Search

Background: In our recent clinical trial, the addition of omalizumab to oral immunotherapy (OIT) for milk allergy improved safety, but no significant clinical benefit was detected., Objective: We sought to investigate mechanisms by which omalizumab modulates immunity in the context of OIT and to identify baseline biomarkers that predict subgroups of patients most likely to benefit from omalizumab., Methods: Blood was obtained at baseline and multiple time points during a placebo-controlled trial of OIT for milk allergy in which subjects were randomized to receive omalizumab or placebo. Immunologic outcomes included measurement of basophil CD63 expression and histamine release and casein-specific CD4 + regulatory T-cell proliferation. Biomarkers were analyzed in relationship to measurements of safety and efficacy., Results: Milk-induced basophil CD63 expression was transiently reduced in whole blood samples from both omalizumab- and placebo-treated subjects. However, IgE-dependent histamine release increased in washed cell preparations from omalizumab- but not placebo-treated subjects. No increase in regulatory T-cell frequency was evident in either group. Subjects with lower rates of adverse reactions, regardless of arm, experienced better clinical outcomes. Pre-OIT basophil reactivity positively associated with occurrence of symptoms during OIT, whereas the baseline milk IgE/total IgE ratio correlated with the likelihood of achieving sustained unresponsiveness. A combination of baseline basophil and serologic biomarkers defined a subset of patients in which adjunctive therapy with omalizumab was associated with attainment of sustained unresponsiveness and a reduction in adverse reactions., Conclusions: Combining omalizumab therapy with milk OIT led to distinct alterations in basophil reactivity but not T-cell responses. Baseline biomarkers can identify subjects most likely to benefit from adjunctive therapy with omalizumab., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Pulmonary arterial hypertension (PH) and chronic kidney disease (CKD) both profoundly impact patient outcomes, whether as primary disease states or as co-morbid conditions. PH is a common co-morbidity in CKD and vice versa. A growing body of literature describes the epidemiology of PH secondary to chronic kidney disease and end-stage renal disease (ESRD) (WHO group 5 PH). But, there are only limited data on the epidemiology of kidney disease in group 1 PH (pulmonary arterial hypertension [PAH]). The purpose of this review is to summarize the current data on epidemiology and discuss potential disease mechanisms and management implications of kidney dysfunction in PAH. Kidney dysfunction, determined by serum creatinine or estimated glomerular filtration rate, is a frequent co-morbidity in PAH and impaired kidney function is a strong and independent predictor of mortality. Potential mechanisms of PAH affecting the kidneys are increased venous congestion, decreased cardiac output, and neurohormonal activation. On a molecular level, increased TGF-β signaling and increased levels of circulating cytokines could have the potential to worsen kidney function. Nephrotoxicity does not seem to be a common side effect of PAH-targeted therapy. Treatment implications for kidney disease in PAH include glycemic control, lifestyle modification, and potentially Renin-Angiotensin-Aldosterone System (RAAS) blockade.

A first-in-human, phase 1, double blind, placebo-controlled, single ascending dose study examined the safety, tolerability, and exploratory efficacy of intravenous infusion of a recombinant growth factor, cimaglermin alfa, in patients with heart failure and left ventricular systolic dysfunction (LVSD). In these patients on optimal guideline-directed medical therapy, cimaglermin treatment was generally tolerated except for transient nausea and headache and a dose-limiting toxicity was noted at the highest planned dose. There was a dose-dependent improvement in left ventricular ejection fraction lasting 90 days following infusion. Thus, cimaglermin is a potential therapy to enhance cardiac function in LVSD and warrants further investigation.

