Family-based analyses reveal novel genetic overlap between cytokine interleukin-8 and risk for suicide attempt.

BACKGROUND: Suicide is major public health concern. It is imperative to find robust biomarkers so that at-risk individuals can be identified in a timely and reliable manner. Previous work suggests mechanistic links between increased cytokines and risk for suicide, but questions remain regarding the etiology of this association, as well as the roles of sex and BMI. METHODS: Analyses were conducted using a randomly-ascertained extended-pedigree sample of 1882 Mexican-American individuals (60% female, mean age = 42.04, range = 18-97). Genetic correlations were calculated using a variance components approach between the cytokines TNF-α, IL-6 and IL-8, and Lifetime Suicide Attempt and Current Suicidal Ideation. The potentially confounding effects of sex and BMI were considered. RESULTS: 159 individuals endorse a Lifetime Suicide Attempt. IL-8 and IL-6 shared significant genetic overlap with risk for suicide attempt (ρg = 0.49, pFDR = 7.67 × 10-03; ρg = 0.53, pFDR = 0.01), but for IL-6 this was attenuated when BMI was included as a covariate (ρg = 0.37, se = 0.23, pFDR = 0.12). Suicide attempts were significantly more common in females (pFDR = 0.01) and the genetic overlap between IL-8 and risk for suicide attempt was significant in females (ρg = 0.56, pFDR = 0.01), but not in males (ρg = 0.44, pFDR = 0.30). DISCUSSION: These results demonstrate that: IL-8 shares genetic influences with risk for suicide attempt; females drove this effect; and BMI should be considered when assessing the association between IL-6 and suicide. This finding represents a significant advancement in knowledge by demonstrating that cytokine alterations are not simply a secondary manifestation of suicidal behavior, but rather, the pathophysiology of suicide attempts is, at least partly, underpinned by the same biological mechanisms responsible for regulating inflammatory response.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Developing preference-based measures for diabetes: DHP-3D and DHP-5D.

AIMS: The aim of this study was to develop two diabetes-specific preference-based measures [the Diabetes Health Profile-3 Dimension (DHP-3D) and the Diabetes Health Profile-5 Dimension (DHP-5D)] for use in the calculation of Quality Adjusted Life Years, a key outcome in economic evaluation. These measures were based on the non-preference-based instrument the Diabetes Health Profile. METHODS: For DHP-3D, psychometric and Rasch analyses were used to develop a health state classification system based on the Diabetes Health Profile-18 (DHP-18). The DHP-5D added two dimensions to the DHP-3D to extend the range of impacts measured. Each classification system was valued by 150 general public respondents in the United Kingdom using Time Trade Off (TTO). Multivariate regression was used to estimate utility value sets. The matched dimensions across each measure were compared using z-score tests. RESULTS: The DHP-3D included three dimensions defined as mood, eating and social limitations, and the DHP-5D added dimensions defined as hypoglycaemic attacks and vitality. For both, the random effects generalized least squares regression model produced consistent value sets, with the DHP-3D and DHP-5D ranging from 0.983 (best state) to 0.717 (worst state), and 0.979 to 0.618 respectively. The addition of the two extra dimensions leads to significant differences for the more severe levels of each matched dimension. CONCLUSIONS: We have developed two diabetes-specific preference-based measures that, subject to psychometric assessment, can be used to provide condition-specific utility values to complement generic utilities from more widely validated measures such as the EuroQol-5 Dimension.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

Identifying clinically relevant prognostic subgroups of postmenopausal women with node-positive hormone receptor-positive early-stage breast cancer treated with endocrine therapy: a combined analysis of ABCSG-8 and ATAC using the PAM50 risk of recurrence score and intrinsic subtype.

