The major histocompatibility complex (MHC) is one of the most intensively investigated, genetically diverse regions of the genome. In its extended form, it encodes more than 400 genes critical to ...immunity but is also involved in many other functions. In 2009, three simultaneously published genome-wide association studies (GWAS) reported the first compelling evidence for involvement of the MHC in schizophrenia susceptibility. In this review, we describe the structure and function of the MHC, discuss some of the challenges for genetic analysis of the region, and provide an update on findings from GWAS studies before describing potential approaches to interpreting the role of the locus in schizophrenia etiology. The GWAS literature supports involvement of the MHC locus in schizophrenia susceptibility. Current evidence suggests that the MHC plays a more significant role in schizophrenia susceptibility than in other psychiatric disorders. Because of the substantial diversity at the locus, there are differences in the implicated risk variants between ancestral groups, as there are for many other disorders. This is somewhat different than the pattern emerging at other loci. The association findings presently capture large genomic regions, with at least some evidence to suggest that multiple signals may be involved. Based on notable successes in other disorders, we suggest approaches to refining association signals at the locus. Finally, we discuss that these genetic data may be used to understand how the MHC contributes to the complex etiology of schizophrenia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Concerns remain for a greater risk of incomplete revascularization and reduced survival with off-pump coronary artery bypass grafting (CABG) surgery compared with on-pump surgery particularly in ...patients with left main disease and extensive underlying myocardial ischemia.
This study sought to compare outcomes following off-pump versus on-pump surgery for left main disease by performing a post hoc analysis from the multicenter, randomized EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial.
The EXCEL trial was designed to compare percutaneous coronary intervention with everolimus-eluting stents versus CABG in patients with left main disease. CABG was performed with or without cardiopulmonary bypass (on-pump vs. off-pump surgery) according to the discretion of the operator. The 3-year outcomes in the off-pump and on-pump groups were compared using inverse probability of treatment weighting (IPTW) for treatment effect estimation.
Among 923 CABG patients, 652 and 271 patients underwent on-pump and off-pump surgery, respectively. Despite a similar extent of disease, off-pump surgery was associated with a lower rate of revascularization of the left circumflex coronary artery (84.1% vs. 90.0%; p = 0.01) and right coronary artery (31.1% vs. 40.6%; p = 0.007). After IPTW adjustment for baseline differences, off-pump surgery was associated with a significantly increased risk of 3-year all-cause death (8.8% vs. 4.5%; hazard ratio: 1.94; 95% confidence interval: 1.10 to 3.41; p = 0.02) and a nonsignificant difference in the risk for the composite endpoint of death, myocardial infarction, or stroke (11.8% vs. 9.2%; hazard ratio: 1.28; 95% confidence interval: 0.82 to 2.00; p = 0.28).
Among patients with left main disease treated with CABG in the EXCEL trial, off-pump surgery was associated with a lower rate of revascularization of the coronary arteries supplying the inferolateral wall and an increased risk of 3-year all-cause death compared with on-pump surgery.
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Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis ...that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 × 10(-)(5), corrected P=2.1 × 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To report the patient-reported health-related quality of life (HR-QoL) outcomes for a multicenter randomized trial evaluating the safety and efficacy of 2 different techniques for dose escalation.
A ...total of 357 men with intermediate- and high-risk prostate cancer were stratified by risk group and randomized (1:1) to either a dose-escalated external beam (DE-EBRT) boost (n=177) or a low-dose-rate prostate brachytherapy (LDR-PB) boost (n=180) as part of combined modality therapy. The HR-QoL was assessed using the SF36v2 questionnaire, with additional scales for urinary, bowel, and sexual function. Date of starting androgen deprivation therapy was considered time zero, the median follow-up of 6 years. Scales were scored from 0 to 100; a decline in a mean score ≥10 compared with baseline was considered a clinically significant decline. This was an intent-to-treat analysis.
Mean domain scores at baseline were well balanced between the 2 treatment arms. A clinically significant decline in mean scores in both the arms compared with baseline was noted for role physical (DE-EBRT -11.4 and LDR-PB -15.3) and sexual function scale (DE-EBRT -15.1 and LDR-PB -19.2). There was a significantly larger drop in mean scores in the LDR-PB group compared with the DE-EBRT group for physical function (-15.3 vs -6.9; P=.03), urinary function (-3.6 vs -0.5; P=.04).
