Michael A. Proschan

Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet

Background The effect of dietary composition on blood pressure is a subject of public health importance. We studied the effect of different levels of dietary sodium, in conjunction with the Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in vegetables, fruits, and low-fat dairy products, in persons with and in those without hypertension. Methods A total of 412 participants were randomly assigned to eat either a control diet typical of intake in the United States or the DASH diet. Within the assigned diet, participants ate foods with high, intermediate, and low levels of sodium for 30 consecutive days each, in random order. Results Reducing the sodium intake from the high to the intermediate level reduced the systolic blood pressure by 2.1 mm Hg (P<0.001) during the control diet and by 1.3 mm Hg (P=0.03) during the DASH diet. Reducing the sodium intake from the intermediate to the low level caused additional reductions of 4.6 mm Hg during the control diet (P<0.001) and 1.7 mm Hg during t...

The Upper Limit of Physiologic Cardiac Hypertrophy in Highly Trained Elite Athletes

BACKGROUND In some highly trained athletes, the thickness of the left ventricular wall may increase as a consequence of exercise training and resemble that found in cardiac diseases associated with left ventricular hypertrophy, such as hypertrophic cardiomyopathy. In these athletes, the differential diagnosis between physiologic and pathologic hypertrophy may be difficult. METHODS To address this issue, we measured left ventricular dimensions with echocardiography in 947 elite, highly trained athletes who participated in a wide variety of sports. RESULTS The thickest left ventricular wall among the athletes measured 16 mm. Wall thicknesses within a range compatible with the diagnosis of hypertrophic cardiomyopathy (greater than or equal to 13 mm) were identified in only 16 of the 947 athletes (1.7 percent); 15 were rowers or canoeists, and 1 was a cyclist. Therefore, the wall was greater than or equal to 13 mm thick in 7 percent of 219 rowers, canoeists, and cyclists but in none of 728 participants in 22 other sports. All athletes with walls greater than or equal to 13 mm thick also had enlarged left ventricular end-diastolic cavities (dimensions, 55 to 63 mm). CONCLUSIONS On the basis of these data, a left-ventricular-wall thickness of greater than or equal to 13 mm is very uncommon in highly trained athletes, virtually confined to athletes training in rowing sports, and associated with an enlarged left ventricular cavity. In addition, the upper limit to which the thickness of the left ventricular wall may be increased by athletic training appears to be 16 mm. Therefore, athletes with a wall thickness of more than 16 mm and a nondilated left ventricular cavity are likely to have primary forms of pathologic hypertrophy, such as hypertrophic cardiomyopathy.

Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals

Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20hi/CD27lo/CD21lo) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20hi/CD27−/CD21lo) when compared with B cells with a classical memory (CD27+) or naive (CD27−/CD21hi) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.

Effects of comprehensive lifestyle modification on diet, weight, physical fitness, and blood pressure control: 18-month results of a randomized trial.

