Alterations in amino acid status in cats with feline dysautonomia

Feline dysautonomia (FD) is a multiple system neuropathy of unknown aetiology. An apparently identical disease occurs in horses (equine grass sickness, EGS), dogs, rabbits, hares, sheep, alpacas and llamas. Horses with acute EGS have a marked reduction in plasma concentrations of the sulphur amino acids (SAA) cyst(e)ine and methionine, which may reflect exposure to a neurotoxic xenobiotic. The aim of this study was to determine whether FD cats have alterations in amino acid profiles similar to those of EGS horses. Amino acids were quantified in plasma/serum from 14 FD cats, 5 healthy in-contact cats which shared housing and diet with the FD cats, and 6 healthy control cats which were housed separately from FD cats and which received a different diet. The adequacy of amino acids in the cats’ diet was assessed by determining the amino acid content of tinned and dry pelleted foods collected immediately after occurrences of FD. Compared with controls, FD cats had increased concentrations of many essential amino acids, with the exception of methionine which was significantly reduced, and reductions in most non-essential amino acids. In-contact cats also had inadequate methionine status. Artefactual loss of cysteine during analysis precluded assessment of the cyst(e)ine status. Food analysis indicated that the low methionine status was unlikely to be attributable to dietary inadequacy of methionine or cystine. Multi-mycotoxin screening identified low concentrations of several mycotoxins in dry food from all 3 premises. While this indicates fungal contamination of the food, none of these mycotoxins appears to induce the specific clinico-pathologic features which characterise FD and equivalent multiple system neuropathies in other species. Instead, we hypothesise that ingestion of another, as yet unidentified, dietary neurotoxic mycotoxin or xenobiotic, may cause both the characteristic disease pathology and the plasma SAA depletion

Latent Constructs in Psychosocial Factors Associated with Cardiovascular Disease: An Examination by Race and Sex

This study examines race and sex differences in the latent structure of 10 psychosocial measures and the association of identified factors with self-reported history of coronary heart disease (CHD). Participants were 4,128 older adults from the Chicago Health and Aging Project. Exploratory factor analysis (EFA) with oblique geomin rotation was used to identify latent factors among the psychosocial measures. Multi-group comparisons of the EFA model were conducted using exploratory structural equation modeling to test for measurement invariance across race and sex subgroups. A factor-based scale score was created for invariant factor(s). Logistic regression was used to test the relationship between the factor score(s) and CHD adjusting for relevant confounders. Effect modification of the relationship by race–sex subgroup was tested. A two-factor model fit the data well (comparative fit index = 0.986; Tucker–Lewis index = 0.969; root mean square error of approximation = 0.039). Depressive symptoms, neuroticism, perceived stress, and low life satisfaction loaded on Factor I. Social engagement, spirituality, social networks, and extraversion loaded on Factor II. Only Factor I, re-named distress, showed measurement invariance across subgroups. Distress was associated with a 37% increased odds of self-reported CHD (odds ratio: 1.37; 95% confidence intervals: 1.25, 1.50; p-value < 0.0001). This effect did not differ by race or sex (interaction p-value = 0.43). This study identified two underlying latent constructs among a large range of psychosocial variables; only one, distress, was validly measured across race–sex subgroups. This construct was robustly related to prevalent CHD, highlighting the potential importance of latent constructs as predictors of cardiovascular disease

Biomarker Associations with Insomnia and Secondary Sleep Outcomes in Persons with and without HIV in the POPPY-Sleep Sub-study: a cohort study

STUDY OBJECTIVES: We investigated associations between inflammatory profiles/clusters and sleep measures in people living with HIV and demographically-/lifestyle-similar HIV-negative controls in the Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY)-Sleep sub-study. METHODS: Primary outcome was insomnia (Insomnia Severity Index [ISI]≥15). Secondary sleep outcomes included 7-day actigraphy (e.g. mean/standard deviation of sleep duration/efficiency), overnight oximetry (e.g. oxygen desaturation index [ODI]) and patient-reported measures (Patient-Reported Outcomes Measurement Information System (PROMIS) sleep questionnaires). Participants were grouped using Principal Component Analysis of 31 biomarkers across several inflammatory pathways followed by cluster analysis. Between-cluster differences in baseline characteristics and sleep outcomes were assessed using Kruskal-Wallis/logistic regression/Chi-squared/Fisher's exact tests. RESULTS: Of the 465 participants included (74% people with HIV, median [interquartile range] age 54 [50-60] years), only 18% had insomnia and secondary sleep outcomes suggested generally good sleep (e.g. ODI 3.1/hr [1.5-6.4]). Three clusters with distinct inflammatory profiles were identified: 'gut/immune activation' (n=47), 'neurovascular' (n=209), and 'reference' (relatively lower inflammation; n=209). The 'neurovascular' cluster included higher proportions of people with HIV, obesity (BMI≥30 kg/m 2), and previous cardiovascular disease, mental health disorder, and arthritis of knee/hip relative to the other two clusters. No clinically relevant between-cluster differences were observed in proportions with insomnia (17%, 18%, 20%) before (p=0.76) or after (p=0.75) adjustment for potential confounders. Few associations were observed among actigraphy, oximetry and PROMIS measures. CONCLUSIONS: Although associations could exist with other sleep measures or biomarker types not assessed, our findings do not support a strong association between sleep and inflammation in people with HIV

How good is probabilistic record linkage to reconstruct reproductive histories? Results from the Aberdeen children of the 1950s study

