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Background Traditional clinical trial designs strive to definitively establish the superiority of an experimental treatment, which results in risk-adverse criteria and large sample sizes. Increasingly, common cancers are recognized as consisting of small subsets with specific aberrations for targeted therapy, making large trials infeasible. Purpose To compare the performance of different trial design strategies over a long-term research horizon. Methods We simulated a series of two-treatment superiority trials over 15 years using different design parameters. Trial parameters examined included the number of positive trials to establish superiority (one-trial vs. two-trial rule), α level (2.5%–50%), and the number of trials in the 15-year period, K (thus, trial sample size). The design parameters were evaluated for different disease scenarios, accrual rates, and distributions of treatment effect. Metrics used included the overall survival gain at a 15-year horizon measured by the hazard ratio (HR), year 15 versus year 0. We also computed the expected total survival benefit and the risk of selecting as new standard of care at year 15 a treatment inferior to the initial control treatment, P(detrimental effect). Results Expected survival benefits over the 15-year horizon were maximized when more (smaller) trials were conducted than recommended under traditional criteria, using the criterion of one positive trial (vs. two), and relaxing the α value from 2.5% to 20%. Reducing the sample size and relaxing the α value also increased the likelihood of selecting an inferior treatment at the end. The impact of α and K on the survival benefit depended on the specific disease scenario and accrual rate: greater gains for relaxing α in diseases with good outcome and/or low accrual rates and greater gains for increasing K for diseases with poor outcomes. Trials with smaller sample size did not perform well when using stringent (standard) level of evidence. For each disease scenario and accrual rate studied, the optimal design, defined as the design that the maximized expected total survival benefit while constraining P(detrimental effect) < 2.5%, specified α = 20% or 10%, and a sample size considerably smaller than that recommended by the traditional designs. The results were consistent under different assumed distributions for treatment effect. Limitations The simulations assumed no toxicity issues and did not consider interim analyses. Conclusions It is worthwhile to consider a design paradigm that seeks to maximize the expected survival benefit across a series of trials, over a longer research horizon. In today’s environment of constrained, biomarker-selected populations, our results indicate that smaller sample sizes and larger α values lead to greater long-term survival gains compared to traditional large trials designed to meet stringent criteria with a low efficacy bar.

Although children with social phobia (SP) and selective mutism (SM) present similarly in a clinical setting, it remains unclear whether children with SM are unable to speak due to overwhelming anxiety, or whether withholding speech functions as an avoidance mechanism. A total of 35 children (ages 5-12 years) with either SM ( n = 10), SP ( n = 11), or no diagnosis ( n = 14) participated in the current study. Measurements included clinician, child, and parent ratings as well as behavioral observations and psychophysiological measures. Independent evaluators and clinicians rated children with SM as more severely impaired, more anxious, and less socially effective, but the groups did not differ in self- or parent-reported anxiety. Psychophysiological measures indicated that children in the SM group experienced less arousal than other children during social interaction tasks. The authors postulate that lack of speech may serve as an avoidance mechanism and thus account for this lack of arousal.

Background— Na V 1.5 is a mechanosensitive voltage-gated sodium-selective ion channel responsible for the depolarizing current and maintenance of the action potential plateau in the heart. Ranolazine is a Na V 1.5 antagonist with antianginal and antiarrhythmic properties. Methods and Results— Mechanosensitivity of Na V 1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. In whole cells, bath flow increased peak inward current in both murine ventricular cardiac myocytes (24±8%) and human embryonic kidney 293 cells heterologously expressing Na V 1.5 (18±3%). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and Na V 1.5-expressing human embryonic kidney 293 cells, negative pressure increased Na V peak currents by 27±18% and 18±4% and hyperpolarized voltage dependence of activation by −11 mV and −10 mV, respectively. In human embryonic kidney 293 cells, negative pressure also increased the window current (250%) and increased late open channel events (250%). Ranolazine decreased pressure-induced shift in the voltage dependence (IC 50 54 μmol/L) and eliminated the pressure-induced increases in window current and late current event numbers. Block of Na V 1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of Na V 1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity. Conclusions— Ranolazine effectively inhibits mechanosensitivity of Na V 1.5. The block of Na V 1.5 mechanosensitivity by ranolazine does not utilize the established binding site and may require bilayer partitioning. Ranolazine block of Na V 1.5 mechanosensitivity may be relevant in disorders of mechanoelectric dysfunction.