Context Can adults make sustained changes in unhealthy lifestyle behaviors? Content In this multicenter trial, 810 adult volunteers with prehypertension or stage 1 hypertension were randomly assigned to a multicomponent behavioral intervention group, a group combining the behavioral intervention plus the Dietary Approaches to Stop Hypertension (DASH) diet, or an advice only group. At 18 months, participants in both behavioral intervention groups had less hypertension, more weight loss, and better reduction in sodium and fat intake than those receiving advice only. The participants in the DASH diet group also increased their intake of fruits, vegetables, and fiber. Implications Motivated adults can sustain several lifestyle changes over 18 months, which might reduce their risk for cardiovascular disease. The Editors The public health burden of chronic diseases related to suboptimal diet and physical inactivity is enormous. It has been estimated that these lifestyle factors contribute to approximately 20% of deaths in the United States (1). Incidence of atherosclerotic cardiovascular disease, overweight and obesity, elevated blood pressure and lipid levels, diabetes, osteoporosis, and cancer is increased by unhealthy lifestyles (2-8). Multiple lifestyle factors, such as physical inactivity; excessive intake of calories, sodium, saturated fat, and cholesterol; and inadequate intake of fruits, vegetables, and low-fat dairy products, are etiologically related to the development of these diseases (4, 5, 8-10). To reduce the burden of chronic disease, increased physical activity and changes in diet are needed, yet few intervention studies have attempted to achieve many lifestyle changes simultaneously. The PREMIER randomized trial tested the effects of 2 multicomponent behavioral interventions on blood pressure (11). Both interventions promoted increased physical activity, weight loss, and reduced sodium intake, each of which is recommended by the 2005 Dietary Guidelines Scientific Advisory Committee (12). One intervention also added the Dietary Approaches to Stop Hypertension (DASH) diet (13). This diet, which is high in fruits, vegetables, and low-fat dairy products and low in saturated fat, total fat, and cholesterol, meets each of the major nutrient recommendations that were established by the Institute of Medicine (14-18). We report the effects of the PREMIER interventions on lifestyle changes and blood pressure status at 18 months. The main results of PREMIER, namely change in blood pressure at 6 months, were reported previously (11). Methods The PREMIER study design and rationale (19) and intervention methods (11) have been described previously. The institutional review boards at each clinical center; an external protocol review committee appointed by the National Heart, Lung, and Blood Institute (NHLBI); and the NHLBI reviewed and approved the protocol (available at www.kpchr.org/public/premier/intervention/default.asp). The NHLBI also appointed a data and safety monitoring board to monitor the trial. Each participant provided written informed consent. The trial was conducted from January 2000 through November 2002. Study Participants Participants were generally healthy adults, age 25 years or older, who had prehypertension or stage 1 hypertension and met the Joint National Committee VI (JNC VI) criteria for a 6-month trial of nonpharmacologic therapy (2). Targeted recruitment methods were used to ensure adequate representation of clinically important subgroups, in particular, African-American persons. Specific methods varied from site to site but included direct mailings, radio and newspaper advertisements, and networking within the local African-American communities. Eligibility criteria included not taking antihypertensive medication and having a systolic blood pressure of 120 to 159 mm Hg and a diastolic blood pressure of 80 to 95 mm Hg, based on the average of 3 screening visits. Persons with prehypertension (systolic blood pressure of 120 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg) were included because of the excess risk for cardiovascular disease in those with blood pressure within this range (20). Major exclusion criteria were a body mass index less than 18.5 kg/mg2 or greater than 45.0 kg/m2, use of antihypertensive drugs or other drugs that affect blood pressure, JNC VI risk category C (target organ damage or diabetes), use of prescription weight loss medications, previous cardiovascular event, congestive heart failure, angina, cancer, and consumption of more than 21 alcoholic drinks per week. Trial Conduct Eligible participants were randomly assigned, with equal probability, to 1 of 3 groups: an advice only comparison group (advice only); an intervention group that targeted established, guideline-recommended lifestyle recommendations (established) (2); or an intervention group targeting the established recommendations and adding the DASH dietary pattern (established plus DASH) (13). Computer-generated treatment assignments were stratified by clinic and hypertension status and were assigned in blocks of varying sizes to provide balance over time. The actual assignments were administered by using a password-protected, Web-based application developed by the coordinating center and accessible only by authorized individuals. All clinic measurement staff were blinded to treatment assignment, and all intervention staff were blinded to clinic measurements. Hypertension was defined by using the JNC VI criteria for hypertension treatment: an average systolic blood pressure of 140 mm Hg, a diastolic blood pressure greater than 90 mm Hg, or use of antihypertensive medication. Normal blood pressure was defined as systolic blood pressure less than 120 mm Hg, diastolic blood pressure less than 80 mm Hg, and no use of antihypertensive medication (21) (Figure). Intervention was provided by masters degreelevel counselors (dietitians and health educators trained in behavioral methods). The counselors were centrally trained before the start of the study, attended annual 3-day training sessions, and participated in monthly conference calls. Figure. Flow diagram of enrollment, measurements, and visit completion. Advice Only Group Participants in the advice group received advice to follow the National High Blood Pressure Education Program lifestyle recommendations for blood pressure control (2). Lifestyle recommendations included reducing weight (if overweight), following a reduced-sodium diet, engaging in regular moderate-intensity physical activity, and eating a heart-healthy diet, including the DASH diet. This advice was provided in two 30-minute individual sessions, 1 immediately after random assignment and 1 after the 6-month data collection visit. A PREMIER counselor reviewed the guidelines with the participant and provided printed educational materials and information about community resources. This intervention did not include advice to keep a food or exercise diary. Behavioral Interventions in the Established and Established plus DASH Groups Participant goals for the established and established plus DASH groups included weight loss of at least 6.8 kg (15 lb) for those with a body mass index of 25 kg/m2 or greater, at least 180 minutes per week of moderate-intensity physical activity, no more than 100 mmol per day of dietary sodium, and alcohol consumption of no more than 30 mL (1 oz) per day (2 drinks) for men and 15 mL (0.5) oz per day (1 drink) for women. Participants assigned to the established plus DASH group (but not those in the established group) also received counseling on the DASH diet, with goals for increased consumption of fruits and vegetables (9 to 12 servings/d) and low-fat dairy products (2 to 3 servings/d) and reduced consumption of saturated fat ( 7% of energy) and total fat ( 25% of energy). The intervention format, contact pattern, and behavior change strategies for the established and established plus DASH groups were identical. During the first 6 months, participants in both behavioral intervention groups attended 14 group sessions and 4 individual sessions; during months 7 to 18, they attended monthly group sessions supplemented with 3 individual counseling sessions. Throughout the trial, participants in the established and established plus DASH groups (but not those in the advice group) kept food diaries, monitored dietary calorie and sodium intakes, and recorded minutes of physical activity. Self-monitoring was used to provide individualized feedback, reinforcement, problem solving, and support. Social support for initial behavior changes and maintenance of change was provided during the group sessions. More detailed descriptions of the behavorial intervention methods are available (22). Measurements Blood pressure was assessed twice at each measurement, and systolic and diastolic blood pressures were calculated by using the mean of all available measurements (4 sets before random assignment, 3 sets at 6 and 18 months, and 1 set at 3 and 12 months). For 4 participants who were started on antihypertensive drug therapy between the 12- and 18-month visits, we obtained an official set of blood pressure measurements before initiation of therapy and used these as our 18-month blood pressure values for analysis. A similar procedure was used to obtain the 6-month blood pressure value for the 1 participant who began taking antihypertensive drugs between the 3- and 6-month visits. Two 24-hour dietary recalls, 1 obtained on a weekday and the other obtained on a weekend, were collected at baseline and at 6 and 18 months by telephone interview (23). Intakes of nutrients and food groups were calculated by using the Nutrition Data System for Research, version NDS-R 1998 (University of Minnesota, Minneapolis, Minnesota). Urinary excretion of sodium (reflecting salt intake) and potassium (reflecting fruit and vegetable intake) was obtained from 24-hour urinary collections at baseline a