At 6 years' follow up, there were no significant differences in mean scores in 9 of 11 scales compared with baseline in both arms. A clinically significant decline in mean scores was noted in both arms for role physical and sexual function scales. There was a statistically significant decline in physical function and urinary function scales in the LDR-PB arm compared with the DE-EBRT arm.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
•Close to 80% of men 4–5 years after LDR prostate brachytherapy will achieve a PSA of 0.2 ng/ml or less.•PSA ≤ 0.2 ng/ml is associated with 97–99% freedom from prostate cancer recurrence at ...10–15 years.•This applies across all risk groups and to LDR brachytherapy alone or combined with ADT and/or EBRT.
To identify a PSA threshold value at an intermediate follow-up time after low dose rate (LDR) prostate brachytherapy associated with cure, defined as long-term (10–15 year) freedom from prostate cancer.
Data from 7 institutions for 14,220 patients with localized prostate cancer treated with LDR brachytherapy, either alone (8552) or with external beam radiotherapy (n = 1175), androgen deprivation (n = 3165), or both (n = 1328), were analyzed. Risk distribution was 42.4% favorable, 49.2% intermediate, and 8.4% high-risk. Patients with clinical failure before 3.5 years were excluded. Kaplan-Meier analysis was used with clinical failure (local, distant, regional or biochemical triggering salvage) as an endpoint for each of four PSA categories: PSA ≤ 0.2, >0.2 to ≤0.5, >0.5 to ≤1.0, and >1.0 ng/mL. PSA levels at 4 years (±6 months) in 8746 patients without clinical failure were correlated with disease status at 10–15 years.
For the 77.1% of patients with 4-year PSA ≤ 0.2, the freedom-from-recurrence (FFR) rates were 98.7% (95% CI 98.3–99.0) at 10 years and 96.1% (95% CI 94.8–97.2) at 15 years. Three independent validation cohorts confirmed 97–99% 10-year FFR rates with 4-year PSA ≤ 0.2. Successive PSA categories were associated with diminished disease-free rates at 10 and 15 years. PSA category was strongly associated with treatment success (p < 0.0005).
Since 98.7% of patients with PSA ≤ 0.2 ng/mL at 4 years after LDR prostate brachytherapy were disease-free beyond 10 years, we suggest adopting this biochemical definition of cure for patients with ≥4 years’ follow-up after LDR brachytherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This paper integrates social norm constructs from different disciplines into an integrated model. Norms exist in the objective social environment in the form of behavioral regularities, patterns of ...sanctioning, and institutionalized practices and rules. They exist subjectively in perceived descriptive norms, perceived injunctive norms, and personal norms. We also distil and delineate three classic theories of why people adhere to norms: internalization, social identity, and rational choice. Additionally, we articulate an emerging theory of how perceived descriptive and injunctive norms function as two distinct navigational devices that guide thoughts and behavior in different ways, which we term “social autopilot” and “social radar.” For each type of norms, we suggest how it may help to understand cultural dynamics at the micro level (the acquisition, variable influence and creative mutation of cultural knowledge) and the macro level (the transmission, diffusion and evolution of cultural practices). Having laid the groundwork for an integrated study of norm—normology, we then introduce the articles of this special issue contributing theoretical refinements and empirical evidence from different methods and levels of analysis. Managerial implications are discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
► We study how cultural metacognition influence creative collaboration in dyads. ► High cultural metacognition in dyads engenders affect-based trust and creativity. ► Affect-based trust mediates ...effects of cultural metacognition on creativity.