Background: Atrial fibrillation (AF) is associated with cardiac fibrosis, which can now be measured noninvasively using T1-mapping with cardiac magnetic resonance imaging (CMRI). This study aimed to assess the impact of AF on ventricular T1 at the time of CMRI., Methods: Subjects with AF scheduled for AF ablation underwent CMRI with standard electrocardiography gating and breath-hold protocols on a 1.5 T scanner with post-contrast ventricular T1 recorded from 6 regions of interest at the mid-ventricle. Baseline demographic, clinical, and imaging characteristics were examined using univariate and multivariable linear regression modeling for an association with myocardial T1., Results: One hundred fifty-seven patients were studied (32% women; median age, 61 years [interquartile range {IQR}, 55-67], 50% persistent AF [episodes>7 days or requiring electrical or pharmacologic cardioversion], 30% in AF at the time of the CMRI). The median global T1 was 404 ms (IQR, 381-428). AF at the time of CMRI was associated with a 4.4% shorter T1 (p=0.000) compared to sinus rhythm when adjusted for age, sex, persistent AF, body mass index, congestive heart failure, and renal dysfunction (estimated glomerular filtration rate<60). A post-hoc multivariate model adjusted for heart rate suggested that heart rate elevation (p=0.009) contributes to the reduction in T1 observed in patients with AF at the time of CMRI. No association between ventricular T1 and AF recurrence after ablation was demonstrated., Conclusion: AF at the time of CMRI was associated with lower post-contrast ventricular T1 compared with sinus rhythm. This effect was at least partly due to elevated heart rate. T1 was not associated with the recurrence of AF after ablation.

Little is known about the right ventricular (RV) proteome in human heart failure (HF), including possible differences compared to the left ventricular (LV) proteome. We used 2-dimensional differential in-gel electrophoresis (pH: 4-7, 10-150 kDa), followed by liquid chromatography tandem mass spectrometry, to compare the RV and LV proteomes in 12 explanted human hearts. We used Western blotting and multiple-reaction monitoring for protein verification and RNA sequencing for messenger RNA and protein expression correlation. In all 12 hearts, the right ventricles (RVs) demonstrated differential expression of 11 proteins relative to the left ventricles (LVs), including lesser expression of CRYM, TPM1, CLU, TXNL1, and COQ9 and greater expression of TNNI3, SAAI, ERP29, ACTN2, HSPB2, and NDUFS3. Principal-components analysis did not suggest RV-versus-LV proteome partitioning. In the nonischemic RVs (n = 6), 7 proteins were differentially expressed relative to the ischemic RVs (n = 6), including increased expression of CRYM, B7Z964, desmin, ANXA5, and MIME and decreased expression of SERPINA1 and ANT3. Principal-components analysis demonstrated partitioning of the nonischemic and ischemic RV proteomes, and gene ontology analysis identified differences in hemostasis and atherosclerosis-associated networks. There were no proteomic differences between RVs with echocardiographic dysfunction (n = 8) and those with normal function (n = 4). Messenger RNA and protein expression did not correlate consistently, suggesting a major role for RV posttranscriptional protein expression regulation. Differences in contractile, cytoskeletal, metabolic, signaling, and survival pathways exist between the RV and the LV in HF and may be related to the underlying HF etiology and differential posttranscriptional regulation.

