Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples

Toward High-Precision Measures of Large-Scale Structure

I review some results of estimation of the power spectrum of density fluctuations from galaxy redshift surveys and discuss advances that may be possible with the Sloan Digital Sky Survey. I then examine the realities of power spectrum estimation in the presence of Galactic extinction, photometric errors, galaxy evolution, clustering evolution, and uncertainty about the background cosmology.Comment: 24 pages, including 11 postscript figures. Uses crckapb.sty (included in submission). To appear in ``Ringberg Workshop on Large-Scale Structure,'' ed D. Hamilton (Kluwer, Amsterdam), p. 39

Skin cancer screening participation and impact on melanoma incidence in Germany – an observational study on incidence trends in regions with and without population-based screening

Background: The SCREEN (Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany) project involved population-wide skin cancer screening with whole-body examination by general physicians and dermatologists. It was conducted in the German state of Schleswig-Holstein (July 2003–June 2004), but not in the German state of Saarland. Methods: The population-based registries of Schleswig-Holstein and Saarland provided data on melanoma incidence before, during, and after SCREEN to assess the association of skin cancer screening with incidence. Results: Approximately 19% of the Schleswig-Holstein population participated in SCREEN (women: 27%, men: 10%). A total of 52% of all melanomas diagnosed during SCREEN in Schleswig-Holstein were detected as part of the project. Melanoma incidence increased during SCREEN (invasive melanoma in women: +8.9 per 100 000 (95% confidence intervals (CI): 6.1; 11.7); men: +4.0 per 100 000 (95% CI: 1.6; 6.4)) and decreased afterwards (women: −10.6 per 100 000 (95% CI: −13.3; −7.9); men: −4.1 per 100 000 (95% CI: −6.5; −1.7)). Similar changes were not observed in Saarland that had no such project. The differences between the two states were greatest among women, the group with the greater SCREEN participation. Conclusion: The SCREEN project had a substantial impact on melanoma incidence. This is consistent with the impact of effective screening for other cancers

Surprising dissimilarities in a newly formed pair of 'identical twin' stars

The mass and chemical composition of a star are the primary determinants of its basic physical properties--radius, temperature, luminosity--and how those properties evolve with time. Thus, two stars born at the same time, from the same natal material, and with the same mass are 'identical twins,' and as such might be expected to possess identical physical attributes. We have discovered in the Orion Nebula a pair of stellar twins in a newborn binary star system. Each star in the binary has a mass of 0.41 +/- 0.01 solar masses, identical to within 2 percent. Here we report that these twin stars have surface temperatures that differ by ~300K (~10%), and luminosities that differ by ~50%, both at high confidence level. Preliminary results indicate that the stars' radii also differ, by 5-10%. These surprising dissimilarities suggest that one of the twins may have been delayed by several hundred thousand years in its formation relative to its sibling. Such a delay could only have been detected in a very young, definitively equal-mass binary system3 such as that reported here. Our findings reveal cosmic limits on the age synchronisation of young binary stars, often used as tests for the age calibrations of star-formation models.Comment: Published in Nature, 19 June 200

Towards agreement on best practice for publishing raw clinical trial data

Many research-funding agencies now require open access to the results of research they have funded, and some also require that researchers make available the raw data generated from that research. Similarly, the journal Trials aims to address inadequate reporting in randomised controlled trials, and in order to fulfil this objective, the journal is working with the scientific and publishing communities to try to establish best practice for publishing raw data from clinical trials in peer-reviewed biomedical journals. Common issues encountered when considering raw data for publication include patient privacy – unless explicit consent for publication is obtained – and ownership, but agreed-upon policies for tackling these concerns do not appear to be addressed in the guidance or mandates currently established. Potential next steps for journal editors and publishers, ethics committees, research-funding agencies, and researchers are proposed, and alternatives to journal publication, such as restricted access repositories, are outlined

Can an hour or two of sun protection education keep the sunburn away? Evaluation of the Environmental Protection Agency's Sunwise School Program

BACKGROUND: Melanoma incidence is rising at a rate faster than any other preventable cancer in the United States. Childhood exposure to ultraviolet (UV) light increases risk for skin cancer as an adult, thus starting positive sun protection habits early may be key to reducing the incidence of this disease. METHODS: The Environmental Protection Agency's SunWise School Program, a national environmental and health education program for sun safety of children in primary and secondary schools (grades K-8), was evaluated with surveys administered to participating students and faculty. RESULTS: Pretests (n = 5,625) and posttests (n = 5,028) were completed by students in 102 schools in 42 states. Significant improvement was noted for the three knowledge variables. Intentions to play in the shade increased from 68% to 75%(p < 0.001) with more modest changes in intentions to use sunscreen. Attitudes regarding healthiness of a tan also decreased significantly. CONCLUSIONS: Brief, standardized sun protection education can be efficiently interwoven into existing school curricula, and result in improvements in knowledge and positive intentions for sun protection

Coherently aligned nanoparticles within a biogenic single crystal: A biological prestressing strategy

In contrast to synthetic materials, materials produced by organisms are formed in ambient conditions and with a limited selection of elements. Nevertheless, living organisms reveal elegant strategies for achieving specific functions, ranging from skeletal support to mastication, from sensors and defensive tools to optical function. Using state-of-the-art characterization techniques, we present a biostrategy for strengthening and toughening the otherwise brittle calcite optical lenses found in the brittlestar Ophiocoma wendtii This intriguing process uses coherent nanoprecipitates to induce compressive stresses on the host matrix, functionally resembling the Guinier-Preston zones known in classical metallurgy. We believe that these calcitic nanoparticles, being rich in magnesium, segregate during or just after transformation from amorphous to crystalline phase, similarly to segregation behavior from a supersaturated quenched alloy

Stress from Uncertainty from Graduation to Retirement—A Population-Based Study of Swiss Physicians

BACKGROUND: Uncertainty shapes many decisions made by physicians everyday. Uncertainty and physicians’ inability to handle it may result in substandard care and unexplained variations in patterns of care. OBJECTIVE: To describe socio-demographic and professional characteristics of reactions to uncertainty among physicians from all specialties, including physicians in training. DESIGN: Cross-sectional postal survey. PARTICIPANT: All physicians practicing in Geneva, Switzerland (n = 1,994). MEASUREMENT: Reaction to medical care uncertainty was measured with the Anxiety Due to Uncertainty and Concern About Bad Outcomes scales. The questionnaire also included items about professional characteristics and work-related satisfaction scales. RESULTS: After the first mailing and two reminders, 1,184 physicians responded to the survey. In univariate analysis, women, junior physicians, surgical specialists, generalist physicians, and physicians with lower workloads had higher scores in both scales. In multivariate models, sex, medical specialty, and workload remained significantly associated with both scales, whereas clinical experience remained associated only with concern about bad outcomes. Higher levels of anxiety due to uncertainty were associated with lower scores of work-related satisfaction, while higher levels of concern about bad outcomes were associated with lower satisfaction scores for patient care, personal rewards, professional relations, and general satisfaction, but not for work-related burden or satisfaction with income-prestige. The negative effect of anxiety due to uncertainty on work-related satisfaction was more important for physicians in training. CONCLUSION: Physicians’ reactions to uncertainty in medical care were associated with several dimensions of work-related satisfaction. Physicians in training experienced the greatest impact of anxiety due to uncertainty on their work-related satisfaction. Incorporating strategies to deal with uncertainty into residency training may be useful