Re-examining the effect of door-to-balloon delay on STEMI outcomes in the context of unmeasured confounders: a retrospective cohort study

Literature studying the door-to-balloon time-outcome relation in coronary intervention is limited by the potential of residual biases from unobserved confounders. This study re-examines the time-outcome relation with further consideration of the unobserved factors and reports the population average effect. Adults with ST-elevation myocardial infarction admitted to one of the six registry participating hospitals in Australia were included in this study. The exposure variable was patient-level door-to-balloon time. Primary outcomes assessed included in-hospital and 30 days mortality. 4343 patients fulfilled the study criteria. 38.0% (1651) experienced a door-to-balloon delay of >90 minutes. The absolute risk differences for in-hospital and 30-day deaths between the two exposure subgroups with balanced covariates were 2.81 (95% CI 1.04, 4.58) and 3.37 (95% CI 1.49, 5.26) per 100 population. When unmeasured factors were taken into consideration, the risk difference were 20.7 (95% CI −2.6, 44.0) and 22.6 (95% CI −1.7, 47.0) per 100 population. Despite further adjustment of the observed and unobserved factors, this study suggests a directionally consistent linkage between longer door-to-balloon delay and higher risk of adverse outcomes at the population level. Greater uncertainties were observed when unmeasured factors were taken into consideration

Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis

Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients. Methods and Findings: We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort. Conclusions: The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC. © 2016 Jiang et al

The Unanticipated Phenomenology of the Blazar PKS 2131-021: A Unique Supermassive Black Hole Binary Candidate

Most large galaxies host supermassive black holes in their nuclei and are subject to mergers, which can produce a supermassive black hole binary (SMBHB), and hence periodic signatures due to orbital motion. We report unique periodic radio flux density variations in the blazar PKS 2131-021, which strongly suggest an SMBHB with an orbital separation of similar to 0.001-0.01 pc. Our 45.1 yr radio light curve shows two epochs of strong sinusoidal variation with the same period and phase to within less than or similar to 2% and similar to 10%, respectively, straddling a 20 yr period when this variation was absent. Our simulated light curves accurately reproduce the "red noise" of this object, and Lomb-Scargle, weighted wavelet Z-transform and least-squares sine-wave analyses demonstrate conclusively, at the 4.6 sigma significance level, that the periodicity in this object is not due to random fluctuations in flux density. The observed period translates to 2.082 +/- 0.003 yr in the rest frame at the z = 1.285 redshift of PKS 2131-021. The periodic variation in PKS 2131-021 is remarkably sinusoidal. We present a model in which orbital motion, combined with the strong Doppler boosting of the approaching relativistic jet, produces a sine-wave modulation in the flux density that easily fits the observations. Given the rapidly developing field of gravitational-wave experiments with pulsar timing arrays, closer counterparts to PKS 2131-021 and searches using the techniques we have developed are strongly motivated. These results constitute a compelling demonstration that the phenomenology, not the theory, must provide the lead in this field