Background: Right ventricular (RV) dysfunction contributes to mortality in chronic heart failure (HF). However, the molecular mechanisms of RV failure remain poorly understood, and RV myocardial biomarkers have yet to be developed., Methods and Results: We performed RNA sequencing (RNA-seq) on 22 explanted human HF RVs and 5 unused donor human heart RVs (DON RV) and compared results to those recently reported from 16 explanted human LVs We used Bowtie-Tophat for transcript alignment and transcriptome assembly, DESeq for identification of differentially expressed genes (DEGs) and Ingenuity for exploration of gene ontologies. In the HF RV, RNA-seq identified 130,790 total RNA transcripts including 13,272 protein coding genes, 10,831 long non-coding RNA genes and 8,605 pseudogenes. There were 800-1000 DEGs between DON and HF RV comparison groups with differences concentrated in cytoskeletal, basement membrane, extracellular matrix (ECM), inflammatory mediator, hemostasis, membrane transport and transcription factor genes, lncRNAs and pseudogenes. In an unbiased approach, the top 10 DEGs SERPINA3, SERPINA5, LCN6, LCN10, STEAP4, AKR1C1, STAC2, SPARCL1, VSIG4 and F8 exhibited no overlap in read counts between DON and HF RVs, high sensitivities, specificities, predictive values and areas under the receiver operating characteristic curves. STEAP4, SPARCL1 and VSIG4 were differentially expressed between RVs and LVs, supporting their roles as RV-specific myocardial biomarkers., Conclusions: Unbiased, comprehensive profiling of the RV transcriptome by RNA-seq suggests structural changes and abnormalities in inflammatory processes and yields specific, novel HF RV vs HF LV myocardial biomarkers not previously identified by more limited transcriptome profiling approaches., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The expression of long noncoding RNAs (lncRNAs) in human heart failure (HF) has not been widely studied. Using RNA sequencing (RNA-Seq), we compared lncRNA expression in 22 explanted human HF hearts with lncRNA expression in 5 unused donor human hearts. We used Cufflinks to identify isoforms and DESeq to identify differentially expressed genes. We identified the noncoding RNAs by cross-reference to Ensembl release 73 (Genome Reference Consortium human genome build 37) and explored possible functional roles using a variety of online tools. In HF hearts, RNA-Seq identified 84,793 total messenger RNA coding and noncoding different transcripts, including 13,019 protein-coding genes, 2,085 total lncRNA genes, and 1,064 pseudogenes. By Ensembl noncoding RNA categories, there were 48 lncRNAs, 27 pseudogenes, and 30 antisense RNAs for a total of 105 differentially expressed lncRNAs in HF hearts. Compared with donor hearts, HF hearts exhibited differential expression of 7.7% of protein-coding genes, 3.7% of lncRNAs (including pseudogenes), and 2.5% of pseudogenes. There were not consistent correlations between antisense lncRNAs and parent genes and between pseudogenes and parent genes, implying differential regulation of expression. Exploratory in silico functional analyses using online tools suggested a variety of possible lncRNA regulatory roles. By providing a comprehensive profile of right ventricular polyadenylated messenger RNA transcriptome in HF, RNA-Seq provides an inventory of differentially expressed lncRNAs, including antisense transcripts and pseudogenes, for future mechanistic study.

We present a simple general method for combining two one-sample confidence procedures to obtain inferences in the two-sample problem. Some applications give striking connections to established methods; for example, combining exact binomial confidence procedures gives new confidence intervals on the difference or ratio of proportions that match inferences using Fisher's exact test, and numeric studies show the associated confidence intervals bound the type I error rate. Combining exact one-sample Poisson confidence procedures recreates standard confidence intervals on the ratio, and introduces new ones for the difference. Combining confidence procedures associated with one-sample t-tests recreates the Behrens-Fisher intervals. Other applications provide new confidence intervals with fewer assumptions than previously needed. For example, the method creates new confidence intervals on the difference in medians that do not require shift and continuity assumptions. We create a new confidence interval for the difference between two survival distributions at a fixed time point when there is independent censoring by combining the recently developed beta product confidence procedure for each single sample. The resulting interval is designed to guarantee coverage regardless of sample size or censoring distribution, and produces equivalent inferences to Fisher's exact test when there is no censoring. We show theoretically that when combining intervals asymptotically equivalent to normal intervals, our method has asymptotically accurate coverage. Importantly, all situations studied suggest guaranteed nominal coverage for our new interval whenever the original confidence procedures themselves guarantee coverage., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Transgenic and toxic models of pulmonary arterial hypertension (PAH) are widely used to study the pathophysiology of PAH and to investigate potential therapies. Given the expense and time involved in creating animal models of disease, it is critical that researchers have tools to accurately assess phenotypic expression of disease. Right ventricular dysfunction is the major manifestation of pulmonary hypertension. Echocardiography is the mainstay of the noninvasive assessment of right ventricular function in rodent models and has the advantage of clear translation to humans in whom the same tool is used. Published echocardiography protocols in murine models of PAH are lacking. In this article, we describe a protocol for assessing RV and pulmonary vascular function in a mouse model of PAH with a dominant negative BMPRII mutation; however, this protocol is applicable to any diseases affecting the pulmonary vasculature or right heart. We provide a detailed description of animal preparation, image acquisition and hemodynamic calculation of stroke volume, cardiac output and an estimate of pulmonary artery pressure.

