Kidney dysfunction in patients with pulmonary arterial hypertension.

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-ß 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.

Child sexual abuse and adulthood-interpersonal outcomes: Examining pathways for intervention.

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

Using the QIDS-SR16 to identify major depressive disorder in primary care medical patients.

Major depressive disorder (MDD) is a serious and prevalent mental health issue. As the majority of MDD cases are identified and treated by one's primary care physician, it is imperative that care providers utilize accurate and efficient methods for diagnosing MDD in primary care settings. The present study is the first to investigate the accuracy of the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR(16)) as a screen for MDD. A heterogeneous sample of 155 primary care patients completed the QIDS-SR(16) prior to attending a primary care appointment. Participants were then assessed for psychopathology using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) by clinicians who were blind to QIDS-SR(16) scores. Scores on the QIDS-SR(16) were compared to clinician-assessed current and lifetime diagnoses derived from the SCID, which represented the gold-standard criterion measure. Receiver operator characteristic analysis was utilized to determine the optimal QIDS-SR(16) cut score to correctly classify participants based on their MDD status as assessed by the SCID. The test revealed a robust area under the curve (.82, p<0.00001) and suggested that a cut score of 13 or 14 provided the best balance of sensitivity (76.5%) and specificity (81.8%) in this primary care sample. Over 80% of participants were correctly classified. Separate analyses by race were conducted to address the possibility that different cut scores may be more accurate for African American and Caucasians. Findings from the present study provide support for the use of the QIDS-SR(16) as a screening measure for identifying primary care patients who will meet diagnostic criteria for MDD based on clinician assessment.

Clinical correlates of blood serotonin levels in patients with mastocytosis.

BACKGROUND: Mastocytosis is a clonal disorder associated with an increased mast cell burden. We have recently demonstrated the ability of human mast cells to express and be activated through multiple serotonin receptors; to synthesize and release serotonin; and that mastocytosis patients may have abnormal serotonin levels. As serotonin has been implicated in the genesis of clinical symptoms found in association with some chronic diseases, we have now determined the whole blood serotonin levels in 29 patients diagnosed with mastocytosis, and correlated these levels with multiple clinical and laboratory parameters. MATERIALS AND METHODS: Patients with mastocytosis were categorized according to disease variant. Blood serotonin values were determined and correlated with values reported for normal subjects; and clinical and laboratory features of the disease. RESULTS: Total blood serotonin levels followed a bimodal distribution in line with our earlier report, unlike the normal distribution reported for normal individuals. Serotonin levels did not correlate with platelet numbers, liver function tests or serum tryptase levels. Patients with lower serotonin values had greater rates of fatigue (P = 0.0001), migraine headaches (P = 0.0028), psychiatric symptoms (P = 0.0001), diarrhoea (P = 0.0407), flushing (0.0085), and abdominal and bone pain (P = 0.0001). CONCLUSIONS: Our study suggests that low blood serotonin levels help define a sub-group of patients with mastocytosis that are more likely to present with neurological and gastrointestinal complaints, and suggests that the use of pharmacologic agents that alter blood serotonin levels could be explored in selected patients.

Internal pilot studies I: type I error rate of the naive t-test.

When sample size is recalculated using unblinded interim data, use of the usual t-test at the end of a study may lead to an elevated type I error rate. This paper describes a numerical quadrature investigation to calculate the true probability of rejection as a function of the time of the recalculation, the magnitude of the detectable treatment effect, and the ratio of the guessed to the true variance. We consider both 'restricted' designs, those that require final sample size at least as large as the originally calculated size, and 'unrestricted' designs, those that permit smaller final sample sizes than originally calculated. Our results indicate that the bias in the type I error rate is often negligible, especially in restricted designs. Some sets of parameters, however, induce non-trivial bias in the unrestricted design.

Internal pilot studies II: comparison of various procedures.

The two-stage design involves sample size recalculation using an interim variance estimate. Stein proposed the design in 1945; biostatisticians recently have shown renewed interest in it. Wittes and Brittain proposed a modification aimed at greater efficiency; Gould and Shih proposed a similar procedure, but with a different interim variance estimate based on blinded data. We compare the power of Stein's original test, an idealized version of the Wittes-Brittain test, and a theoretical optimal test which can be approximated in practice. We also compare two procedures that control the conditional type I error rate given the actual final sample size: Gould and Shih's procedure and a newly proposed 'second segment' procedure. The comparison among the first three procedures indicates that the Stein test is, unexpectedly, the test of choice under the original design alternative, whereas the approximate-optimal and Wittes-Brittain procedures appear to have superior power for detecting smaller treatment differences. As between the latter two procedures, the second segment procedure is more powerful when many observations are likely to be taken after the interim resizing, whereas otherwise the Gould-Shih procedure is superior.

Simple method of multipurpose airway access through percutaneous tracheostomy in rabbits (Oryctolagus cuniculus).

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.

Blinded subjective rankings as a method of assessing treatment effect: a large sample example from the Systolic Hypertension in the Elderly Program (SHEP).

