Citations

Background Adenosine‐assisted transthoracic Doppler‐derived coronary flow reserve ( TDE ‐ CFR ) reflects coronary vascular function. The prognostic and incremental value of left anterior descending coronary artery TDE ‐ CFR above myocardial perfusion scintigraphy in patients with suspected myocardial ischemia has not yet been studied. Methods and Results Three hundred seventy‐one patients (mean age, 62.3±8.7 years; 46.8% males) referred to myocardial perfusion scintigraphy attributed to suspected myocardial ischemia were included in the study. The TDE ‐ CFR result was blinded to the referring physician. Patients were followed up regarding major cardiovascular events, defined as cardiovascular death, myocardial infarction, or acute revascularization during a median follow‐up time of 4.5 years. A TDE ‐ CFR value of ≤2.0 was considered reduced. Major cardiovascular events occurred during follow‐up in 60 patients (16.2%). A reduced TDE ‐ CFR was detected in 76 patients (20.5%). Patients with reduced TDE ‐ CFR had an event rate of 36.8% compared to 10.8% in patients with normal TDE ‐ CFR (unadjusted hazard ratio, 4.63; 95% CI, 2.78–7.69; P <0.001). In a multivariate model, TDE ‐ CFR remained a significant independent predictor of major cardiovascular events. The major cardiovascular events rate was 7.5% in patients without myocardial perfusion scintigraphy‐detected myocardial ischemia and normal TDE ‐ CFR (n=200), 24.2% in patients without ischemia but with reduced TDE ‐ CFR (n=33), and 46.5% in patients with both myocardial perfusion scintigraphy–detected myocardial ischemia and a reduced TDE ‐ CFR (n=43; P <0.001). Conclusions Coronary microvascular dysfunction, as determined by TDE ‐ CFR, is a strong independent predictor of cardiovascular events and adds incremental prognostic value compared with myocardial perfusion scintigraphy. The current study supports routine assessment of CFR in patients with suspected ischemic heart disease.

OBJECTIVE The Diabetes Control and Complications Trial (DCCT) demonstrated the beneficial effects of intensive versus conventional therapy on the development and progression of microvascular complications of type 1 diabetes. These beneficial effects were almost completely explained by the difference between groups in the levels of HbA1c, which in turn were associated with the risk of these complications. We assessed the association of glucose variability within and between quarterly 7-point glucose profiles with the development and progression of retinopathy, nephropathy, and cardiovascular autonomic neuropathy during the DCCT. RESEARCH DESIGN AND METHODS Measures of variability included the within-day and updated mean (over time) of the SD, mean amplitude of glycemic excursions (MAGE), and M-value, and the longitudinal within-day, between-day, and total variances. Imputation methods filled in the 16.3% of expected glucose values that were missing. RESULTS Cox proportional hazards models assessed the association of each measure of glycemic variation, as a time-dependent covariate, with the risk of retinopathy and nephropathy, and a longitudinal logistic regression model did likewise for cardiovascular autonomic neuropathy. Adjusted for mean blood glucose, no measure of within-day variability was associated with any outcome. Only the longitudinal mean M-value (over time) was significantly associated with microalbuminuria when adjusted for the longitudinal mean blood glucose and corrected for multiple tests using the Holm procedure. CONCLUSIONS Overall, within-day glycemic variability, as determined from quarterly glucose profiles, does not play an apparent role in the development of microvascular complications beyond the influence of the mean glucose.

Abstract Background The American Board of Anesthesiology administers written and oral examinations for its primary certification. This retrospective cohort study tested the hypothesis that the risk of a disciplinary action against a physician’s medical license is lower in those who pass both examinations than those who pass only the written examination. Methods Physicians who entered anesthesiology training from 1971 to 2011 were followed up to 2014. License actions were ascertained via the Disciplinary Action Notification Service of the Federation of State Medical Boards. Results The incidence rate of license actions was relatively stable over the study period, with approximately 2 to 3 new cases per 1,000 person-years. In multivariable models, the risk of license actions was higher in men (hazard ratio = 1.88 [95% CI, 1.66 to 2.13]) and lower in international medical graduates (hazard ratio = 0.73 [95% CI, 0.66 to 0.81]). Compared with those passing both examinations on the first attempt, those passing neither examination (hazard ratio = 3.60 [95% CI, 3.14 to 4.13]) and those passing only the written examination (hazard ratio = 3.51 [95% CI, 2.87 to 4.29]) had an increased risk of receiving an action from a state medical board. The risk was no different between the latter two groups ( P = 0.81), showing that passing the oral but not the written primary certification examination is associated with a decreased risk of subsequent license actions. For those with residency performance information available, having at least one unsatisfactory training record independently increased the risk of license actions. Conclusions These findings support the concept that an oral examination assesses domains important to physician performance that are not fully captured in a written examination.

AbstractLittle is known about individuals’ motivation, perception, and treatment beliefs towards the use of genetic information in risk estimates for coronary heart disease (CHD). In this study, participants at intermediate 10‐year risk of CHD were randomized to receive either their estimated conventional risk score (CRS) alone, or a CRS and a genetic risk score (GRS), by a genetic counselor. Surveys on motivation to participate in and perception of genetic testing for CHD were administered at 3 months and treatment beliefs at 6 months following risk disclosure. Survey responses used Likert scales. Linear and logistic regression were used for analysis. Overall, motivation to participate in genomic clinical trials was favorable and did not differ between the CRS and GRS groups (16.95 ± 0.82 vs. 17.58 ± 0.83, p = 0.091), but participants who initially received their GRS indicated a greater desire to find ways to improve health as a reason for participation (OR: 0.53 (95%CI: 0.29, 0.94), p = 0.028). Perception of genetic testing was also favorable in both groups (15.29 ± 0.39 vs. 15.12 ± 0.40, p = 0.835). Participants who initially received their GRS were more inclined to recommend genetic testing to family and friends (9.95 ± 1.88 vs. 10.52 ± 2.17, p = 0.023). In the MI‐GENES study, motivation to participate in and perception of genetic testing among study participants were overall favorable. Genetic risk disclosure was associated with increased motivation to recommend genetic testing to family and friends.

ObjectiveTo develop response criteria for adult dermatomyositis (DM) and polymyositis (PM).MethodsExpert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus.ResultsConsensus was reached for a conjoint analysis–based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0–100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001).ConclusionThe response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

Abstract Glioblastoma (GBM) represents one of the most aggressive cancer types with the vast majority of patients succumbing to disease within the first five years. This dire prognosis reflects the limited efficacy of our frontline therapies which include radiation therapy and temozolomide (TMZ) chemotherapy. The cellular response to these therapies is critically mediated by DNA damage response signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR). Preliminary studies from our laboratory suggest the ATR inhibitor VX-970 has single agent efficacy in both established and primary GBM cell lines. Moreover, combined treatment with TMZ demonstrated therapeutic responses that, following regression analysis, were deemed synergistic (p&lt;0.001). Validation studies using siRNA confirmed ATR as a central mediator of TMZ sensitivity as knockdown of ATM elicited no added benefit when tested in combination. VX-970 also enhanced radiation effects in neurosphere formation assays to suggest it may also be used as a radiosensitizer. While the specific mechanism responsible for these observations has yet to be determined, VX-970 treatment was found to exert anti-proliferative effects in a dose-dependent manner. This collection of work suggests that ATR inhibition may represent a worthwhile treatment strategy in GBM. Citation Format: Danielle Burgenske, Ann Mladek, Jann Sarkaria. The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B21.