BACKGROUND: Probabilistic record linkage is widely used in epidemiology, but studies of its validity are rare. Our aim was to validate its use to identify births to a cohort of women, being drawn from a large cohort of people born in Scotland in the early 1950s. METHODS: The Children of the 1950s cohort includes 5868 females born in Aberdeen 1950–56 who were in primary schools in the city in 1962. In 2001 a postal questionnaire was sent to the cohort members resident in the UK requesting information on offspring. Probabilistic record linkage (based on surname, maiden name, initials, date of birth and postcode) was used to link the females in the cohort to birth records held by the Scottish Maternity Record System (SMR 2). RESULTS: We attempted to mail a total of 5540 women; 3752 (68%) returned a completed questionnaire. Of these 86% reported having had at least one birth. Linkage to SMR 2 was attempted for 5634 women, one or more maternity records were found for 3743. There were 2604 women who reported at least one birth in the questionnaire and who were linked to one or more SMR 2 records. When judged against the questionnaire information, the linkage correctly identified 4930 births and missed 601 others. These mostly occurred outside of Scotland (147) or prior to full coverage by SMR 2 (454). There were 134 births incorrectly linked to SMR 2. CONCLUSION: Probabilistic record linkage to routine maternity records applied to population-based cohort, using name, date of birth and place of residence, can have high specificity, and as such may be reliably used in epidemiological research

Investigating the global dispersal of chickens in prehistory using ancient mitochondrial dna signatures

Data from morphology, linguistics, history, and archaeology have all been used to trace the dispersal of chickens from Asian domestication centers to their current global distribution. Each provides a unique perspective which can aid in the reconstruction of prehistory. This study expands on previous investigations by adding a temporal component from ancient DNA and, in some cases, direct dating of bones of individual chickens from a variety of sites in Europe, the Pacific, and the Americas. The results from the ancient DNA analyses of forty-eight archaeologically derived chicken bones provide support for archaeological hypotheses about the prehistoric human transport of chickens. Haplogroup E mtDNA signatures have been amplified from directly dated samples originating in Europe at 1000 B.P. and in the Pacific at 3000 B.P. indicating multiple prehistoric dispersals from a single Asian centre. These two dispersal pathways converged in the Americas where chickens were introduced both by Polynesians and later by Europeans. The results of this study also highlight the inappropriate application of the small stretch of D-loop, traditionally amplified for use in phylogenetic studies, to understanding discrete episodes of chicken translocation in the past. The results of this study lead to the proposal of four hypotheses which will require further scrutiny and rigorous future testingExcavations in Fais by MI were made possible by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. DB gratefully acknowledges support from the Marsden Fund, and the Allan Wilson Centre for Molecular Ecology and Evolution. During the course of this research AS was supported by a Postgraduate Scholarship from the University of Auckland and a Fellowship from the Allan Wilson Centre for Molecular Ecology and Evolutio

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Improving the evidence base of Markov models used to estimate the costs of scaling up antiretroviral programmes in resource-limited settings

<p>Abstract</p> <p>Background</p> <p>Despite concerns about affordability and sustainability, many models of the lifetime costs of antiretroviral therapy (ART) used in resource limited settings are based on data from small research cohorts, together with pragmatic assumptions about life-expectancy. This paper revisits these modelling assumptions in order to provide input to future attempts to model the lifetime costs and the costs of scaling up ART.</p> <p>Methods</p> <p>We analysed the determinants of costs and outcomes in patients receiving ART in line with standard World Health Organization (WHO) guidelines for resource poor settings in a private sector managed ART programme in South Africa. The cohort included over 5,000 patients with up to 4 years (median 19 months) on ART. Generalized linear and Cox proportional hazards regression models were used to establish cost and outcome determinants respectively.</p> <p>Results</p> <p>The key variables associated with changes in mean monthly costs were: being on the second line regimen; receiving ART from 4 months prior to 4 months post treatment initiation; having a recent or current CD4 count <50 cells/µL or 50-199 cells/µl; having mean ART adherence <75% as determined by monthly pharmacy refill data; and having a current or recent viral load >100,000 copies/mL. In terms of the likelihood of dying, the key variables were: baseline CD4 count<50 cells/µl (particularly during the first 4 months on treatment); current CD4 count <50 cells/µl and 50-199 cells/µl (particularly during later periods on treatment); and being on the second line regimen. Being poorly adherent and having an unsuppressed viral load was also associated with a higher likelihood of dying.</p> <p>Conclusions</p> <p>While there are many unknowns associated with modelling the resources needed to scale-up ART, our analysis has suggested a number of key variables which can be used to improve the state of the art of modelling ART. While the magnitude of the effects associated with these variables would be likely to differ in other settings, the variables influencing costs and survival are likely to be generalizable. This is of direct relevance to those concerned about assessing the long-term costs and sustainability of expanded access to ART.</p

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Societal Burden of Clinically Anxious Youth Referred for Treatment: A Cost-of-illness Study

A prevalence-based cost-of-illness study using a societal perspective was conducted to investigate the cost-of-illness in clinically anxious youth aged 8–18 in The Netherlands. Discriminant validity of the cost diary used was obtained by comparing costs of families with an anxious child (n = 118) to costs of families from the general population (n = 41). To examine the convergent validity, bottom-up acquired costs derived from cost diaries were compared to top-down acquired costs obtained from national registrations. Bottom-up acquired costs measured by means of cost diaries amounted to €2,748 per family of a clinically referred anxious child per annum. Societal costs of families with clinically anxious children were almost 21 times as high compared to families from the general population. With respect to convergent validity, total health care costs using the bottom-up approach from clinically anxious children were quite comparable to those of top-down data of anxious children, although costs within the subcategories differed considerably. Clinical anxiety disorders in childhood cost the Dutch society more than 20 million euros a year. Based on results of discriminate and convergent validity, the cost diary seems a valid method in establishing cost-of-illness in childhood anxiety disorders