Boganmeldelser

Book review

Accuracy of the Aspartic Acid Racemization Technique in Age Estimation of Mammals and the Influence of Body Temperature

The aspartic acid racemization (AAR) technique has been applied for age estimation of humans and other mammals for more than four decades. In this study, eye lenses from 124 animals representing 25 mammalian species were collected and D/L ratios obtained using the AAR technique. The animals were either of known age or had the age estimated by other methods. The purpose of the study was to: a) estimate the accuracy of the AAR technique, and b) examine the effect of body temperature on racemization rates. Samples from four of the 25 species covered the range of ages that is needed to estimate species-specific racemization rates. The sample size from a single species of known age, the pygmy goat (Capra hircus, n = 35), was also large enough to investigate the accuracy of ages obtained using the AAR technique. The 35 goats were divided into three datasets: all goats (n = 35), goats >0.5 yrs old (n = 26) and goats >2 yrs old (n = 19). Leave-one-out analyses were performed on the three sets of data. Normalized root mean squared errors for the group of goats >0.5 yrs old were found to be the smallest. The higher variation in D/L measurements found for young goats 0.5 yrs old was for three age groups of the goats: 0.934 yrs for young goats 8 yrs (n = 4). Thus, the age of an adult or an old animal can be predicted with approximately 10% accuracy, whereas the age of a young animal is difficult to predict. A goat specific racemization rate, as a 2kAsp value, was estimated to 0.0107 ± 3.8 x 10-4 SE (n = 26). The 2kAsp values from 12 species, four estimated in this study and another eight published, were used to examine the effect of core body temperature on the rate of racemization. A positive relationship between AAR and temperature was found (r2 = 0.321) but results also suggest that other factors besides temperature are involved in the racemization process in living animals. Based on our results we emphasize that non-species-specific racemization rates should be used with care in AAR age estimation studies and that the period of postnatal growth of the eye lens be considered when estimating species-specific D/L0 values and ages of young individuals

WHO/ILO work-related burden of disease and injury: Protocol for systematic reviews of exposure to long working hours and of the effect of exposure to long working hours on depression

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing a joint methodology for estimating the national and global work-related burden of disease and injury (WHO/ILO joint methodology), with contributions from a large network of experts. In this paper, we present the protocol for two systematic reviews of parameters for estimating the number of deaths and disability-adjusted life years from depression attributable to exposure to long working hours, to inform the development of the WHO/ILO joint methodology. Objectives: We aim to systematically review studies on occupational exposure to long working hours (Systematic Review 1) and systematically review and meta-analyse estimates of the effect of long working hours on depression (Systematic Review 2), applying the Navigation Guide systematic review methodology as an organizing framework, conducting both systematic reviews in tandem and in a harmonized way. Data sources: Separately for Systematic Reviews 1 and 2, we will search electronic academic databases for potentially relevant records from published and unpublished studies, including Medline, EMBASE, Web of Science, CISDOC and PsycINFO. We will also search electronic grey literature databases, Internet search engines and organizational websites; hand search reference list of previous systematic reviews and included study records; and consult additional experts. Study eligibility and criteria: We will include working-age (≥15 years) participants in the formal and informal economy in any WHO and/or ILO Member State, but exclude child workers (<15 years) and unpaid domestic workers. For Systematic Review 1, we will include quantitative prevalence studies of relevant levels of occupational exposure to long working hours (i.e. 35–40, 41–48, 49–54 and ≥55 h/week) stratified by country, sex, age and industrial sector or occupation, in the years 2005–2018. For Systematic Review 2, we will include randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of the relative effect of relevant level(s) of long working hours on the incidence of or mortality due to depression, compared with the theoretical minimum risk exposure level (i.e. 35–40 h/week). Study appraisal and synthesis methods: At least two review authors will independently screen titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. At least two review authors will assess risk of bias and the quality of evidence, using the most suited tools currently available. For Systematic Review 2, if feasible, we will combine relative risks using meta-analysis. We will report results using the guidelines for accurate and transparent health estimates reporting (GATHER) for Systematic Review 1 and the preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) for Systematic Review 2. PROSPERO registration number: CRD42018085729The publication was prepared with financial support from the World Health Organization cooperative agreement with the Centres for Disease Control and Prevention National Institute for Occupational Safety and Health of the United States of America on implementing Resolution WHA 60.26 “Workers' Health: Global Plan of Action” (Grant 1 E11 OH0010676-02)

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation