Population-based study of the association of variants in mismatch repair genes with prostate cancer risk and outcomes.

BACKGROUND: Mismatch repair (MMR) gene activity may be associated with prostate cancer risk and outcomes. This study evaluated whether single nucleotide polymorphisms (SNP) in key MMR genes are related to prostate cancer outcomes. METHODS: Data from two population-based case-control studies of prostate cancer among Caucasian and African-American men residing in King County, Washington were combined for this analysis. Cases (n = 1,458) were diagnosed with prostate cancer in 1993 to 1996 or 2002 to 2005 and were identified through the Seattle-Puget Sound Surveillance Epidemiology and End Results cancer registry. Controls (n = 1,351) were age-matched to cases and were identified through random digit dialing. Logistic regression was used to assess the relationship between haplotype-tagging SNPs and prostate cancer risk and disease aggressiveness. Cox proportional hazards regression was used to assess the relationship between SNPs and prostate cancer recurrence and prostate cancer-specific death. RESULTS: Nineteen SNPs were evaluated in the key MMR genes: five in MLH1, 10 in MSH2, and 4 in PMS2. Among Caucasian men, one SNP in MLH1 (rs9852810) was associated with overall prostate cancer risk [odds ratio, 1.21; 95% confidence interval (95% CI), 1.02, 1.44; P = 0.03], more aggressive prostate cancer (odds ratio, 1.49; 95% CI, 1.15, 1.91; P < 0.01), and prostate cancer recurrence (hazard ratio, 1.83; 95% CI, 1.18, 2.86; P < 0.01), but not prostate cancer-specific mortality. A nonsynonymous coding SNP in MLH1, rs1799977 (I219V), was also found to be associated with more aggressive disease. These results did not remain significant after adjusting for multiple comparisons. CONCLUSION: This population-based case-control study provides evidence for a possible association with a gene variant in MLH1 in relation to the risk of overall prostate cancer, more aggressive disease, and prostate cancer recurrence, which warrants replication

Analysis of recently identified prostate cancer susceptibility loci in a population-based study: Associations with family history and clinical features.

Purpose: Two recent genome-wide association studies have highlighted several SNPs purported to be associated with prostate cancer risk. We investigated the significance of these SNPs in a population-based study of Caucasian men, testing the effects of each SNP in relation to family history of prostate cancer and clinicopathological features of disease. Experimental Design: We genotyped 13 SNPs in 1,308 prostate cancer patients and 1,267 unaffected controls frequency matched to cases by five-year age groups. The association of each SNP with disease risk and stratified by family history of prostate cancer and clinicopathological features of disease was calculated using logistic and polytomous regression. Results: These results confirm the importance of multiple previously reported SNPs in relation to prostate cancer susceptibility; 11 of the 13 SNPs were significantly associated with risk of developing prostate cancer. However, none of the SNP associations were of comparable magnitude to that associated with having a first-degree family history of the disease. Risk estimates associated with SNPs rs4242382 and rs2735839 varied by family history, while risk estimates for rs10993994 and rs5945619 varied by Gleason score. Conclusions: Our results confirm that several recently identified SNPs are associated with prostate cancer risk; however the variant alleles only confer a low to moderate relative risk of disease and are generally not associated with more aggressive disease features

Association of FGFR4 genetic polymorphisms with prostate cancer risk and prognosis

The fibroblast growth factor receptor 4 (FGFR4) is thought to be involved in many critical cellular processes and has been associated with prostate cancer risk. Four single nucleotide polymorphisms within or near FGFR4 were analysed in a population-based study of 1458 prostate cancer patients and 1352 age-matched controls. We found no evidence to suggest that any of the FGFR4 SNP genotypes were associated with prostate cancer risk or with disease aggressiveness, Gleason score or stage. A weak association was seen between rs351855 and prostate cancer-specific mortality. Subset analysis of cases that had undergone radical prostatectomy revealed an association between rs351855 and prostate cancer risk. While our results confirm an association between FGFR4 and prostate cancer risk in radical prostatectomy cases, they suggest that the role of FGFR4 in disease risk and outcomes at a population-based level appears to be minor

Influence of Large-scale Interplanetary Structures on the Propagation of Solar Energetic Particles: The Multispacecraft Event on 2021 October 9

An intense solar energetic particle (SEP) event was observed on 2021 October 9 by multiple spacecraft distributed near the ecliptic plane at heliocentric radial distances R ≲ 1 au and within a narrow range of heliolongitudes. A stream interaction region (SIR), sequentially observed by Parker Solar Probe (PSP) at R = 0.76 au and 48° east from Earth (ϕ = E48°), STEREO-A (at R = 0.96 au, ϕ = E39°), Solar Orbiter (SolO; at R = 0.68 au, ϕ = E15°), BepiColombo (at R = 0.33 au, ϕ = W02°), and near-Earth spacecraft, regulated the observed intensity-time profiles and the anisotropic character of the SEP event. PSP, STEREO-A, and SolO detected strong anisotropies at the onset of the SEP event, which resulted from the fact that PSP and STEREO-A were in the declining-speed region of the solar wind stream responsible for the SIR and from the passage of a steady magnetic field structure by SolO during the onset of the event. By contrast, the intensity-time profiles observed near Earth displayed a delayed onset at proton energies ≳13 MeV and an accumulation of ≲5 MeV protons between the SIR and the shock driven by the parent coronal mass ejection (CME). Even though BepiColombo, STEREO-A, and SolO were nominally connected to the same region of the Sun, the intensity-time profiles at BepiColombo resemble those observed near Earth, with the bulk of low-energy ions also confined between the SIR and the CME-driven shock. This event exemplifies the impact that intervening large-scale interplanetary structures, such as corotating SIRs, have in shaping the properties of SEP events

Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P &lt; 0.0001), lower modularity (P &lt; 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions

Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer

Background: The presence of the TMPRSS2-ERG fusion gene in prostate tumors has recently been associated with an aggressive phenotype, as well as recurrence and death from prostate cancer. These associations suggest the hypothesis that the gene fusion may be used as a prognostic indicator for prostate cancer. Methods: In this study, fluorescent in situ hybridization (FISH) assays were used to assess TMPRSS2-ERG fusion status in a group of 214 prostate cancer cases from two population-based studies. The FISH assays were designed to detect both fusion type (deletion vs. translocation) and the number of fusion copies (single vs. multiple). Genotyping of four ERG and one TMPRSS2 SNPs using germline DNA was also performed in a sample of the cases (n = 127). Results: Of the 214 tumors scored for the TMPRSS2-ERG fusion, 64.5% were negative and 35.5% were positive for the fusion. Cases with the TMPRSS2-ERG fusion did not exhibit reduced prostate cancer survival (HR = 0.92, 95% CI = 0.22-3.93), nor was there a significant difference in causespecific survival when stratifying by translocation or deletion (HR = 0.84, 95% CI = 0.23-3.12) or by the number of retained fusion copies (HR = 1.22, 95% CI = .45-3.34). However, evidence for reduced prostate cancer-specific survival was apparent in those cases whose tumor had multiple copies of the fusion. The variant T allele of the TMPRSS2 SNP, rs12329760, was positively associated with TMPRSS2-ERG fusion by translocation (p = 0.05) and with multiple copies of the gene fusion (p = 0.03). Conclusion: If replicated, the results presented here may provide insight into the mechanism by which the TMPRSS2-ERG gene fusion arises and also contribute to diagnostic evaluations for determining the subset of men who will go on to develop metastatic prostate cancer.This work was supported by NIH grants RO1 CA56678, RO1 CA114524, and P50 CA97186; additional support was provided by the Fred Hutchinson Cancer Research Center and the Intramural Program of the National Human Genome Research Institute

Timing of decompression in patients with acute spinal cord injury: a systematic review

Study Design: Systematic review. Objective: To conduct a systematic review and synthesis of the literature to assess the comparative effectiveness, safety, and cost-effectiveness of early (24 hours) in adults with acute spinal cord injury (SCI). Methods: A systematic search was conducted of Medline, EMBASE, the Cochrane Collaboration Library, and Google Scholar to identify studies published through November 6, 2014. Studies published in any language, in humans, and with an abstract were considered for inclusion. Included studies were critically appraised and the overall strength of evidence was determined using methods proposed by the Grading of Recommendation Assessment, Development and Evaluation working group. Results: The search yielded 449 potentially relevant citations. Sixteen additional primary studies were identified through other sources. Six studies met inclusion criteria. All but 2 studies were considered to have moderately high risk of bias. Across studies and injury levels, the impact of early surgical decompression (<= 24 hours) on clinically important improvement in neurological status was variable. Isolated studies reported statistically significant and clinically important improvements at 6 months (cervical injury, low strength of evidence) and following discharge from inpatient rehabilitation (all levels, very low strength of evidence) but not at other time points; another study observed a statistically significant 6 point improvement in ASIA Impairment Scale (AIS) among patients with AIS B, C, or D, but not for those with AIS A (very low strength of evidence). In one study of acute central cord syndrome without instability, a clinically and statistically meaningful improvement in total motor scores was reported at 6 and 12 months in patients treated early (versus late). There were, however, no significant differences in AIS improvement between early and late surgical groups at 6- or 12-months (very low strength of evidence). One of 3 studies found a shorter length of hospital stay associated with early surgical decompression. Of 3 studies reporting on safety, no significant differences in rates of complications (including mortality, neurologic deterioration, pneumonia or pressure ulcers) were noted between early and late decompression groups. Conclusions: Results surrounding the efficacy of early versus late decompressive surgery, as well as the quality of evidence available, were variable depending on the level of SCI, timing of follow-up, and specific outcome considered. Existing evidence supports improved neurological recovery among cervical SCI patients undergoing early surgery; however, evidence regarding remaining SCI populations and clinical outcomes was inconsistent

An overview of the first 5 years of the ENIGMA obsessive-compulsive disorder working group: The power of worldwide collaboration

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA

The thalamus and its subnuclei—a gateway to obsessive-compulsive disorder

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T-1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered (https://osf.io/73dvy) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status