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

Protocol for the development of guidance for stakeholder engagement in health and healthcare guideline development and implementation

Stakeholder engagement has become widely accepted as a necessary component of guideline development and implementation. While frameworks for developing guidelines express the need for those potentially affected by guideline recommendations to be involved in their development, there is a lack of consensus on how this should be done in practice. Further, there is a lack of guidance on how to equitably and meaningfully engage multiple stakeholders. We aim to develop guidance for the meaningful and equitable engagement of multiple stakeholders in guideline development and implementation. METHODS: This will be a multi-stage project. The first stage is to conduct a series of four systematic reviews. These will (1) describe existing guidance and methods for stakeholder engagement in guideline development and implementation, (2) characterize barriers and facilitators to stakeholder engagement in guideline development and implementation, (3) explore the impact of stakeholder engagement on guideline development and implementation, and (4) identify issues related to conflicts of interest when engaging multiple stakeholders in guideline development and implementation. DISCUSSION: We will collaborate with our multiple and diverse stakeholders to develop guidance for multi-stakeholder engagement in guideline development and implementation. We will use the results of the systematic reviews to develop a candidate list of draft guidance recommendations and will seek broad feedback on the draft guidance via an online survey of guideline developers and external stakeholders. An invited group of representatives from all stakeholder groups will discuss the results of the survey at a consensus meeting which will inform the development of the final guidance papers. Our overall goal is to improve the development of guidelines through meaningful and equitable multi-stakeholder engagement, and subsequently to improve health outcomes and reduce inequities in health

Multi-element cylindrical electrostatic lens systems for focusing and controlling charged particles

This paper describes theoretical modelling of electrostatic lenses based on 3, 4 and 5 closely spaced cylindrical electrodes, respectively. In each case, modelling is carried out numerically using commercial packages SIMION and LENSYS, and a variety of performance parameters are obtained. These include the magnification, the 3rd order spherical and chromatic aberration coefficients. Special cases such as zoom lens (i.e., lenses whose magnification may be changed without losing focus) are considered. Results are obtained as a function of the ratios of the electrode lengths and gaps, and as a function of ratios of the controlling voltages. As a result, it is shown that how a multi-element lens system can be operated with the whole focal properties in a useful mode for using in experimental studies.Comment: 20 pages, 15 figure

Chronic non-specific low back pain - sub-groups or a single mechanism?

Copyright 2008 Wand and O'Connell; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain is a substantial health problem and has subsequently attracted a considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions for chronic non-specific low back pain indicate limited effectiveness for most commonly applied interventions and approaches. Discussion: Many clinicians challenge the results of clinical trials as they feel that this lack of effectiveness is at odds with their clinical experience of managing patients with back pain. A common explanation for this discrepancy is the perceived heterogeneity of patients with chronic non-specific low back pain. It is felt that the effects of treatment may be diluted by the application of a single intervention to a complex, heterogeneous group with diverse treatment needs. This argument presupposes that current treatment is effective when applied to the correct patient. An alternative perspective is that the clinical trials are correct and current treatments have limited efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important that the sub-grouping paradigm is closely examined. This paper argues that there are numerous problems with the sub-grouping approach and that it may not be an important reason for the disappointing results of clinical trials. We propose instead that current treatment may be ineffective because it has been misdirected. Recent evidence that demonstrates changes within the brain in chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of cortical reorganisation and degeneration. This perspective offers interesting insights into the chronic low back pain experience and suggests alternative models of intervention. Summary: The disappointing results of clinical research are commonly explained by the failure of researchers to adequately attend to sub-grouping of the chronic non-specific low back pain population. Alternatively, current approaches may be ineffective and clinicians and researchers may need to radically rethink the nature of the problem and how it should best be managed

Intertester agreement and validity of identifying lumbar pain provocative movement patterns using active and passive accessory movement tests

Objective: The purpose of this study was to evaluate the interexaminer agreement and validity of active and passive pain provocation tests in the lumbar spine. Methods: Two blinded raters examined 36 participants, 18 of whom were asymptomatic and 18 reported subacute nonspecific low back pain (LBP). Two types of pain provocation tests were performed: (1) physiological movements in single (flexion/extension) and, when necessary, combined planes and (2) passive accessory intervertebral movement tests of each lumbar vertebra in prone with the lumbar spine in neutral, flexion, and extension position .Results: The interobserver agreement in both groups was good to excellent for the identification of flexion (κ =0.87-1) or extension (κ =0.65-0.74) as the most painful pattern of spinal movement. In healthy participants, 0% was identified as having a flexion provocative pattern and 8.8% were identified as having an extension provocative pattern. In the LBP group, 20% were identified as having flexion provocative pattern vs 60% with an extension provocative pattern. The average interexaminer agreement for passive accessory intervertebral movement tests in both groups was moderate to excellent (κ =0.42-0.83). The examiners showed good sensitivity (0.67-0.87) and specificity (0.82-0.85) to distinguish participants with LBP using this combined examination procedure. Conclusion: The use of a combination of pain provocative tests was found to have acceptable interexaminer reliability and good validity in identifying the main pain provocative movement pattern and the lumbar segmental level of involvement. These pain provocation tests were able to distinguish participants with LBP from asymptomatic participants and may help clinicians in directing manual therapy treatment

Orbital decay in an accreting and eclipsing 13.7 minute orbital period binary with a luminous donor

We report the discovery of ZTF J0127+5258, a compact mass-transferring binary with an orbital period of 13.7 minutes. The system contains a white dwarf accretor, which likely originated as a post-common envelope carbon-oxygen (CO) white dwarf, and a warm donor ($T_{\rm eff,\,donor}= 16,400\pm1000\,\rm K$). The donor probably formed during a common envelope phase between the CO white dwarf and an evolving giant which left behind a helium star or helium white dwarf in a close orbit with the CO white dwarf. We measure gravitational wave-driven orbital inspiral with $\sim 35\sigma$ significance, which yields a joint constraint on the component masses and mass transfer rate. While the accretion disk in the system is dominated by ionized helium emission, the donor exhibits a mixture of hydrogen and helium absorption lines. Phase-resolved spectroscopy yields a donor radial-velocity semi-amplitude of $771\pm27\,\rm km\, s^{-1}$, and high-speed photometry reveals that the system is eclipsing. We detect a {\it Chandra} X-ray counterpart with $L_{X}\sim 3\times 10^{31}\,\rm erg\,s^{-1}$. Depending on the mass-transfer rate, the system will likely evolve into either a stably mass-transferring helium CV, merge to become an R Crb star, or explode as a Type Ia supernova in the next million years. We predict that the Laser Space Interferometer Antenna (LISA) will detect the source with a signal-to-noise ratio of $24\pm6$ after 4 years of observations. The system is the first \emph{LISA}-loud mass-transferring binary with an intrinsically luminous donor, a class of sources that provide the opportunity to leverage the synergy between optical and infrared time domain surveys, X-ray facilities, and gravitational-wave observatories to probe general relativity, accretion physics, and binary evolution.Comment: 13 pages, 7 figures, 2 tables, submitted to ApJ

Caenorhabditis elegans behavioral genetics: where are the knobs?

Thousands of behavioral mutants of Caenorhabditis elegans have been studied. I suggest a set of criteria by which some genes important in the evolution of behavior might be recognized, and identify neuropeptide signaling pathways as candidates