Stem cell factor-dependent KIT activation is an essential process for mast cell homeostasis. The two major splice variants of KIT differ by the presence or absence of four amino acids (GNNK) at the juxta-membrane region of the extracellular domain. We hypothesized that the expression pattern of these variants differs in systemic mastocytosis and that transcripts containing the KIT D816V mutation segregate preferentially to one GNNK variant. A quantitative real-time PCR assay to assess GNNK(-) and GNNK(+) transcripts from bone marrow mononuclear cells was developed. The GNNK(-)/GNNK(+) copy number ratio showed a trend toward a positive correlation with the percentage of neoplastic mast cell involvement, and KIT D816V containing transcripts displayed a significantly elevated GNNK(-)/GNNK(+) copy number ratio. Relative expression of only the GNNK(-) variant correlated with increasing percentage of neoplastic mast cell involvement. A mast cell transfection system revealed that the GNNK(-) isoform of wild type KIT was associated with increased granule formation, histamine content, and growth. When accompanying the KIT D816V mutation, the GNNK(-) isoform enhanced cytokine-free metabolism and moderately reduced sensitivity to the tyrosine kinase inhibitor, PKC412. These data suggest that neoplastic mast cells favor a GNNK(-) variant predominance, which in turn enhances the activating potential of the KIT D816V mutation and thus could influence therapeutic sensitivity in systemic mastocytosis., (Published by Elsevier Inc.)

Background: Evaluation of anti-infective drugs for licensure often relies on a noninferiority (NI) design where new drug B is noninferior to comparator drug A if the difference in success rates is reliably not worse than some fixed margin. The margin must be based on historical studies that estimate the magnitude of the benefit of drug A over placebo. This approach hampers drug development because the obligatory evidence for margin determination is often nonexistent., Purpose: To develop a new method for licensure of anti-infective drugs when there is no historical evidence for reliable construction of the NI margin., Methods: The minimum inhibitory concentration (MIC) measures the minimum amount of drug that it takes to inhibit growth of bacteria in vitro. Patients who are infected with bacteria that have a low MIC to a given drug are expected to have good outcomes when treated with that drug. Thus, a differential effect of drug B versus drug A, if it exists, is likely to occur in patients whose pathogens have discordant MICs (e.g., low MIC for drug B, high MIC for drug A, or vice versa). A new paradigm for licensure of anti-infective drugs is proposed where a clinically acceptable NI margin is selected and licensure supported if the NI margin is met and B is reliably demonstrated superior to A in a subset of patients whose paired MICs favor B. The requirement for some evidence of superiority encourages a study that is carefully designed and executed., Results: Simulations indicate that the approach shows promise in realistic settings, provided adequate data are available. A simulated example illustrates use of the methods., Limitations: If the data have small sample size, weak MIC/success relationship, or high correlation between MIC-A, MIC-B, this procedure will have poor power., Conclusion: Discordant MIC analysis may offer a novel path to licensure for certain anti-infective drugs.

We examined a dual pathway, longitudinal mediational model in which child sexual abuse (CSA) influences adulthood-interpersonal functioning and sexual risk through its impact on resiliency resources and psychological distress. Women were recruited from two obstetrics and gynecological clinics serving primarily low-income, inner-city women (N = 693) and interviewed at pretest (Time 1) and 6-month follow-up (Time 2). The proposed mediators were resiliency resources (i.e., self-esteem and self-efficacy) and psychological distress (i.e., depressive and posttraumatic stress symptoms). The interpersonal outcomes were general interpersonal problems (measured via recent loss of interpersonal resources, lack of perceived current social support, and recent social conflict) and HIV/sexual risk (measured via lack of confidence asserting safe-sex practices, intimate-partner risk, and perceived barriers to safe sex). A respecified, partial structural equation model implying full mediation supported our hypotheses. Model fit was assessed using the chi-square goodness-of-fit statistic, comparative-fit index (CFI), root mean square error of approximation (RMSEA), and standardized root mean square residual (SRMR; CFI = .96, RMSEA = .05, SRMR = .04). The impact of CSA on interpersonal problems was mediated through its effect on psychological distress, whereas the impact of CSA on HIV/sexual risk was mediated through its effect on resiliency resources. Implications for intervention are discussed. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

We propose an approach to analyze survival time in a crossover clinical trial by performing a primary ranking on whether events occur and a secondary ranking on event times. This hierarchical ranking method is meant to reflect the idea that the goal of therapy is to prevent a clinical event and, failing that, to delay the occurrence of the event, hopefully for a substantial amount of time. We compare our approach with other methods including one method proposed by Feingold and Gillespie, a recommended procedure. The power is similar in many settings, but the hierarchical ranking can have substantially greater power under certain censoring patterns and also under a cure model, or models where treatment induces a substantial delay in some fraction of patients. We additionally feel that the hierarchical ranking method should be more clinically relevant in many settings. The method can also be applied to continuous outcomes censored by a limit of detection, such as HIV viremia., (Copyright © 2011 John Wiley & Sons, Ltd.)