Designed extension of studies based on conditional power.

: We propose a flexible method of extending a study based on conditional power. The possibility for extension when the p value at the planned end is small but not statistically significant is built in to the design of the study. The significance of the treatment difference at the planned end is used to determine the number of additional observations needed and the critical value necessary for use after accruing those additional observations. It may therefore be thought of as a two-stage procedure. Even though the observed treatment difference at stage 1 is used to make decisions, the Type I error rate is protected.

Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy

In HIV-1-infected individuals on currently recommended antiretroviral therapy (ART), viremia is reduced to <50 copies of HIV-1 RNA per milliliter, but low-level residual viremia appears to persist over the lifetimes of most infected individuals. There is controversy over whether the residual viremia results from ongoing cycles of viral replication. To address this question, we conducted 2 prospective studies to assess the effect of ART intensification with an additional potent drug on residual viremia in 9 HIV-1-infected individuals on successful ART. By using an HIV-1 RNA assay with single-copy sensitivity, we found that levels of viremia were not reduced by ART intensification with any of 3 different antiretroviral drugs (efavirenz, lopinavir/ritonavir, or atazanavir/ritonavir). The lack of response was not associated with the presence of drug-resistant virus or suboptimal drug concentrations. Our results suggest that residual viremia is not the product of ongoing, complete cycles of viral replication, but rather of virus output from stable reservoirs of infection.