BACKGROUND: In the adjuvant treatment of hormone receptor-positive (HR+) breast cancer, variables like tumour size, grade and nodal status have great impact on therapy decisions. As most node-positive patients with HR+ breast cancer currently receive adjuvant chemotherapy improved methods for characterization of individuals' metastasis risk are needed to reduce overtreatment. PATIENTS AND METHODS: Tissue specimens from node-positive patients of the ABCSG-8 and ATAC trials who received adjuvant tamoxifen and/or anastrozole were included in this study. Analysing RNA from paraffin blocks using the PAM50 test, the primary objective was to evaluate the prognostic information of the risk of recurrence (ROR) score added to combined clinical standard variables in patients with one positive node (1N+) and in patients with two or three positive nodes (2-3N+), using log-likelihood ratio tests. RESULTS: At a median follow-up of 9.6 years, distant metastases occurred in 97 (18%) of 543 node-positive patients. In a multivariate analysis, the PAM50-derived ROR score provided reliable prognostic information in addition to and beyond established clinical factors for 1N+ (P < 0.0001) and 2-3N+ patients (P = 0.0002). Ten-year distant recurrence risk was significantly increased in the high-risk compared with the low-risk group derived from ROR score for 1N+ [25.5%, 95% confidence interval (CI) 17.5% to 36.1%versus 6.6%, 95% CI 3.3% to 12.8%] and compared with the combined low/intermediate risk group for 2-3N+ patients (33.7%, 95% CI 25.5% to 43.8% versus 12.5%, 95% CI 6.6% to 22.8%). Additionally, the luminal A intrinsic subtype (IS) exhibited significantly lower risk of distant recurrence compared with the luminal B subtype in 1N+ and 2-3N+ patients. CONCLUSION: PAM50 ROR score and IS can identify node-positive patient subgroups with limited risk of metastasis after endocrine therapy, for whom adjuvant chemotherapy can be spared. The PAM50 test is a valuable tool in determining treatment of node-positive early-stage breast cancer patients.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Neurological soft signs in obsessive-compulsive disorder: two empirical studies and meta-analysis.

BACKGROUND: Neurological soft signs (NSS) have been inconsistently reported in obsessive-compulsive disorder (OCD) but may make an impact on treatment response. Method The current study examined the presence of NSS in two independent European samples of OCD patients (combined 85 patients and 88 matched healthy controls) using a standardized instrument and conducted a meta-analysis of all published studies identified in the literature with the aim to provide a more definitive answer to the question of whether OCD patients are characterized by increased NSS. RESULTS: Both empirical studies found elevated NSS scores in patients compared with matched controls. The results of the meta-analysis, which included 15 studies (combined 498 patients and 520 controls) showed large effect sizes (Hedges' g=1.27, 95% confidence interval 0.80-1.75), indicating that OCD patients have significantly higher rates of NSS than matched controls on both sides of the body and in multiple domains (motor coordination, sensory integration and primitive reflexes). The results were robust and remained largely unchanged in our reliability analyses, which controlled for possible outliers. Meta-regression was employed to examine the role of potential variables of interest including sociodemographic variables, symptom severity, medication effects and the use of different instruments, but none of these variables was clearly associated with NSS. CONCLUSIONS: As a group, OCD patients are characterized by increased rates of NSS, compared with healthy controls. However, their origins and potential clinical importance remain to be clarified. Future directions for research are discussed.

Short Communication: Identification of equine corticotropin-like intermediate lobe peptide (CLIP) binding to an adrenocortipcotrophic hormone (ACTH) assay capture antibody.

A chemiluminescent immunoassay is commonly employed to measure adrenocorticotrophic hormone (ACTH) concentrations to assist pituitary pars intermedia dysfunction diagnosis. In a previous study, seasonally-dependent assay cross-reactivity to endogenous equine corticotropin-like intermediate lobe peptide (CLIP, ACTH 18-39) was suspected. The present study aimed to demonstrate binding of endogenous equine CLIP to the capture antibody of the ACTH chemiluminescent immunoassay. Liquid chromatography - mass spectrometry (LCMS) methods were optimised to identify selected ions from synthetic human ACTH, α-melanocyte stimulating hormone (α-MSH, ACTH 1-17) and CLIP. Synthetic ACTH and CLIP bound to the capture antibody of the chemiluminescent ACTH assay, but α-MSH did not. Equine endogenous CLIP was detected by LCMS in pony plasma taken in the autumn and could be eluted from the capture antibody of the ACTH chemiluminescent immunoassay. Further research is required to enable quantification of CLIP. Equine CLIP may alter measured ACTH concentrations in vivo.