STAT3 transcription factor signaling in specific T helper cell differentiation has been well described, although the broader roles for STAT3 in lymphocyte memory are less clear. Patients with autosomal-dominant hyper-IgE syndrome (AD-HIES) carry dominant-negative STAT3 mutations and are susceptible to a variety of bacterial and fungal infections. We found that AD-HIES patients have a cell-intrinsic defect in the number of central memory CD4(+) and CD8(+) T cells compared to healthy controls. Naive T cells from AD-HIES patients had lower expression of memory-related transcription factors BCL6 and SOCS3, a primary proliferation defect, and they failed to acquire central memory-like surface phenotypes in vitro. AD-HIES patients showed a decreased ability to control varicella zoster virus (VZV) and Epstein-Barr virus (EBV) latency, and T cell memory to both of these viruses was compromised. These data point to a specific role for STAT3 in human central memory T cell formation and in control of certain chronic viruses., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Minimization as an alternative to randomization is gaining popularity for small clinical trials. In response to critics' questions about the proper analysis of such a trial, proponents have argued that a rerandomization approach, akin to a permutation test with conventional randomization, can be used. However, they add that this computationally intensive approach is not necessary because its results are very similar to those of a t-test or test of proportions unless the sample size is very small. We show that minimization applied with unequal allocation causes problems that challenge this conventional wisdom., (© 2011, The International Biometric Society No claim to original US Federal works.)

This paper extends standard methodology for noninferiority trial design from a binary endpoint to an ordered three-level endpoint, such as "success," "intermediate," and "failure." A metric that summarizes outcome on this endpoint is proposed, and the corresponding sample size requirements are presented. This ordered endpoint can be collapsed into two different binary endpoints, respectively lumping "intermediate" outcomes with "success" or with "failure." We describe how the ordered three-level endpoint compares with these two binary endpoints with respect to the noninferiority margin and sample size requirements.

The approach to early termination for efficacy in a trial where events occur over time but the primary question of interest relates to a long-term binary endpoint is not straightforward. This article considers comparison of treatment groups with Kaplan-Meier (KM) proportions evaluated at increasing times from randomization, at increasing calendar testing times. This strategy is employed to improve the ability to detect important treatment effects and provide critical treatments to patients in a timely manner. This dynamic Kaplan-Meier (DKM) approach is shown to be robust; that is, it produces high power and early termination time across a wide range of circumstances. In contrast, a fixed time KM comparison and the log-rank test are both shown to be more variable in performance. Practical considerations of implementing the DKM method are discussed.

Idiopathic anaphylaxis remains a perplexing disorder in which existing prophylactic therapy is inadequate. In this prospective study, we sought to determine whether patients with idiopathic anaphylaxis might have evidence for a clonal disorder of mast cells related to mastocytosis and for which novel targeted therapies might be considered. We report 12 patients with "idiopathic" anaphylaxis who did not exhibit either urticaria pigmentosa or the characteristic bone marrow biopsy finding of multifocal mast-cell aggregates observed in systemic mastocytosis. Of these 12 patients, 5 had evidence of 1 or more minor criteria for mastocytosis. C-KIT mutational analysis was positive for the 816D>V activating mutation in 3 of 3 patients in CD25(+) bone marrow cells where the analysis was performed. These results demonstrate the presence of an aberrant mast-cell population carrying clonal markers in a subset of patients diagnosed with "idiopathic" anaphylaxis, who may respond to inhibitors targeting mutated C-KIT. This intramural clinical trial was conducted in 2003 and 2004 and was registered at (http://clinicalcenter.nih.gov) with a study number 03-I-0010. Since the study is now closed, it is no longer available online.