We propose that managers adept at thinking about their cultural assumptions (cultural metacognition) are more likely than others to develop affect-based trust in their relationships with people from different cultures, enabling creative collaboration. Study 1, a multi-rater assessment of managerial performance, found that managers higher in metacognitive cultural intelligence (CQ) were rated as more effective in intercultural creative collaboration by managers from other cultures. Study 2, a social network survey, found that managers lower in metacognitive CQ engaged in less sharing of new ideas in their intercultural ties but not intracultural ties. Study 3 required participants to work collaboratively with a non-acquaintance from another culture and found that higher metacognitive CQ engendered greater idea sharing and creative performance, so long as they were allowed a personal conversation prior to the task. The effects of metacognitive CQ in enhancing creative collaboration were mediated by affect-based trust in Studies 2 and 3.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background Goal-directed actions depend on our capacity to integrate the anticipated consequences of an action with the value of those consequences, with the latter derived from direct ...experience or inferred from predictive stimuli. Schizophrenia is associated with poor goal-directed performance, but whether this reflects a deficit in experienced or predicted value or in integrating these values with action-outcome information is unknown, as is the locus of any associated neuropathology. Methods We assessed the contribution of these sources of value to goal-directed actions in people with schizophrenia (SZ) ( n = 18) and healthy adults ( n = 18). Participants learned to use specific actions to liberate snack foods from a vending machine. They also learned about the reward value of the foods, changes in reward value, and the relationship between various predictive stimuli and food delivery. We then evaluated the ability of subjects to use experienced or predicted value to guide goal-directed actions while undergoing functional magnetic resonance imaging. Results Acquisition and sensitivity to experienced changes in outcome value did not differ in SZ and healthy adults. The SZ were, however, deficient in their ability to integrate action-outcome learning with outcome values to guide choice, more so when actions were guided by experienced than by predicted values. These effects were differentially associated with reductions in activity in caudate and limbic structures, respectively. Conclusions This novel assessment of goal-directed learning revealed dysfunction in corticostriatal control associated with a profound deficit in integrating changes in experienced value with the action-outcome association in schizophrenia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The frequency of and relationship between hospital readmissions and outcomes after revascularization for left main coronary artery disease (LMCAD) are unknown.
The purpose of this study was to study ...the incidence, predictors, and clinical impact of readmissions following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for LMCAD.
In the EXCEL (XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, 1,905 patients with LMCAD were randomized to PCI vs CABG. The cumulative incidence of readmissions was analyzed with multivariable Anderson-Gill and joint frailty models to account for recurrent events and the competing risk of death. The impact of readmission on subsequent mortality within 5-year follow-up was determined in a time-adjusted Cox proportional hazards model.
Within 5 years, 1,868 readmissions occurred in 851 of 1,882 (45.2%) hospital survivors (2.2 ± 1.9 per patient with readmissions, range 1-16), approximately one-half for cardiovascular causes and one-half for noncardiovascular causes (927 49.6% and 941 50.4%, respectively). One or more readmissions occurred in 463 of 942 (48.6%) PCI patients vs 388 of 940 (41.8%) CABG patients (P = 0.003). After multivariable adjustment, PCI remained an independent predictor of readmission (adjusted HR: 1.22; 95% CI: 1.10-1.35; P < 0.0001), along with female sex, comorbidities, and the extent of CAD. Readmission was independently associated with subsequent all-cause death, with interaction testing indicating a higher risk after PCI than CABG (adjusted HR: 5.72; 95% CI: 3.42-9.55 vs adjusted HR: 2.72; 95% CI: 1.64-4.88, respectively; Pint = 0.03).
In the EXCEL trial, readmissions during 5-year follow-up after revascularization for LMCAD were common and more frequent after PCI than CABG. Readmissions were associated with an increased risk of all-cause death, more so after PCI than with CABG.
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This article describes a novel system for quantitative and volumetric measurement of tissue elasticity in the prostate using simultaneous multi-frequency tissue excitation. Elasticity is computed by ...using a local frequency estimator to measure the three-dimensional local wavelengths of steady-state shear waves within the prostate gland. The shear wave is created using a mechanical voice coil shaker which transmits simultaneous multi-frequency vibrations transperineally. Radio frequency data is streamed directly from a BK Medical 8848 transrectal ultrasound transducer to an external computer where tissue displacement due to the excitation is measured using a speckle tracking algorithm. Bandpass sampling is used that eliminates the need for an ultra-fast frame rate to track the tissue motion and allows for accurate reconstruction at a sampling frequency that is below the Nyquist rate. A roll motor with computer control is used to rotate the transducer and obtain 3D data. Two commercially available phantoms were used to validate both the accuracy of the elasticity measurements as well as the functional feasibility of using the system for in vivo prostate imaging. The phantom measurements were compared with 3D Magnetic Resonance Elastography (MRE), where a high correlation of 96% was achieved. In addition, the system has been used in two separate clinical studies as a method for cancer identification. Qualitative and quantitative results of 11 patients from these clinical studies are presented here. Furthermore, an AUC of 0.87±0.12 was achieved for malignant vs. benign classification using a binary support vector machine classifier trained with data from the latest clinical study with leave one patient out cross-validation.
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