An initiative to provide emergency healthcare for older people in the community: the impact on carers.

The increase in the size and age of the UK older population has had a major effect on emergency services. Many older people will visit the emergency department but not necessarily require significant clinical intervention. The Paramedic Practitioner in Older People's Support (PPOPS) scheme was set up to provide community-based clinical assessment of older patients contacting the emergency services with minor acute conditions as an alternative approach to emergency department transfer. Patient carers were followed-up to evaluate the impact of this scheme when compared with standard transfer to the emergency department. Postal questionnaires, including items on the level of care provided, satisfaction with care received and carer impact, were administered to 561 carers. The overall response rate was 71.5% (401/561). The carers were predominantly female, approximately 60 years of age and family members, with more than three-quarters providing some form of physical care before the patient episode. Overall, carers did report an increase in the level of care provided before episode, significantly more so in the emergency department group (p=0.003). These increases related to more input needed in supporting physical activities. The carers in the PPOPS group were more likely to report greater satisfaction with their impression of care and staff attitude and would prefer treatment at home for the patient than those in the emergency department group (p<0.001). A minor health event does impact on the life of a carer. However, community-based schemes, such as PPOPS, do not increase the burden on carers and have high levels of satisfaction among this important group of the community.

Serum amyloid A and plasma fibrinogen concentrations in horses following emergency exploratory celiotomy.

BACKGROUND: Acute-phase proteins may help assess the nature and severity of lesions and outcome in horses undergoing colic surgery. OBJECTIVES: To compare serum amyloid A and plasma fibrinogen concentrations ([SAA] and [fibrinogen]) in the immediate post-operative period after exploratory celiotomy and determine their value in assessment of post-operative complications and survival to discharge. STUDY DESIGN: Observational study. METHODS: This study included horses over 1 year of age undergoing exploratory celiotomy. Surgical procedures, lesions, post-operative care, complications and survival to discharge were recorded. [SAA] and [fibrinogen] were measured prior to surgery and 5 days post-operatively. Statistical analyses included Yate's Chi-square test, linear mixed effects model, Mann-Whitney U test and logistic regression. RESULTS: Of 300 horses, 52.0% developed post-operative complications and 83.7% survived to discharge, with significantly reduced chance of survival in horses that developed post-operative complications (P<0.01). Median [SAA] at days 1, 2, 3, 4 and 5 and median [fibrinogen] at days 3, 4 and 5 were significantly different between horses that did and did not develop post-operative complications (P<0.05). Median [SAA] at days 1, 4 and 5 were significantly different between horses that did and did not survive to discharge (P<0.05). Logistic regression revealed post-operative complications to be associated with strangulating lesions (OR 2.35, 95% confidence interval [CI] 1.41-3.91, P≤0.001) and higher [fibrinogen] at admission (OR 1.21, 95% CI 1.00-1.45, P<0.05), and survival to discharge to be associated with lower [SAA] at 5 days post-operatively (OR 0.965, 95% CI 0.94-0.99, P = 0.002). MAIN LIMITATIONS: A large variety of lesions and complications prevented detailed analysis of associations between inflammatory markers, lesions and complications. CONCLUSIONS: Horses that develop post-operative complications have acute-phase responses of greater magnitudes and durations compared with those that do not develop complications. This is also seen in horses that do not survive to discharge. Measuring [SAA] daily and [fibrinogen] at admission, may help predict the development of post-operative complications.

Distinct mechanism for antidepressant activity by blockade of central substance P receptors.

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

Is it cost effective to introduce paramedic practitioners for older people to the ambulance service? Results of a cluster randomised controlled trial.