Serum mast cell tryptase levels are used as a diagnostic criterion and surrogate marker of disease severity in mastocytosis. Approximately 29% of the healthy population lacks alpha tryptase genes; however, it is not known whether lack of alpha tryptase genes leads to variability in tryptase levels or impacts on disease severity in mastocytosis. We have thus analyzed tryptase haplotype in patients with mastocytosis, computing correlations between haplotype and plasma total and mature tryptase levels; and disease category. We found: (1) the distribution of tryptase haplotype in patients with mastocytosis appeared consistent with Hardy-Weinberg equilibrium and the distribution in the general population; (2) the disease severity and plasma tryptase levels were not affected by the number of alpha or beta tryptase alleles in this study; and (3) information about the tryptase haplotype did not provide any prognostic value about the severity of disease. Total and mature tryptase levels positively correlated with disease severity, as well as prothrombin time and partial thromboplastin time, and negatively correlated with the hemoglobin concentration.

Background: Mastocytosis is associated with a pathological increase in tissue mast cells. Associated skeletal problems include a decrease in bone density and pathological fractures., Methods: In order to explore the relationship between bone density and the severity of mastocytosis, 21 patients with mastocytosis who underwent dual-energy X-ray absorptiometry were entered into this study. Correlation coefficients were computed between Z-scores and demographic, clinical and laboratory data. Femoral neck Z-scores correlated with serum tryptase levels when all the patients were considered (p=0.029)., Results and Conclusion: Patients with less severe disease had significantly lower values at the L1-L4 spine (p=0.046) and femoral neck (p=0.029) Z-scores compared to patients with more severe disease. Most patients who had low Z-scores (between -1 and -2.5) were under 50 years of age, had less severe disease and had lower serum tryptase levels. A history of gastroesophageal reflux disease and a history of hypotensive episodes correlated with lower L1-L4 spine Z-scores (p<0.05). Thus, patients with less severe disease and lower serum tryptase levels should in particular have their bone density determined with treatment appropriate to the findings., (Copyright (c) 2006 S. Karger AG, Basel.)

The success of hepatocellular therapies using stem or progenitor cell populations is dependent upon multiple factors including the donor cell, microenvironment, and etiology of the liver injury. The following experiments investigated the impact of TGF-beta1 on a previously described population of hepatic progenitor cells (HPC). The majority of the hepatic progenitor cells were resistant to endogenously produced TGF-beta1's proapoptotic and anti-proliferative effects unlike more well-differentiated cellular populations (e.g., mature hepatocytes). Surprisingly, in vitro TGF-beta1 supplementation significantly inhibited de novo hepatic progenitor cell colony formation possibly via an indirect mechanism(s). Therefore despite the HPC's direct resistance to supplemental TGF-beta1, this cytokine's inhibitory effect on colony formation could have a potential negative impact on the use of these cells as a therapy for patients with liver disease.

While the intent-to-treat (ITT) analysis is widely accepted for superiority trials, there remains debate about its role in non-inferiority trials. It is often said that the ITT tends to be anti-conservative in the demonstration of non-inferiority. This concern has led to some reliance on per-protocol (PP) analyses that exclude patients on the basis of post-baseline events, despite the inherent bias of such analyses. We compare ITT and PP results from antibiotic trials presented to the public at the FDA's Anti-infective Drug Advisory Committee from 1999 to 2003. While the number of available trials is too small to produce clear conclusions, these data did not support the assumption that the ITT would lead to smaller treatment difference than the PP, in the setting of antibiotic trials. Possible explanations are discussed., (2004 by John Wiley & Sons, Ltd.)

Before percutaneous tracheostomy, rabbits were anesthetized and placed in the supine position with the head extended. A needle cricothyroidotomy was then performed. With the help of a guidewire and vessel dilator, a sheath introducer with sideport extension was secured into the airway. This system provided airway access for introduction or sampling of materials while the animal was breathing around the sheath introducer or through the sideport. This simple procedure was used successfully in more than 25 rabbits that recuperated and lived for several days without ongoing medical support.

Optimal critical values and times of intermediate testing points are determined to minimize expected sample size in a variety of situations. Two-stage and three-stage models are considered for a variety of values of power. We investigate the robustness of the optimality parameters.

