The Association Between Dimethylacetamide Exposure and Liver Toxicity:A Large Retrospective Analysis in Workers From Four European Factories

Objective: This study examines the association between 8-h time weighted N, N-dimethylacetamide (DMAc) air exposure and potential hepatocellular injury in a retrospective study among fibre-production workers in four European factories. Methods and Results: Twenty-nine (1.5%) of 1844 alanine aminotransferase (ALT) observations had liver values two times above normal; 0.2% three times above normal and 0.05% five times above normal. Two (0.1%) observations were indicative of hepatocellular injury. Logistic regression analyses showed an odds ratio for elevated ALT of 0.88 per 1 ppm (P trend = 0.39). Linear random effects regression analyses showed a decrease of one international unit (IU/L) ALT per 1 ppm increase of DMAc exposure (P = 0.002). Conclusions: This study found no association between DMAc exposure and hepatoxicity amongst European workers. The prevalence of elevated liver values was lower compared to the general population without occupational exposure

Personality as a Predictor of Disability in Multiple Sclerosis.

As personality changes and personality disorders are frequently observed in multiple sclerosis (MS), personality may be a prognostic factor for this disease. The present study investigated the influence of personality on disability, progression, and treatment adherence in MS. Personality was assessed in 41 patients with Relapsing-Remitting MS (30 females; mean age = 42.63 years) using the NEO Personality Inventory-3rd edition. Disability was measured with the Expanded Disability Status Scale, and treatment adherence information was collected from the Swiss MS Cohort. Correlation, multiple linear and partial least square regressions were performed to examine relations between personality, disability, and treatment adherence in MS. After accounting for age and time since disease onset, our analysis revealed that Neuroticism (β = 0.32, p = 0.01) and its Vulnerability facet (β = 0.28, p < 0.05) predicted greater disability, whereas Extraversion (β = -0.25, p = 0.04) and its Activity facet (β = -0.23, p < 0.05) predicted milder disability. Regarding disability progression, correlational analysis revealed that it was negatively correlated with Extraversion (r = -0.44, p = 0.02) and the Feelings facet of Openness (r = -0.41, p = 0.03), but regressions failed to highlight any predictive links. No significant results could be demonstrated for treatment adherence. Overall, our study showed that some personality traits can impact disability in MS, indicating that these should be considered in clinical practice, as they could be used to adapt and improve patients' clinical support

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Breast cancer risk genes: association analysis in more than 113,000 women

BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)Molecular tumour pathology - and tumour geneticsMTG1 - Moleculaire genetica en pathologie van borstkanke

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease

The relationship between toluene diisocyanate exposure and respiratory health problems: A meta-analysis of epidemiological studies

Human epidemiological studies have shown inconclusive results over the effects of diisocyanates on respiratory health problems. A meta-analysis combined evidence on the association between occupational asthma (OA), respiratory function, and toluene diisocyanate (TDI) inhalation exposure. Sixty-one articles on occupational toluene diisocyanate exposure were identified via two databases. Fourteen studies were included in the meta-analysis. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the studies. Odds ratios (ORasthma) for the association between TDI exposure compared to non-exposure and OA were calculated. The difference in mean differences (MD) of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), and the annual mean change differences-in milliliters per year (mL/yr)-in FEV1 and FVC pulmonary function between TDI exposed and non-exposed, were calculated. When applicable, a random effects meta-analysis was performed. The overall summary ORasthma for TDI exposed versus non-exposed was 1.18 (95% CI = 0.78-1.79). The summary of the predicted mean percentage difference (MD%predicted) between exposed versus non-exposed was 2.96% for FEV1 and 3.75% for FVC. A very small decrease of 5 mL/yr for FEV1 and 10 mL/yr for FVC, respectively, was observed between the exposed and the non-exposed groups. There was moderate to low heterogeneity between study results, and most studies were evaluated as high-quality. This meta-analysis found no statistically significant adverse association between TDI occupational exposure and OA. No meaningful differences in lung function were detected between exposed and unexposed groups

The Association Between Dimethylacetamide Exposure and Liver Toxicity: A Large Retrospective Analysis in Workers From Four European Factories

Objective: This study examines the association between 8-h time weighted N, N-dimethylacetamide (DMAc) air exposure and potential hepatocellular injury in a retrospective study among fibre-production workers in four European factories. Methods and Results: Twenty-nine (1.5%) of 1844 alanine aminotransferase (ALT) observations had liver values two times above normal; 0.2% three times above normal and 0.05% five times above normal. Two (0.1%) observations were indicative of hepatocellular injury. Logistic regression analyses showed an odds ratio for elevated ALT of 0.88 per 1 ppm (P trend = 0.39). Linear random effects regression analyses showed a decrease of one international unit (IU/L) ALT per 1 ppm increase of DMAc exposure (P = 0.002). Conclusions: This study found no association between DMAc exposure and hepatoxicity amongst European workers. The prevalence of elevated liver values was lower compared to the general population without occupational exposure

How Reliable Are Hog Futures as Forecasts?

The Chicago Mercantile Exchange hog futures contract was revamped in 1997 and it is one of the largest futures markets for a nonstorable commodity. The literature is divided on whether or not futures prices for nonstorables provide reliable forecasts of cash prices. We find that from 1998 to 2004, the hog futures market was an unbiased predictor of cash prices. Copyright 2008, Oxford University Press.

PUVA plus interferon α2b in the treatment of advanced or refractory to PUVA early stage mycosis fungoides: A case series

Background The combination of PUVA with variable doses of systemically administered interferon α2b (IFN-α2b) reduces the number of PUVA treatments and the dose of IFN-α2b required to produce remission in all mycosis fungoides (MF) stages. Objectives To evaluate the efficacy of the combination of PUVA and IFN-α2b in patients with late stage or refractory to treatment early stage MF. Methods The combination of PUVA three times weekly and IFN-α2b 2-5 MU three times weekly was retrospectively reviewed in 22 patients. Kaplan-Meyer method and log-rank test was used for statistical analysis. Results Twenty-two patients were analysed, seven with refractory to PUVA early stage MF, seven with tumour stage, five with erythrodermic MF and three with Sézary syndrome (SS). The overall response rate (complete or partial response) was 68%, including 10 complete responses (CR) (45%) and five partial responses (PR) (23%). Significantly, more patients of the early stage group achieved CR compared with the advanced stage group (86% vs. 27%, P = 0.03). Within the advanced stage group, CR rates were 14% vs. 37% in stage IIB and III/SS patients respectively, but the difference was not statistically significant. Patients with early stage disease had a 2-year PFS of 100% vs. 27% for the advanced stage group (P < 0.001). Sustained remissions (>2 years) were achieved in five out of six complete responders in the early stage group of patients. Conclusion This combination of IFN-α2b and PUVA is an effective and safe treatment for refractory to treatment early stage MF patients as well as treatment-naïve advanced stage patients. Its efficacy is more pronounced in the former patient group. © 2010 European Academy of Dermatology and Venereology