BACKGROUND: A scheme to train paramedics to undertake a greater role in the care of older people following a call for an emergency ambulance was developed in a large city in the UK. OBJECTIVES: To assess the cost effectiveness of the paramedic practitioner (PP) scheme compared with usual emergency care. METHODS: A cluster randomised controlled trial was undertaken of PP compared with usual care. Weeks were allocated to the study group at random to the PP scheme either being active (intervention) or inactive (control). Resource use data were collected from routine sources, and from patient-completed questionnaires for events up to 28 days. EQ-5D data were also collected at 28 days. RESULTS: Whereas the intervention group received more PP contact time, it reduced the proportion of emergency department (ED) attendances (53.3% vs 84.0%) and time in the ED (126.6 vs 211.3 minutes). There was also some evidence of increased use of health services in the days following the incident for patients in the intervention group. Overall, total costs in the intervention group were 140 UK pounds lower when routine data were considered (p = 0.63). When the costs and QALY were considered simultaneously, PP had a greater than 95% chance of being cost effective at 20 000 UK pounds per QALY. CONCLUSION: Several changes in resource use are associated with the use of PP. Given these economic results in tandem with the clinical, operational and patient-related benefits, the wider implementation and evaluation of similar schemes should be considered.

Validity and application of immunoturbidimetric and enzyme-linked immunosorbent assays for the measurement of adiponectin concentration in ponies.

BACKGROUND: Circulating adiponectin concentrations were lower in ponies with a history of endocrinopathic laminitis and in nonlaminitic ponies that subsequently developed laminitis. The assays used in these studies have been discontinued or are no longer valid. OBJECTIVES: (1) to determine the validity of immunoturbidimetric (IT) and enzyme linkedimmunosorbent (ELISA) assays for equine total and high molecular weight (HMW) [adiponectin] measurement and (2) to investigate the association between [adiponectin] measured using these assays and endocrinopathic laminitis. STUDY DESIGN: Method validation and cohort study. METHODS: Accuracy and precision of IT and ELISA assays for measuring total (TAC) and HMW (HMWAC) [adiponectin] were determined. Using the IT assay, the effects of anti-coagulant and storage temperature were assessed, TAC was measured in previously laminitic (PL) and never laminitic (NL) ponies (n = 6/group). Comparison with a previously validated radioimmunoassay was made in NL ponies (n = 223). Association between TAC and subsequent laminitis development in NL ponies was investigated using univariable logistic regression and ROC curve analysis. RESULTS: The IT assay was precise and demonstrated good agreement with the previously validated radioimmunoassay. TAC was significantly (P<0.01) lower in PL (mean ± s.d. 8.9 ± 2.9 µg/mL) compared to NL (24.2 ± 11.8 µg/mL) ponies and in NL ponies that developed laminitis within 12 months (median 4.8 µg/mL; IQR 2.65-13.4 µg/mL) compared to those that remained nonlaminitic (19.9 µg/mL; 9.95-31.5 µg/mL). TAC was significantly (P = 0.01) associated with laminitis occurrence within 12 months. Use of the area under the ROC curve to distinguish animals that did and did not develop laminitis showed good accuracy (0.76). None of the ELISA methods validated satisfactorily. MAIN LIMITATIONS: Laminitis risk is based on data from ponies in one region. CONCLUSIONS: The IT method is suitable for measurement of equine TAC. TAC is lower in ponies with previous or future laminitis. The ELISA methods are not suitable for measurement of equine HMWAC or TAC.

Plasma adrenocorticotropic hormone (ACTH) concentrations in ponies measured by two different assays suggests seasonal cross-reactivity or interference.

BACKGROUND: Analysis of plasma adrenocorticotropic hormone concentration [ACTH] aids diagnosis of pituitary pars intermedia dysfunction (PPID). Comparisons of the validated chemiluminescent-immunoassay (CI) and immunofluorescent (IF) assays are limited. OBJECTIVES: To compare the results of [ACTH] analysis by CI and IF methods of samples collected in autumn and spring and assess cross-reactivity. STUDY DESIGN: Method comparison. METHODS: Plasma from nonlaminitic ponies was analysed concurrently using the IF and CI methods in autumn and the following spring. Diagnostic thresholds for the IF method were derived using ROC curves and Youden indices to correspond with CI thresholds. Assay specificity was assessed using commercially available ACTH fragments and degradation products of endogenous ACTH. RESULTS: CI and IF methods yielded different results (P<0.001); mean differences (CI-IF), (95% confidence intervals): Autumn (n=99) 38.6 (30.6-46.5) pg/ml, Spring (n=88) 5.1 (3.9-6.3) pg/ml. The association between CI and IF results differed in autumn and spring, consistent with seasonally dependent cross-reactivity or interference. Good (κ=0.66-0.74) agreement was obtained for binary interpretation in spring between IF and CI using thresholds of >24 and >29 pg/ml respectively and in autumn between IF and CI using thresholds of >27 and >47 pg/ml respectively or >33 and >77 pg/ml respectively. Of 88 ponies with both spring and autumn samples, 56 (64%) exceeded a published autumn CI threshold (>47 pg/ml), of which 39 (70%) were below the equivalent threshold (<29 pg/ml) the following spring without treatment. The CI assay showed apparent increases in [ACTH] following addition of CLIP (ACTH 18-39). Degradation of ACTH during storage affected the assays differently. MAIN LIMITATIONS: Limited numbers of PPID cases were included. Immunoreactivity of commercially available peptides may differ from their endogenous equivalents. CONCLUSIONS: The methods yielded different absolute values but the agreement for binary classification was good. An altered pituitary secretome in autumn that affects apparent [ACTH] values is likely. The Summary is available in Spanish - see Supporting information.

Use of the oral sugar test in ponies when performed with or without prior fasting.

BACKGROUND: It is recommended that the oral sugar test (OST) for insulin dysregulation (ID) be performed after an overnight fast, but fasting is impractical in ponies kept solely at pasture. There are few data on OST repeatability and reliability in ponies. OBJECTIVES: To report 1) whether OST results obtained in the morning after an overnight fast or without fasting in the afternoon (FASTING/FED) can be used interchangeably, 2) time of highest insulin concentration Tmax [insulin], repeatability and reliability of insulin response to the OST when FASTING or FED and 3) dichotomous agreement (ID/normal) within a small sample when FASTING or FED. STUDY DESIGN: Method comparison study. METHODS: Oral sugar tests were performed on four occasions in 10 adult native British ponies, twice FASTING and twice FED. Insulin concentrations were measured by radioimmunoassay at 0-120 min (T0,30,60,75,90,120 ). Differences between FASTING and FED results were assessed using mixed effects models. Indices of repeatability and reliability were calculated; dichotomous agreement was reported using kappa statistics. RESULTS: Serum [insulin] was significantly (P≤0.05) higher at T60 -T90 with prior fasting (estimated differences [95% confidence intervals]): T60 : 23.5 µiu/ml (8.7-38.4 µiu/ml), T75 : 27.1 µiu/ml (12.3-41.8 µiu/ml), T90 : 15.1 (0.36-29.9 µiu/ml). Most frequently, Tmax [ins] occurred at T30 . At any single time point, within-subject coefficients of variation were: FASTING: 40% and FED: 31%. The 95% limits for repeatability were FASTING: 29-340%, FED: 41-240%. Test reliabilities were FASTING: 0.70 and FED: 0.67. For dichotomous interpretation similar results (kappa = 0.7) were obtained using cut-offs of [Insulin] >60 µiu/ml at T60 or T90 for FASTING and [Insulin] >51 µiu/ml at T30 or T60 for FED samples. MAIN LIMITATIONS: Oral sugar tests were performed on a small number of animals on one pasture during one season (spring). CONCLUSIONS: Clinicians should beware of interpreting changes in absolute OST results owing to poor repeatability. When stabling is unavailable, OSTs of ponies at pasture may yield similar dichotomous results without prior fasting.

The lipidome in major depressive disorder: Shared genetic influence for ether-phosphatidylcholines, a plasma-based phenotype related to inflammation, and disease risk.