Phase I of the Trials of Hypertension Prevention (TOHP) was a National Heart, Lung, and Blood Institute-sponsored, 3-year, national, multicenter, randomized, controlled trial designed to test the feasibility and efficacy of three life-style (weight loss, sodium restriction, and stress management) and four nutrition supplement (calcium, magnesium, fish oil, and potassium) interventions aimed at lowering diastolic blood pressure in those whose blood pressure was initially in the high normal range (80 to 89 mm Hg). A total of 2182 volunteers were recruited and allocated to the various treatment arms, such that each hypothesis was tested with a power of 85% or higher to detect a diastolic blood pressure treatment effect of 2 mm Hg. The four nutrition supplement interventions were delivered in a double-blinded fashion and the three life-style interventions, single (observed) -blinded. Phase I was designed to provide a rigorous test of short-term lowering of blood pressure for each of the seven treatments chosen and provides the basis for planning of a subsequent long-term trial of hypertension prevention.

This article considers the effect of misclassification of potential participants during the run-in period preceding randomization in a clinical trial. We present a simple mathematical model of adherence that allows for misclassification. Simulations based on this model assess the impact of a run-in period on statistical power. The run-in period is most effective when there is a high proportion of poor adherers and a low rate of misclassification. In situations with either a high degree of adherence or substantial misclassification, the run-in period may reduce the efficiency of the trial, particularly when the cost of recruitment is high. We also discuss the early adherence in two recently conducted trials that had no run-in periods in order to estimate the extent of misclassification and consequent effect on power that would have been observed had a run-in occurred.

Investigators often design clinical trials without knowing precisely the values of such necessary parameters as the variances or the event rates in the control group. In order to determine reasonable values for such parameters, they may design a small pilot study external to the main trial. In this paper we propose designs, which we term internal pilot studies, that designate a portion of the main trial as a pilot phase. At the end of the internal pilot study, the investigators recompute preselected parameters and recalculate required sample size. The study then proceeds with the modifications dictated by the internal pilot. Final analyses of the results incorporate all data, disregarding the fact that part of the data came from a pilot phase. As one example of this type of design, we consider a study to compare two normally distributed means. By simulation, we show a numerical example for which the effect of the procedure on the alpha-level is negligible, but the potential gain in power considerable. We urge considering a similar approach for a number of types of endpoints.

The randomized multicenter trials indicate that survival in patients with coronary artery disease and left ventricular dysfunction is enhanced by surgical therapy compared with medical therapy. This beneficial effect of coronary bypass surgery was demonstrated in patients with either three vessel or left main coronary artery disease, but not in those with one or two vessel disease. To determine whether subgroups of mildly symptomatic patients with one or two vessel coronary artery disease and left ventricular dysfunction have an increased risk of death or cardiac events during medical therapy, 53 consecutive patients with angiographically defined one or two vessel disease and impaired left ventricular function (ejection fraction 20% to 40%) were studied by exercise electrocardiography (ECG) and rest and exercise radionuclide angiography. All but two patients had previous myocardial infarction, and all were asymptomatic or only mildly symptomatic during medical therapy. By univariate life table analysis, mortality during medical therapy was associated significantly with the ST segment response to exercise (p less than 0.05) and with both the exercise ejection fraction (p less than 0.05) and the magnitude of change in ejection fraction with exercise (p less than 0.005). In patients with an exercise ejection fraction greater than 30%, the probability of survival at 6 years was 97 +/- 3% (+/- SE) compared with a survival rate of 62 +/- 14% in the remaining subjects (p less than 0.005). Similarly, 6 year survival was 100% in patients whose ejection fraction increased from the value at rest but was only 74 +/- 10% in the remaining patients (p less than 0.005). Exercise capacity was not associated with survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Optimal allocation strategies for the comparison of proportions, p1 and p2, in two groups are discussed. Allocations which (i) maximize the precision in the estimation of the difference p1-p2, (ii) maximize the precision in the estimation of the ratio p1/p2, (iii) maximize the power to detect a group difference, and (iv) minimize the total cost of a study are compared. The recommended allocation varies markedly with the desired objective. Furthermore, there is a wide range of allocation schemes which are effectively optimal with regard to each criterion considered. A study of congenital malformations occurring in pregnancies of diabetic women is used to illustrate how these considerations apply to the planning of a study.

