Associations between socio-economic factors and alcohol consumption: A population survey of adults in England.

AIM: To gain a better understanding of the complex relationships of different measures of social position, educational level and income with alcohol consumption in England. METHOD: Between March 2014 and April 2018 data were collected on n = 57,807 alcohol drinkers in England taking part in the Alcohol Toolkit Study (ATS). Respondents completed the AUDIT-C measure of frequency of alcohol consumption, amount consumed on a typical day and binge drinking frequency. The first two questions were used to derive a secondary measure of quantity: average weekly unit consumption. Socio-economic factors measured were: social-grade (based on occupation), employment status, educational qualifications, home and car ownership and income. Models were constructed using ridge regression to assess the contribution of each predictor taking account of high collinearity. Models were adjusted for age, gender and ethnicity. RESULTS: The strongest predictor of frequency of alcohol consumption was social-grade. Those in the two lowest occupational categories of social grade (e.g. semi-skilled and unskilled manual workers, and unemployed, pensioners, casual workers) has fewer drinking occasions than those in professional-managerial occupations (β = -0.29, 95%CI -0.34 to -0.25; β = -0.31, 95%CI -0.33 to -0.29). The strongest predictor of consumed volume and binge drinking frequency was lower educational attainment: those whose highest qualification was an A-level (i.e. college/high school qualification) drank substantially more on a typical day (β = 0.28, 95%CI 0.25 to 0.31) and had a higher weekly unit intake (β = 3.55, 95%CI 3.04 to 4.05) than those with a university qualification. They also reported a higher frequency of binge drinking (β = 0.11, 95%CI 0.09 to 0.14). Housing tenure was a strong predictor of all drinking outcomes, while employment status and car ownership were the weakest predictors of most outcomes. CONCLUSION: Social-grade and educational attainment appear to be the strongest socioeconomic predictors of alcohol consumption indices in England, followed closely by housing tenure. Employment status and car ownership have the lowest predictive power

Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study

Background: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. Patients and Methods: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. Results: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. Conclusions: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence

Unravelling the alcohol harm paradox: a population-based study of social gradients across very heavy drinking thresholds

Background: There is consistent evidence that individuals in higher socioeconomic status groups are more likely to report exceeding recommended drinking limits, but those in lower socioeconomic status groups experience more alcohol-related harm. This has been called the ‘alcohol harm paradox’. Such studies typically use standard cut-offs to define heavy drinking, which are exceeded by a large proportion of adults. Our study pools data from six years (2008–2013) of the population-based Health Survey for England to test whether the socioeconomic distribution of more extreme levels of drinking could help explain the paradox. Methods: The study included 51,498 adults from a representative sample of the adult population of England for a cross-sectional analysis of associations between socioeconomic status and self-reported drinking. Heavy weekly drinking was measured at four thresholds, ranging from 112 g+/168 g + (alcohol for women/men, or 14/21 UK standard units) to 680 g+/880 g + (or 85/110 UK standard units) per week. Heavy episodic drinking was also measured at four thresholds, from 48 g+/64 g + (or 6/8 UK standard units) to 192 g+/256 g + (or 24/32 UK standard units) in one day. Socioeconomic status indicators were equivalised household income, education, occupation and neighbourhood deprivation. Results: Lower socioeconomic status was associated with lower likelihoods of exceeding recommended limits for weekly and episodic drinking, and higher likelihoods of exceeding more extreme thresholds. For example, participants in routine or manual occupations had 0.65 (95 % CI 0.57–0.74) times the odds of exceeding the recommended weekly limit compared to those in ‘higher managerial’ occupations, and 2.15 (95 % CI 1.06–4.36) times the odds of exceeding the highest threshold. Similarly, participants in the lowest income quintile had 0.60 (95 % CI 0.52–0.69) times the odds of exceeding the recommended weekly limit when compared to the highest quintile, and 2.30 (95 % CI 1.28–4.13) times the odds of exceeding the highest threshold. Conclusions: Low socioeconomic status groups are more likely to drink at extreme levels, which may partially explain the alcohol harm paradox. Policies that address alcohol-related health inequalities need to consider extreme drinking levels in some sub-groups that may be associated with multiple markers of deprivation. This will require a more disaggregated understanding of drinking practice

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants with Treatment Resistance in Schizophrenia

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10501) and individuals with non-TRS (n = 20325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85490 participants (48635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P =.001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P =.04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The destiny of an abstract: What predicts publication as a full text journal article?

Aim: The progress of a discipline depends on the knowledge widely shared, an aim fulfilled by publications. But which are the factors influencing publication? We examine predictors of a subsequent publication for abstracts submitted to the annual scientific conference of the German Society of Orthodontics (DGKFO). Methods: For all 288 abstracts presented in 2014 and 2015 we recorded presentation format, number and gender of authors, study design and university affiliation. Subsequent publication as a peer-reviewed full-text article was researched over a period of more than three years. Results: A total of 88 abstracts (30.6 %) were published in full-text after a mean time span of 1.2 +/- 1.6 years after the respective conference. In multivariate logistic regression, secondary studies (OR 9.27 [1.51-57.04]; p= 0.016), a higher number of authors (OR 1.21 [1.02-1.43]; p= 0.030), a higher percentage of female authors (OR 1.01 [1.00-1.03]; p= 0.036) but male gender of the first author (OR 2.10 [1.11-3.98]; p=0.023) resulted in a higher probability of getting published as a journal paper. Conclusion: Our investigation shows that secondary studies, a higher number of authors, a higher percentage of women among the authors and male first authors are predictive factors of publication. After more than three years, only about one third of the abstracts presented at the DGKFO annual scientific conference have been published as a full-text journal article, meaning that a huge part of knowledge remains unshared