Ronald W. Helms

A Pilot Study of Aerosolized Amiloride for the Treatment of Lung Disease in Cystic Fibrosis

Excessive active absorption of sodium is a unique abnormality of the airway epithelium in patients with cystic fibrosis. This defect is associated with thickened mucus and poor clearance of airway secretions and may contribute to the pulmonary disease in these patients. To study whether the inhibition of excessive absorption of sodium might affect the course of lung disease in cystic fibrosis, we performed a double-blind, crossover trial comparing aerosolized amiloride (5 mmol per liter; 3.5 ml four times daily), a sodium-channel blocker, with vehicle alone. Fourteen of the 18 adult patients initially enrolled in the study completed the one-year trial (25 weeks for each treatment). The mean (+/- SEM) loss of forced vital capacity (FVC) was reduced from 3.39 +/- 1.13 ml per day during treatment with vehicle alone to 1.44 +/- 0.67 ml per day during treatment with amiloride (P less than 0.04). A measured index of sputum viscosity and elasticity was abnormal during treatment with vehicle alone and improved during treatment with amiloride. Calculated indexes of mucociliary and cough clearance also improved during amiloride treatment. No systemic, respiratory, or subjective toxic effects of amiloride were noted. We conclude from this preliminary study that aerosolized amiloride can be safely administered to adults with cystic fibrosis. The slowing of the loss of FVC and the improvement in sputum viscosity and elasticity suggest a beneficial clinical effect. Aerosolized amiloride deserves further evaluation in the treatment of lung disease in patients with cystic fibrosis.

Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model.

ObjectiveTo develop a model to predict transmission of HIV-1 from men to women. DesignHIV-1 in seminal plasma, and endocervical CCR5 receptors were correlated with epidemiological studies of HIV-1 transmission to develop a probabilistic model. SettingsSemen samples were collected from patient subjects in Seattle Washington, Chapel Hill, North Carolina, and St. Gallen, Switzerland. Endocervical biopsy specimens were obtained from women in Chicago, Illinois. ParticipantsEighty-six men (not receiving antireroviral therapy) in whom CD4 cell count and semen volume were available, and 24 women in whom the number of endocervical CCR5 receptors were determined. Main outcome measuresPrediction of transmission of HIV-1 from men to women per episode of vaginal intercourse based on the absolute burden of HIV (volume × HIV RNA copies/ml seminal plasma). ResultsThe model suggests efficient heterosexual transmission of HIV-1 when semen viral burden is high. When semen contains 100 000 copies of non-syncytium-inducing (NSI) HIV RNA the probability of HIV-1 transmission is 1 per 100 episodes of intercourse; conversely, with 1000 copies NSI HIV RNA in semen, transmission probability is 3 per 10 000 episodes of intercourse. ConclusionsThis model links biological and epidemiological data related to heterosexual HIV-1 transmission. The model can be used to estimate transmission of HIV from men with high semen viral burden from inflammation, or reduced burden after antiretroviral therapy. The results offer a biological explanation for the magnitude of the HIV epidemic in places where earlier studies have shown men have high semen viral burden, such as in sub-Saharan Africa. The model can be used to develop and test HIV-1 prevention strategies.

Stroke with transfusions changing to hydroxyurea (SWiTCH)

Stroke is a devastating complication of sickle cell anemia (SCA) with high recurrence if untreated. Chronic transfusions reduce recurrent strokes but have associated morbidities including iron overload. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) was a multicenter phase 3 randomized trial comparing standard treatment (transfusions/chelation) to alternative treatment (hydroxyurea/phlebotomy) for children with SCA, stroke, and iron overload. SWiTCH was a noninferiority trial with a composite primary end point, allowing an increased stroke risk but requiring superiority for removing iron. Subjects on standard treatment received monthly transfusions plus daily deferasirox iron chelation. Subjects on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose (MTD), followed by monthly phlebotomy. Subjects on standard treatment (N = 66) maintained 30% sickle hemoglobin (HbS) and tolerated deferasirox at 28.2 ± 6.0 mg/kg/d. Subjects on alternative treatment (N = 67) initiated hydroxyurea and 60 (90%) reached MTD at 26.2 ± 4.9 mg/kg/d with 29.1% ± 6.7% fetal hemoglobin (HbF). Adjudication documented no strokes on transfusions/chelation but 7 (10%) on hydroxyurea/phlebotomy, still within the noninferiority stroke margin. The National Heart, Lung, and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content, indicating futility for the composite primary end point. Transfusions and chelation remain a better way to manage children with SCA, stroke, and iron overload.