The relationship between obesity and hypertension has been investigated in a large number of cross-sectional population studies and a smaller number of prospective, observational studies. The results indicate that in most populations, blood pressure increases linearly with increasing body weight or body mass index. The relationship is present across all subgroups, although the magnitude of the association appears greater in whites than blacks and greater in younger than older persons. It is estimated that as much as one-third of all hypertension may be attributable to obesity in populations where hypertension and obesity are widely prevalent. Evidence from prospective studies and clinical trials suggests that hypertension in obese patients increases the risk of cardiovascular disease and that drug treatment of hypertension reduces the risk. However, it is uncertain whether the risks associated with hypertension and the benefits of treatment are as great in obese hypertensives as they are in lean hypertensives. The effects of weight reduction on blood pressure have been investigated in a small number of randomized, controlled trials involving a total of about 600 participants. Overall, the results of the trials indicate that weight reduction lowers blood pressure over intervals of up to one year. The magnitude of the blood pressure response appears to be directly proportional to the amount of weight loss achieved. However, the latter is inversely related to the length of follow-up. Adequate maintenance of weight loss remains a major problem for the much-needed, long-term trials of the effects of weight reduction on blood pressure and the cardiovascular complications of hypertension.

A case-control study was performed to determine the relationship between galactorrhea and the use of oral contraceptives as well as other risk factors. The cases included all 109 Olmsted County residents who satisfied the diagnostic criteria for galactorrhea between 1970 and 1980. Control subjects were selected from a sampling frame of all medical registrations and matched to the cases by age, year, and residency. Pituitary adenomas were strongly associated with galactorrhea, as the relative risk was 23.2 (95% confidence interval 2.0 to 90.0). In galactorrhea cases without pituitary adenomas there was an association with oral contraceptives (ever use versus never use), as the relative risk was 2.3 (95% confidence interval 1.3 to 4.4). Among current users of oral contraceptives, the risk of galactorrhea was not increased, but there was a trend of diminishing risk with duration of use. The estimate of relative risk was 3.1 after discontinuation of oral contraceptive use and was highest for the first year after discontinuation (5.5), compared with a year or more after discontinuation (2.1). Thus, galactorrhea was associated with the cessation of oral contraceptives.

To determine the relation among ventricular arrhythmias, prognostic factors and reversible ischemia in coronary artery disease, 131 drug-free, minimally symptomatic patients were studied by radionuclide angiography and 24 hour Holter electrocardiographic monitoring. High grade ventricular arrhythmias (couplets, salvos of premature ventricular complexes and R on T phenomenon) were observed in 33 patients (25%) and were related to lower rest and exercise ejection fraction, greater number of stenotic coronary arteries and higher prevalence of regional wall motion abnormalities at rest (all p less than or equal to 0.1). Among patients with subnormal rest ejection fraction, high grade arrhythmias occurred with greater prevalence in those with reversible left ventricular dysfunction (reduction in ejection fraction) during exercise compared with those with a normal ejection fraction response (59 versus 23%, p less than 0.05), a relation observed principally in patients with multivessel disease. These data indicate that in minimally symptomatic patients with coronary artery disease, arrhythmias are related to both extent of disease and severity of regional and global ventricular dysfunction and are most prevalent in patients with ventricular dysfunction and evidence of inducible ischemia, factors indicating poor long-term prognosis during medical therapy.

Factorial designs in clinical trials allow for the study of several medical treatments simultaneously. This paper distinguishes among different types of settings in which factorial designs are useful. For the experiment that involves investigation of several new or untested therapies, we introduce a model that incorporates rates of non-compliance to therapy as well as various degrees of subadditivity of treatment effects. We compare the operating characteristics of the factorial under this model with those of competing designs and show that a modest negative interaction can considerably diminish the power to detect treatment effects in the factorial even in cases that have little power to detect this interaction. We urge, therefore, that designers of clinical trials with factorial layouts posit realistic estimates of interactions among treatments in order to assure adequate power to detect beneficial effects of treatment.