To identify genes influencing blood pressure response to an angiotensin II receptor blocker, single nucleotide polymorphisms identified by genome-wide association analysis of the response to candesartan were validated by opposite direction associations with the response to a thiazide diuretic, hydrochlorothiazide. We sampled 198 white and 193 blacks with primary hypertension from opposite tertiles of the race-sex–specific distributions of age-adjusted diastolic blood pressure response to candesartan. There were 285 polymorphisms associated with the response to candesartan at P <10 −4 in whites. A total of 273 of the 285 polymorphisms, which were available for analysis in a separate sample of 196 whites, validated for opposite direction associations with the response to hydrochlorothiazide (Fisher χ 2 1-sided P =0.02). Among the 273 polymorphisms, those in the chromosome 11q21 region were the most significantly associated with response to candesartan in whites (eg, rs11020821 near FUT4 , P =8.98×10 −7 ), had the strongest opposite direction associations with response to hydrochlorothiazide (eg, rs3758785 in GPR83 , P =7.10×10 −3 ), and had the same direction associations with response to candesartan in the 193 blacks (eg, rs16924603 near FUT4 , P =1.52×10 −2 ). Also notable among the 273 polymorphisms was rs11649420 on chromosome 16 in the amiloride-sensitive sodium channel subunit SCNN1G involved in mediating renal sodium reabsorption and maintaining blood pressure when the renin-angiotensin system is inhibited by candesartan. These results support the use of genomewide association analyses to identify novel genes predictive of opposite direction associations with blood pressure responses to inhibitors of the renin-angiotensin and renal sodium transport systems.

What's known on the subject? and What does the study add? Postoperative complications for open radical nephrectomy ( ORN ), laparoscopic radical nephrectomy ( LRN ), and open partial nephrectomy ( OPN ) and its relationship with hospitalisation costs and mortality remain poorly described. The present population‐based study suggests modest differences in postoperative complications estimated at 27%, 23%, and 24% among patients with kidney cancer undergoing ORN , LRN , and OPN , respectively. Moreover, postoperative complications were associated with higher mortality, length of stay and total costs of hospitalisation. Objectives The association of complications after renal surgery for renal cell carcinoma ( RCC ) with in‐hospital mortality and costs remains to be defined. To describe the incidence of complications after open radical nephrectomy ( ORN ), laparoscopic RN ( LRN ), and open partial nephrectomy ( OPN ); and to evaluate its relationship with in‐hospital mortality and total costs. Patients and Methods We identified 49 983 individuals who underwent ORN (35 712), LRN (5327), or OPN (8944) for RCC at 2037 hospitals from the Nationwide Inpatient Sample 2001–2008. The outcomes assessed were in‐hospital mortality and total hospitalisation costs. Multivariable logistic regression and generalised estimating equations were used to test the associations between complications and in‐hospital mortality and total costs. Results With 26.0% of patients experiencing postoperative complications, there were modest differences in the proportion of patients with complications after ORN , LRN , and OPN at 27.0%, 22.6%, and 24.0%, respectively ( P < 0.001). After adjusting for patient and hospital variables, postoperative complications resulted in higher odds of in‐hospital death for ORN (odds ratio [ OR ] 7.20; P < 0.001), LRN ( OR 12.04; P < 0.001), and OPN ( OR 7.82; P < 0.001). Adjusted total costs also rose significantly with the presence of any postoperative complications compared with those without any complications for ORN ($21 242 vs $13 183; P < 0.001), LRN ($19 548 vs $12 555; P < 0.001), and OPN ($18 883 vs $12 098; P < 0.001). Conclusions With about a quarter of patients experiencing postoperative complications, adverse events for ORN , LRN , and OPN carry a significant risk of in‐hospital death and higher total costs. Efforts to reduce postoperative complications may correlate with substantial reductions in hospital mortality and total costs.

Abstract Background: Current management of lung nodules is complicated by nontherapeutic resections and missed chances for cure. We hypothesized that a serum proteomic signature may add diagnostic information beyond that provided by combined clinical and radiographic data. Methods: Cohort A included 265 and cohort B 114 patients. Using multivariable logistic regression analysis we calculated the area under the receiver operating characteristic curve (AUC) and quantified the added value of a previously described serum proteomic signature beyond clinical and radiographic risk factors for predicting lung cancer using the integration discrimination improvement (IDI) index. Results: The average computed tomography (CT) measured nodule size in cohorts A and B was 37.83 versus 23.15 mm among patients with lung cancer and 15.82 versus 17.18 mm among those without, respectively. In cohort A, the AUC increased from 0.68 to 0.86 after adding chest CT imaging variables to the clinical results, but the proteomic signature did not provide meaningful added value. In contrast, in cohort B, the AUC improved from 0.46 with clinical data alone to 0.61 when combined with chest CT imaging data and to 0.69 after adding the proteomic signature (IDI of 20% P = 0.0003). In addition, in a subgroup of 100 nodules between 5 and 20 mm in diameter, the proteomic signature added value with an IDI of 15% (P ≤ 0.0001). Conclusions: The results show that this serum proteomic biomarker signature may add value to the clinical and chest CT evaluation of indeterminate lung nodules. Impact: This study suggests a possible role of a blood biomarker in the evaluation of indeterminate lung nodules. Cancer Epidemiol Biomarkers Prev; 21(5); 786–92. ©2012 AACR.