Mario A. Cleves

Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism

Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S‐adenosylmethionine (SAM) to S‐adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age‐matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene–gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol‐O‐methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione‐S‐transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.

Diabetes mellitus and birth defects.

OBJECTIVE The purpose of this study was to examine associations between diabetes mellitus and 39 birth defects. STUDY DESIGN This was a multicenter case-control study of mothers of infants who were born with (n = 13,030) and without (n = 4895) birth defects in the National Birth Defects Prevention Study (1997-2003). RESULTS Pregestational diabetes mellitus (PGDM) was associated significantly with noncardiac defects (isolated, 7/23 defects; multiples, 13/23 defects) and cardiac defects (isolated, 11/16 defects; multiples, 8/16 defects). Adjusted odds ratios for PGDM and all isolated and multiple defects were 3.17 (95% CI, 2.20-4.99) and 8.62 (95% CI, 5.27-14.10), respectively. Gestational diabetes mellitus (GDM) was associated with fewer noncardiac defects (isolated, 3/23 defects; multiples, 3/23 defects) and cardiac defects (isolated, 3/16 defects; multiples, 2/16 defects). Odds ratios between GDM and all isolated and multiple defects were 1.42 (95% CI, 1.17-1.73) and 1.50 (95% CI, 1.13-2.00), respectively. These associations were limited generally to offspring of women with prepregnancy body mass index > or =25 kg/m(2). CONCLUSION PGDM was associated with a wide range of birth defects; GDM was associated with a limited group of birth defects.

Good and poor adherence: optimal cut-point for adherence measures using administrative claims data

ABSTRACT Objective: To identify the adherence value cut-off point that optimally stratifies good versus poor compliers using administratively derived adherence measures, the medication possession ratio (MPR) and the proportion of days covered (PDC) using hospitalization episode as the primary outcome among Medicaid eligible persons diagnosed with schizophrenia, diabetes, hypertension, congestive heart failure (CHF), or hyperlipidemia. Research design and methods: This was a retrospective analysis of Arkansas Medicaid administrative claims data. Patients ≥18 years old had to have at least one ICD-9-CM code for the study diseases during the recruitment period July 2000 through April 2004 and be continuously eligible for 6 months prior and 24 months after their first prescription for the target condition. Adherence rates to disease-specific drug therapy were assessed during 1 year using MPR and PDC. Main outcome measure and analysis scheme: The primary outcome measure was any-cause and disease-related hospitalization. Univariate logistic regression models were used to predict hospitalizations. The optimum adherence value was based on the adherence value that corresponded to the upper most left point of the ROC curve corresponding to the maximum specificity and sensitivity. Results: The optimal cut-off adherence value for the MPR and PDC in predicting any-cause hospitalization varied between 0.63 and 0.89 across the five cohorts. In predicting disease-specific hospitalization across the five cohorts, the optimal cut-off adherence values ranged from 0.58 to 0.85. Conclusions: This study provided an initial empirical basis for selecting 0.80 as a reasonable cut-off point that stratifies adherent and non-adherent patients based on predicting subsequent hospitalization across several highly prevalent chronic diseases. This cut-off point has been widely used in previous research and our findings suggest that it may be valid in these conditions; it is based on a single outcome measure, and additional research using these methods to identify adherence thresholds using other outcome metrics such as laboratory or physiologic measures, which may be more strongly related to adherence, is warranted.

Maternal Smoking and Congenital Heart Defects

OBJECTIVES. In a population-based case-control study, we investigated the association between congenital heart defects and maternal smoking. METHODS. The National Birth Defects Prevention Study enrolled 3067 infants with nonsyndromic congenital heart defects and their parents and 3947 infants without birth defects and their parents. Affected infants had ≥1 of the following defects: conotruncal, septal, anomalous pulmonary venous return, atrioventricular septal defects, and left-sided or right-sided obstructive heart defects. Mothers of case and control infants were asked if they smoked during the periconceptional period, defined as 1 month before pregnancy through the first trimester. Maternal home and workplace exposure to tobacco smoke during the same period was also determined. Logistic regression was used to compute odds ratios and 95% confidence intervals while controlling for potential confounders. RESULTS. Case infants were more likely to be premature and have lower birth weight than control infants. Women who smoked anytime during the month before pregnancy to the end of the first trimester were more likely to have infants with septal heart defects than women who did not smoke during this time period. This association was stronger for mothers who reported heavier smoking during this period. This relation was independent of potential confounding factors, including prenatal vitamin use, alcohol intake, maternal age, and race or ethnicity. Women who smoked ≥25 cigarettes per day were more likely than nonsmoking mothers to have infants with right-sided obstructive defects. There was no increased risk of congenital heart defects with maternal exposure to environmental tobacco smoke. CONCLUSIONS. Maternal smoking during pregnancy was associated with septal and right-sided obstructive defects. Additional investigation into the timing of tobacco exposure and genetic susceptibilities that could modify this risk will provide a more precise evidence base on which to build clinical and public health primary prevention strategies.

An empirical basis for standardizing adherence measures derived from administrative claims data among diabetic patients.

Objective:To compare the predictive validity of 8 different adherence measures by studying the variability explained between each measure and 2 outcome measures: hospitalization episodes and total nonpharmacy cost among Medicaid eligible persons diagnosed with diabetes. Research Design:This study was a retrospective analysis of the Arkansas Medicaid administrative claims data from January 2000 to December 2006. Subjects:Diabetic (ICD-9-CM = 250.0x–250.9x, where x = 0 or 2) patients were identified in the recruitment period July 2000 through April 2004. Patients had to be ≥18 years old and have at least 2 prescription fills in the index period for an oral antidiabetic drug. Measures:Adherence rates to oral antidiabetic therapy were contrasted using the following 8 measures; including the medication possession ratio (MPR), proportion of days covered (PDC), refill compliance rate (RCR), compliance ratio (CR), medication possession ratio, modified (MPRm), continuous measure of medication gaps (CMG), and continuous multiple interval measure of oversupply (CMOS and continuous, single interval measure of medication acquisition (CSA). Multivariate and univariate linear and logistic regression models were used to prospectively predict nonpharmacy costs and hospitalizations in the follow-up year. Results:A total of 4943 diabetic patients were studied. In predicting any cause hospitalization, univariate models with PDC and CMG had the highest predictive validity (C-statistic: 0.544). Multivariate models with MPR, PDC, CMG or continuous multiple interval measure of oversupply (CMOS) as adherence measures had the highest C-statistics of 0.701 in predicting diabetes specific hospitalizations. None of the adherence measures were significantly associated with nonpharmacy cost. Conclusions:MPR and PDC had the highest predictive validity for hospitalization episodes. These 2 measures should be considered first when selecting among adherence measures when using administrative prescription claims data.

Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study.

OBJECTIVE To estimate the association between antibacterial medications and selected birth defects. DESIGN, SETTING, AND PARTICIPANTS Population-based, multisite, case-control study of women who had pregnancies affected by 1 of more than 30 eligible major birth defects identified via birth defect surveillance programs in 10 states (n = 13 155) and control women randomly selected from the same geographical regions (n = 4941). MAIN EXPOSURE Reported maternal use of antibacterials (1 month before pregnancy through the end of the first trimester). MAIN OUTCOME MEASURE Odds ratios (ORs) measuring the association between antibacterial use and selected birth defects adjusted for potential confounders. RESULTS The reported use of antibacterials increased during pregnancy, peaking during the third month. Sulfonamides were associated with anencephaly (adjusted OR [AOR] = 3.4; 95% confidence interval [CI], 1.3-8.8), hypoplastic left heart syndrome (AOR = 3.2; 95% CI, 1.3-7.6), coarctation of the aorta (AOR = 2.7; 95% CI, 1.3-5.6), choanal atresia (AOR = 8.0; 95% CI, 2.7-23.5), transverse limb deficiency (AOR = 2.5; 95% CI, 1.0-5.9), and diaphragmatic hernia (AOR = 2.4; 95% CI, 1.1-5.4). Nitrofurantoins were associated with anophthalmia or microphthalmos (AOR = 3.7; 95% CI, 1.1-12.2), hypoplastic left heart syndrome (AOR = 4.2; 95% CI, 1.9-9.1), atrial septal defects (AOR = 1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (AOR = 2.1; 95% CI, 1.2-3.9). Other antibacterial agents that showed associations included erythromycins (2 defects), penicillins (1 defect), cephalosporins (1 defect), and quinolones (1 defect). CONCLUSIONS Reassuringly, penicillins, erythromycins, and cephalosporins, although used commonly by pregnant women, were not associated with many birth defects. Sulfonamides and nitrofurantoins were associated with several birth defects, indicating a need for additional scrutiny.