Because many randomized clinical trials study more than one important outcome variable, evaluation of efficacy is often difficult and not completely satisfactory. This paper considers the use of a procedure for endpoint determination described by Follmann et al., that allows raters to integrate subjectively all relevant information about an individual's clinical course into a single univariate assessment. To explore the method's feasibility, we tested the procedure with data from a completed clinical trial, the Systolic Hypertension in the Elderly Program (SHEP). We provided raters blinded to treatment assignment with cards that schematically represent the clinical trajectories of SHEP study participants. The raters independently ranked these trajectories. The method combined ranks across raters to determine a single rank for each study participant; we used a rank procedure to test treatment effect. The major findings were: (i) the raters showed a high level of concordance of rankings; (ii) tests of treatment effect were highly statistically significant; (iii) three statistical methods were effective for implementing the ranking in the large study size case. These methods were use of: (a) scoring rules; (b) incomplete block designs, and (c) categorical ranking.

Optimization of multistage testing times and critical values in clinical trials.

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.

Trials of hypertension prevention. Phase I design.

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.

The run-in period in clinical trials. The effect of misclassification on efficiency.

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.

Calcium and blood pressure. An epidemiologic perspective.

We reviewed the research literature on the epidemiologic relationship between blood pressure levels and calcium, with an emphasis on dietary intake. A conceptual framework for causal inference is summarized; then the designs and results of observational and intervention studies are presented. Of 25 reports of observational studies relating intake of calcium or calcium-rich foods to blood pressure, the majority found some evidence of an inverse association. However, many analyses did not support this relationship, and only two studies have confirmed the inverse association with a prospective design. Nineteen randomized controlled clinical trials of calcium supplementation have been reported, excluding those exclusively in pregnant women. Eleven of these showed no significant effects on blood pressure; in two trials, both systolic and diastolic pressure were significantly reduced; and in the remainder results were equivocal. Pooled analyses yielded estimates of a small (1.8 mm Hg), significant reduction in systolic blood pressure, but no effect on diastolic pressure. Epidemiologic relationships with serum and urinary calcium, and the possible mechanisms of these effects, are also discussed. We conclude that the evidence from studies in humans is suggestive, but not conclusive, regarding a role for calcium in hypertension. Recommendations for further epidemiologic studies are presented.

The role of internal pilot studies in increasing the efficiency of clinical trials.

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.

Relation between exertional ischemia and prognosis in mildly symptomatic patients with single or double vessel coronary artery disease and left ventricular dysfunction at rest.

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)

Factorial designs in clinical trials: the effects of non-compliance and subadditivity.

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.

A multicenter trial of antithymocyte globulin in aplastic anemia and related diseases.

One hundred fifty patients with bone marrow failure were treated in three groups with antithymocyte globulin (ATG; Upjohn, Kalamazoo, MI) in a multicenter trial. Patients were assessed at 3, 6, and 12 months after initiation of treatment by three criteria: transfusion independence, clinical improvement, and blood counts. Group I consisted of 77 patients with acute severe aplastic anemia, randomized to receive either ten or 28 days of ATG. There was no significant difference between the two arms of this protocol: 47% of all patients were clinically improved and 31% were transfusion independent at 3 months. Of the severely affected patients, 27% died before 3 months; most deaths occurred early in treatment. Factors associated with survival in severely affected patients included male sex, age less than 40 years, absolute neutrophil count greater than 200/microL, and idiopathic etiology. Neutrophil counts generally increased by 8 weeks after treatment, but patients continued to show improvement to 1 year posttreatment. In Group II, 44 patients with moderate or chronic severe aplastic anemia were randomized to receive either ten days of ATG or 3 months of high-dose nandrolone decanoate. No patient initially treated with androgens recovered, but 28% of ATG-treated cases achieved transfusion independence at 3 months. Group III consisted of patients with a variety of bone marrow failure syndromes. Patients with pancytopenia and cellular bone marrow showed response rates similar to those of patients with chronic or moderate aplastic anemia.

Testicular function in type II hyperlipoproteinemic patients treated with lovastatin (mevinolin) or neomycin.

Steroid synthesis requires cholesterol derived from de novo synthesis or plasma lipoproteins. Low density lipoproteins appear to be the major contributor of cholesterol for steroid synthesis in man. Patients with disorders of low density lipoproteins or the low density lipoprotein receptor have reduced cortisol production in response to ACTH. Therapeutic agents designed to lower plasma cholesterol could, therefore, adversely affect steroid hormone production. Lovastatin (mevinolin) is a new hypolipidemic agent which blocks cholesterol synthesis by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. In beagle dogs, lovastatin at 40-180 times the clinically effective dose in man, has been associated with an increase in spontaneous testicular atrophy. Accordingly, the effect of lovastatin on testicular function and lipoprotein levels was studied in 16 hyperlipidemic men in a randomized, double blind, cross-over study with another hypolipidemic agent, neomycin. Serum testosterone, PRL, LH, and FSH; LHRH-stimulated LH and FSH concentrations; and testicular size were measured, and semen analyses were made. We found no evidence that lovastatin had adverse effects on testicular function despite significant alterations in plasma lipoprotein concentrations.

Obesity and hypertension: epidemiological and clinical issues.

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.

Determinants of ventricular arrhythmias in mildly symptomatic patients with coronary artery disease and influence of inducible left ventricular dysfunction on arrhythmia frequency.

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.