Wilcoxon-Mann-Whitney or t-test? On assumptions for hypothesis tests and multiple interpretations of decision rules

In a mathematical approach to hypothesis tests, we start with a clearly defined set of hypotheses and choose the test with the best properties for those hypotheses. In practice, we often start with less precise hypotheses. For example, often a researcher wants to know which of two groups generally has the larger responses, and either a t-test or a Wilcoxon-Mann-Whitney (WMW) test could be acceptable. Although both t-tests and WMW tests are usually associated with quite different hypotheses, the decision rule and p-value from either test could be associated with many different sets of assumptions, which we call perspectives. It is useful to have many of the different perspectives to which a decision rule may be applied collected in one place, since each perspective allows a different interpretation of the associated p-value. Here we collect many such perspectives for the two-sample t-test, the WMW test and other related tests. We discuss validity and consistency under each perspective and discuss recommendations between the tests in light of these many different perspectives. Finally, we briefly discuss a decision rule for testing genetic neutrality where knowledge of the many perspectives is vital to the proper interpretation of the decision rule.

Morphology of the “athlete's heart” assessed by echocardiography in 947 elite athletes representing 27 sports

In the present study, we used echocardiography to investigate the morphologic adaptations of the heart to athletic training in 947 elite athletes representing 27 sports who achieved national or international levels of competition. Cardiac morphology was compared for these sports, using multivariate statistical models. Left ventricular (LV) diastolic cavity dimension above normal (> 54 mm, ranging up to 66 mm) was identified in 362 (38%) of the 947 athletes. LV wall thickness above normal (> 12 mm, ranging up to 16 mm) was identified in only 16 (1.7%) of the athletes. Athletes training in the sports examined showed considerable differences with regard to cardiac dimensions. Endurance cyclists, rowers, and swimmers had the largest LV diastolic cavity dimensions and wall thickness. Athletes training in sports such as track sprinting, field weight events, and diving were at the lower end of the spectrum of cardiac adaptations to athletic training. Athletes training in sports associated with larger LV diastolic cavity dimensions also had higher values for wall thickness. Athletes training in isometric sports, such as weightlifting and wrestling, had high values for wall thickness relative to cavity dimension, but their absolute wall thickness remained within normal limits. Analysis of gender-related differences in cardiac dimensions showed that female athletes had smaller LV diastolic cavity dimension (average 2 mm) and smaller wall thickness (average 0.9 mm) than males of the same age and body size who were training in the same sport.(ABSTRACT TRUNCATED AT 250 WORDS)

Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics: A Randomized Clinical Trial

IMPORTANCE The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations. OBJECTIVE To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics. DESIGN, SETTING, AND PATIENTS Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012). INTERVENTIONS In the studys first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks. MAIN OUTCOMES AND MEASURES The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]). RESULTS In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events. CONCLUSION AND RELEVANCE In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01441180.

IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection.

Interleukin 7 (IL-7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL-7 (rhIL-7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebo-controlled study, a single subcutaneous dose of rhIL-7 was well tolerated with biologic activity demonstrable at 3 microg/kg and a maximum tolerated dose of 30 microg/kg. Injection site reactions and transient elevations of liver function tests were the most notable side effects. Transient increases in plasma HIV-RNA levels were observed in 6 of 11 IL-7-treated patients. Recombinant hIL-7 induced CD4 and CD8 T cells to enter cell cycle; cell-cycle entry was also confirmed in antigen-specific CD8 T cells. Administration of rhIL-7 led to transient down-regulation of the IL-7 receptor alpha chain (CD127) in both CD4(+) and CD8(+) T cells. Single-dose rhIL-7 increased the numbers of circulating CD4(+) and CD8(+) T cells, predominantly of central memory phenotype. The frequency of CD4(+) T cells with a regulatory T-cell phenotype (CD25(high) CD127(low)) did not change after rhIL-7 administration. Thus, rhIL-7 has a biologic and toxicity profile suggesting a potential for therapeutic trials in HIV infection and other settings of lymphopenia. This clinical trial has been registered at http://www.clinicaltrials.gov under NCT0099671.