gender of the parent who maltreated the child seem associated with the decision whether a case was opened for continuing services. In addition, we inspected whether the intersections between migration background and parent gender were correlated with disparities in decision-making. PARTICIPANTS AND SETTING Our multinational sample consisted of 1189 cases that were involved with child protection agencies in England, the Netherlands, and Germany. METHODS We systematically coded and analyzed child protection case files. We conducted logistic regression analysis to investigate for disparities in decision-making. RESULTS The intersectional analysis showed that maltreatment committed by mothers (OR = 2.25, p =  .001) and migrant fathers (OR = 2.21, p =  .030) was associated with an increased likelihood to provide ongoing services. However, country specific analyses showed that these effects were most pertinent in the English sample. CONCLUSIONS These findings suggest a need to address migration background and gender disparities in child protection practice. Future research could investigate whether other contextual factors (e.g. characteristics of the professional and agency) seem associated with disparities in decision-making. BACKGROUND Child sexual abuse (CSA) can impact survivor's sexuality, notably regarding sexual self-concept, a key component of sexual well-being. Yet, sexual self-concept has been understudied among CSA survivors and gender differences have been sparsely investigated. OBJECTIVE The current study aimed to identify CSA survivors' distinct profiles according to their sexual self-concept, and compare these profiles based on factors such as CSA characteristics, gender, current age, sexual functioning and adult sexual assault (ASA). PARTICIPANTS AND SETTING A total of 176 CSA survivors (60 % women, 40 % men), recruited through community organizations for CSA victims and social media publications, completed an online survey. METHODS Hierarchical cluster analysis was performed using the Sexuality Scale (Snell & Papini, 1989). Chi-square and ANOVA tests were used to compare the groups on external variables. RESULTS Cluster analysis revealed the best overall fit for a three-group model. The Confident and non-preoccupied profile (48 %) is characterized by a moderate score on sexual esteem and the lowest scores of sexual preoccupation and depression.