BACKGROUND: The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular, there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated. METHODS: In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range=3-80), we used mass spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD. RESULTS: We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD. CONCLUSIONS: This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD.

Effect of a national urgent care telephone triage service on population perceptions of urgent care provision: controlled before and after study.

OBJECTIVE: To measure the effect of an urgent care telephone service NHS 111 on population perceptions of urgent care. DESIGN: Controlled before and after population survey, using quota sampling to identify 2000 respondents reflective of the age/sex profile of the general population. SETTING: England. 4 areas where NHS 111 was introduced, and 3 control areas where NHS 111 had yet to be introduced. PARTICIPANTS: 28 071 members of the general population, including 2237 recent users of urgent care. INTERVENTION: NHS 111 offers advice to members of the general population seeking urgent care, recommending the best service to use or self-management. Policymakers introduced NHS 111 to improve access to urgent care. OUTCOMES MEASURES: The primary outcome was change in satisfaction with recent urgent care use 9 months after the launch of NHS 111. Secondary outcomes were change in satisfaction with urgent care generally and with the national health service. RESULTS: The overall response rate was 28% (28 071/100 408). 8% (2237/28 071) had used urgent care in the previous 3 months. Of the 652 recent users of urgent care in the NHS 111 intervention areas, 9% (60/652) reported calling NHS 111 in the 'after' period. There was no evidence that the introduction of NHS 111 was associated with a changed perception of recent urgent care. For example, the percentage rating their experience as excellent remained at 43% (OR 0.97, 95% CI 0.69 to 1.37). Similarly, there was no change in population perceptions of urgent care generally (1.06, 95% CI 0.95 to 1.17) or the NHS (0.94, 95% CI 0.85 to 1.05) following the introduction of NHS 111. CONCLUSIONS: A new telephone triage service did not improve perceptions of urgent care or the health service. This could be explained by the small amount of NHS 111 activity in a large emergency and urgent care system.

A database survey of equine tumours in the United Kingdom.

REASONS FOR PERFORMING STUDY: Survey data on equine tumours are sparse compared with other species and may have changed over time. OBJECTIVES: To describe the most frequently diagnosed equine tumours recorded by a diagnostic pathology laboratory over 29 years, to identify background factors associated with tumour type, and to identify any changes in the tumours diagnosed or the background of cases submitted during the study period. STUDY DESIGN: Observational; cross-sectional analysis of records of a diagnostic pathology laboratory. METHODS: The records of all neoplastic equine histology submissions to the University of Bristol (January 1982-December 2010) were accessed from a database, and a list of diagnoses compiled. The 6 most commonly diagnosed tumour types were analysed using logistic regression to identify background factors associated with tumour type. The overall population of equine tumour submissions and the relative frequency of diagnosis of the most common tumour types were compared between decades. RESULTS: There were 964 cases included. The most frequently diagnosed tumours were: sarcoid (24% cases), squamous cell carcinoma (SCC) (19%), lymphoma (14%), melanoma (6%), gonadal stromal tumour (6%) and mast cell tumour (MCT) (4%). With sarcoid, Thoroughbred/Thoroughbred cross and gelding as reference categories: increasing age was significantly associated with the odds of each of the other tumour types, mares were at reduced risk of SCC, Arab/Arab cross had a higher risk of MCT, Cob/Cob cross had an increased risk of SCC and MCT, and ponies had an increased risk of melanoma. The mean age of submissions increased in each successive decade and the breed composition became broader. Sarcoids and lymphoma formed a smaller proportion of diagnoses in later decades. CONCLUSIONS: The types of tumours submitted to this laboratory have changed over the last 3 decades. Current data inform clinicians and researchers and further studies are warranted to follow trends.

Genome-wide significant loci for addiction and anxiety.

BACKGROUND: Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. METHODS: Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. RESULTS: Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2-q21.2, LOD=3.322) and a broad anxiety phenotype (12q24.32-q24.33, LOD=2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg=0.550-0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1-q33.2, LOD=3.054) and drug dependence-anxiety (18p11.23-p11.22, LOD=3.425). CONCLUSIONS: This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics.