A set of easy and stringent criteria to identify immune-related adverse events (IrAE Scoring System, ISS) improves correlation with outcome in a phase 1-2 trial population

Background The benefit from immune checkpoint inhibitors (IO) is tempered by immune-related adverse events (IrAEs), which involve diverse organs, have varying biology, onset time, and severity. Several reports have found correlation between IrAE and better outcome, suggesting they may even serve as a surrogate of response, but studies are conflicting on the magnitude and significance of this correlation. Estimating the true incidence of IrAEs is particularly important in the early phase 1/2 trial setting, in order to avoid the risk of both over- and under-estimation. A key issue is the lack of IrAE diagnostic criteria, necessary to discriminate pure IrAEs from other treatment-related adverse events not sustained by an autoimmune process. Methods Of 421 patients enrolled in phase 1-2 trials, we identified patients treated with immune-oncology (IO) drugs and analysed clinical characteristics, temporal dynamics and correlation with survival of treatment-related events, identifying “High Confidence IrAEs” (HC IrAE) by careful reconsideration of available clinical parameters. We developed an IrAE Scoring System (ISS) based on 5 parameters, each ranging 0-2: available biopsy or specific test, response to immunosuppression, temporal correlation, evidence ruling out alternative cause, known IO relationship. Correlation with Overall Survival was explored by multivariate Cox proportional hazard analysis including multiple covariates (BMI, Age, tumor type, NLR, prior IO, prior Autoimmune disease, PS, baseline disease burden). To mitigate immortal time-bias, analyses were conducted i) at 2-month landmark and ii) modeling IrAEs as time-dependent covariate. Results 204 patients were treated with IO agents (41 with anti-PD(L)1 alone, 33 with non-PD(L)1 agents, 130 with combinations). 53 (25.9%) patients developed ≥ 1 treatment-related adverse event (85 total events). ISS score ranged from 0 to 8; by ROC analysis, a cutoff ≥ 5 achieved 100% specificity and 90% sensitivity to identify bona fide IrAEs. Based on this, we identified 3 groups of patients: 151 never experiencing an IrAE (“no-IrAE”), 33 low-confidence IrAE with ISS score 0-4 (“LC-IrAE”) and 20 high-confidence IrAE with ISS 5-8 (“HC-IrAE”). Compared to no-IrAE, patients experiencing HC-IrAEs had significantly lower Hazard ratio (HR) both in landmark analysis (HR=?0.242, 95% CI 0.117-0.500, p=0.0001) and IrAE as time-dependent covariate analysis ?(HR=0.244, 95% CI 0.116-0.511, p=0.0001); HR for patients experiencing LC IrAE, instead, was not statistically significant (figure 1). Conclusions ISS criteria provide a simple system to identify high confidence IrAEs, leading to more reliable estimates of IrAE incidence with significant impact on survival

Epidemiologic heterogeneity of common mood and anxiety disorders over the lifecourse in the general population: a systematic review

Background Clinical evidence has long suggested there may be heterogeneity in the patterns and predictors of common mood and anxiety disorders; however, epidemiologic studies have generally treated these outcomes as homogenous entities. The objective of this study was to systematically review the epidemiologic evidence for potential patterns of heterogeneity of common mood and anxiety disorders over the lifecourse in the general population. Methods We reviewed epidemiologic studies examining heterogeneity in either the nature of symptoms experienced ( symptom syndromes ) or in patterns of symptoms over time ( symptom trajectories ). To be included, studies of syndromes were required to identify distinct symptom subtypes, and studies of trajectories were required to identify distinct longitudinal patterns of symptoms in at least three waves of follow-up. Studies based on clinical or patient populations were excluded. Results While research in this field is in its infancy, we found growing evidence that, not only can mood and anxiety disorders be differentiated by symptom syndromes and trajectories, but that the factors associated with these disorders may vary between these subtypes. Whether this reflects a causal pathway, where genetic or environmental factors influence the nature of the symptom or trajectory subtype experienced by an individual, or whether individuals with different subtypes differed in their susceptibility to different environmental factors, could not be determined. Few studies addressed issues of comorbidity or transitions in symptoms between common disorders. Conclusion Understanding the diversity of these conditions may help us identify preventable factors that are only associated with some subtypes of these common disorders

Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants.

BACKGROUND: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. METHODS AND RESULTS: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10-8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6). CONCLUSIONS: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction

A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology

BACKGROUND: Understanding variations in the incidence of schizophrenia is a crucial step in unravelling the aetiology of this group of disorders. The aims of this review are to systematically identify studies related to the incidence of schizophrenia, to describe the key features of these studies, and to explore the distribution of rates derived from these studies. METHODS: Studies with original data related to the incidence of schizophrenia (published 1965–2001) were identified via searching electronic databases, reviewing citations and writing to authors. These studies were divided into core studies, migrant studies, cohort studies and studies based on Other Special Groups. Between- and within-study filters were applied in order to identify discrete rates. Cumulative plots of these rates were made and these distributions were compared when the underlying rates were sorted according to sex, urbanicity, migrant status and various methodological features. RESULTS: We identified 100 core studies, 24 migrant studies, 23 cohort studies and 14 studies based on Other Special Groups. These studies, which were drawn from 33 countries, generated a total of 1,458 rates. Based on discrete core data for persons (55 studies and 170 rates), the distribution of rates was asymmetric and had a median value (10%–90% quantile) of 15.2 (7.7–43.0) per 100,000. The distribution of rates was significantly higher in males compared to females; the male/female rate ratio median (10%–90% quantile) was 1.40 (0.9–2.4). Those studies conducted in urban versus mixed urban-rural catchment areas generated significantly higher rate distributions. The distribution of rates in migrants was significantly higher compared to native-born; the migrant/native-born rate ratio median (10%–90% quantile) was 4.6 (1.0–12.8). Apart from the finding that older studies reported higher rates, other study features were not associated with significantly different rate distributions (e.g. overall quality, methods related to case finding, diagnostic confirmation and criteria, the use of age-standardization and age range). CONCLUSIONS: There is a wealth of data available on the incidence of schizophrenia. The width and skew of the rate distribution, and the significant impact of sex, urbanicity and migrant status on these distributions, indicate substantial variations in the incidence of schizophrenia

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization

A longitudinal study of the relationship between depressive symptoms and cigarette use among African American adolescents

The relationship between depressive symptoms and cigarette use was examined in a sample of 623 African Americans during adolescence and transition to adulthood by using hierarchical linear modeling. Participants in the study were interviewed across 6 occasions over 8 years. Results indicate that depressive symptoms tend to decrease over time, whereas cigarette use tends to increase for both female and male adolescents. The results also suggest that depressive symptoms predict later cigarette use. Male adolescents who reported more depressive symptoms were more likely than female adolescents to use cigarettes as a way to cope with their mood. These results suggest that depressive symptoms may be important to consider when developing smoking cessation interventions for African American youth.NIDA NIH HH

Do frequent moderate exacerbations contribute to progression of chronic obstructive pulmonary disease in patients who are ex-smokers?

Jorge Dreyse,1 Orlando D&iacute;az,1 Paula Repetto,2 Arturo Morales,1 Fernando Sald&iacute;as,1 Carmen Lisboa11Department of Pulmonary Diseases, School of Medicine, 2School of Psychology, Pontificia Universidad Cat&oacute;lica de Chile, Santiago, ChileBackground: In addition to smoking, acute exacerbations are considered to be a contributing factor to progression of chronic obstructive pulmonary disease (COPD). However, these findings come from studies including active smokers, while results in ex-smokers are scarce and contradictory. The purpose of this study was to evaluate if frequent acute moderate exacerbations are associated with an accelerated decline in forced expiratory volume in one second (FEV1) and impairment of functional and clinical outcomes in ex-smoking COPD patients.Methods: A cohort of 100 ex-smoking patients recruited for a 2-year follow-up study was evaluated at inclusion and at 6-monthly scheduled visits while in a stable condition. Evaluation included anthropometry, spirometry, inspiratory capacity, peripheral capillary oxygen saturation, severity of dyspnea, a 6-minute walking test, BODE (Body mass index, airflow Obstruction, Dyspnea, Exercise performance) index, and quality of life (St&nbsp;George&rsquo;s Respiratory Questionnaire and Chronic Respiratory Disease Questionnaire). Severity of exacerbation was graded as moderate or severe according to health care utilization. Patients were classified as infrequent exacerbators if they had no or one acute exacerbation/year and frequent exacerbators if they had two or more acute exacerbations/year. Random effects modeling, within hierarchical linear modeling, was used for analysis.Results: During follow-up, 419 (96% moderate) acute exacerbations were registered. At baseline, frequent exacerbators had more severe disease than infrequent exacerbators according to their FEV1 and BODE index, and also showed greater impairment in inspiratory capacity, forced vital capacity, peripheral capillary oxygen saturation, 6-minute walking test, and quality of life. However, no significant difference in FEV1 decline over time was found between the two groups (54.7&plusmn;13 mL/year versus 85.4&plusmn;15.9 mL/year in frequent exacerbators and infrequent exacerbators, respectively). This was also the case for all other measurements.Conclusion: Our results suggest that frequent moderate exacerbations do not contribute to accelerated clinical and functional decline in COPD patients who are ex-smokers.Keywords: chronic obstructive pulmonary disease, acute exacerbations, disease progression, FEV1, BODE index, health statu

Advances in the Diagnosis of Human Strongyloidiasis

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