Genetic predictors for stroke in children with sickle cell anemia.

Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A(-) variant deficiency, and β-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA.

Modeling Development of Sleep–Wake Behaviors: I. Using the Mixed General Linear Model

The purpose of this paper is to demonstrate the use of the mixed general linear model (MixMod) for modeling development of sleep-wake behaviors in preterm infants. The mixed general linear model allows the concurrent identification of both group and individual developmental patterns in longitudinal data sets with inconsistently timed data, irregularly timed data, and randomly missing values. This statistical technique is well suited to data from preterm infants because these infants enter and leave longitudinal studies at varying times depending on their health status. One sleep organizational variable--the regularity of respiration in quiet sleep--obtained from a study of 37 preterm infants was used as an example. Seven infant characteristics were used as covariates. The various steps involved in conducting a mixed model analysis of this variable are illustrated. The strengths and limitations of this technique are discussed.

Stroke with transfusions changing to hydroxyurea (SWiTCH): A phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload†

Stroke occurs in 5–10% of children with sickle cell anemia (SCA) and has a high (>50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long‐term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload.

MSQ: Migraine-specific quality-of-life questionnaire. Further investigation of the factor structure

SummaryMSQ, the 16-item Migraine—Specific Quality—of—Life Questionnaire (Version 1.0), was developed by Glaxo Wellcome Inc. to assess the effect of migraine and its treatment on patients’ health—related quality of life (HR-QOL). The MSQ was hypothesised to measure 3 meaningful dimensions: (i) Role Function—Restrictive; (ii) Role Function—Preventive; and (iii) Emotional Function. The objective of this research was to further investigate the number of dimensions as well as the items contained in each dimension through principal components factor analysis of clinical trial data. Secondary objectives were to determine whether the factor structure changed in post—treatment visits compared with screening visits, to make recommendations for coding the MSQ when the patient did not have a migraine in the previous 4 weeks, and to modify the MSQ if so indicated by this research. Results supported the existence of 3 distinct factors which agreed strongly with the hypothesised dimensions. The analysis of post—treatment data suggested that the underlying factor structure of the MSQ varies as a result of treatment. Based on evaluations of the ‘did not have a migraine’ response, it was concluded that it be dropped from the MSQ. All these changes have been incorporated into MSQ (Version 2.0) which is being evaluated in studies to determine if its psychometric properties are different than the properties of the previous version.

Maximum likelihood estimation for incomplete repeated-measures experiments under an ARMA covariance structure.

A stochastic model is presented for the analysis of incomplete repeated-measures experiments. The general linear model is used to relate the response measures to other variables which are thought to account for inherent variation; an autoregressive moving average (ARMA) time series representation is used to model disturbance terms. Maximum likelihood estimation procedures are considered, and the properties of these estimators are derived. It is concluded that while the assumptions underpinning the ARMA covariance models may be somewhat restrictive, they provide a useful inferential vehicle, particularly in the presence of missing values.

Chronic transfusion practice for children with sickle cell anaemia and stroke

Chronic transfusions to maintain haemoglobin S (HbS) ≤30% are the mainstay of treatment for children with sickle cell anaemia (SCA) and previous stroke. This HbS target is often hard to maintain, however, and values achieved in current practice are unknown. In preparation for the Phase III Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, we collected data on 295 children with SCA and stroke who received transfusions at 23 institutions. The overall average pre‐transfusion %HbS was 35 ± 11% (institutional range 22–51%). Receiving scheduled transfusions on time was the most predictive variable for maintaining HbS at the ≤30% goal.

A mixed linear model with linear covariance structure: a sensitivity analysis of maximum likelihood estimators

Incomplete and mistimed longitudinal data are common problems in longitudinal studies of free living populations. One possible approach to the analysis of longitudinal data with randomly missing or mistimed data uses a mixed effects model. While the theory underlying this approach is not new (Harville, 1977), very little has been published about its actual application. The objective of this paper is to examine the behavior of the maximum likelihood estimates of mixed effects model parameters when the distribution of the parameters underlying the data is known. Specifically, the effects of different values of the error covariance parameters and missing and mistimed data are considered. Two iterative methods, the Method of Scoring and the EM algorithm, were utilized to solve the maximum likelihood equations. In the setting considered here, the Method of Scoring and the EM algorithm worked well for the analysis of longitudinal data with missing and/or mistimed data. The variance of the parameter estimates in...