LONG-TERM FOLLOWUP OF TREATMENT FOR PEYRONIE’S DISEASE: MODELING THE PENIS OVER AN INFLATABLE PENILE PROSTHESIS

PURPOSE We originally reported inflatable penile implants used to treat impotence in patients with Peyronies disease in 1993. We now present a historical prospective study of 104 patients in whom the modeling procedure was used to correct Peyronies curvature after implantation with the Mentor Alpha 1dagger and AMS 700CXdouble dagger penile prostheses. We compared revision-free survival experience of these implants with 905 similar implants in men with nonPeyronies disease. MATERIALS AND METHODS The reasons for revision were classified as mechanical failure, patient dissatisfaction, infection and medical causes, including reoperation for straightening. Overall and cause specific revision-free survival in the 2 study cohorts was compared. Maximum followup was more than 12 years and average followup was more than 5. RESULTS No significant difference in device survival was observed in the 2 study cohorts in 5 years. Similarly each prosthesis provided the same permanent straightening without the need for revision. In Peyronies disease cases mechanical survival of the Mentor Alpha 1 was superior to that of the AMS 700CX (p = 0.0270). There was no significant difference in mechanical reliability of the devices in nonPeyronies disease cases. CONCLUSIONS Implantation and modeling appear to provide permanent straightening without an increase in revisions. In the nonmodeled group there was no significant difference in mechanical reliability of the AMS 700CX or Mentor Alpha 1. In modeled cases the Mentor Alpha 1 appeared less likely to fail mechanically than the AMS 700CX when followed more than 5 years. Based on this single series modeling may predispose the AMS 700CX to earlier mechanical failure.

Comparison of mechanical reliability of original and enhanced mentor alpha I penile prosthesis

PURPOSE We report the results of a prospective study of 1,381 Mentor Alpha I penile prostheses implanted to treat impotence, and compare original and enhanced penile prosthesis mechanical reliability. MATERIALS AND METHODS The study consisted of 410 original models manufactured before November 1992 and 971 enhanced models manufactured since December 1992. Implants were further stratified as first time (virgin) or replacements of a previous implant. Mechanical failure-free survival rates for the original prosthetic and enhanced models were compared. RESULTS The 5-year survival rate increased from 75.3% for the original to 92.6% for the enhanced model overall (log rank p<0.0001), and from 75.3 to 93.6%, respectively, for the virgin implants only (log rank p<0.0001). The estimated failure rate of approximately 5.6% for the original model was fairly consistent during followup, while the significantly lower failure rate of 1.3% for the enhanced model was not. The failure rate of the enhanced model implants was about 0.8% per year during the first 3.5 years and increased to approximately 3.1% per year thereafter. CONCLUSIONS Our results strongly support the premise that mechanical reliability is superior with the enhanced compared to the original model.

Prospective Validation of Eight Different Adherence Measures for Use with Administrative Claims Data among Patients with Schizophrenia

OBJECTIVE The aim of this study was to compare the predictive validity of eight different adherence measures by studying the variability explained between each measure and hospitalization episodes among Medicaid-eligible persons diagnosed with schizophrenia on antipsychotic monotherapy. METHODS This study was a retrospective analysis of the Arkansas Medicaid administrative claims data. Continuously eligible adult schizophrenia (ICD-9-CM = 295.**) patients on antipsychotic monotherapy were identified in the recruitment period from July 2000 through April 2004. Adherence rates to antipsychotic therapy in year 1 were calculated using eight different measures identified from the literature. Univariate and multivariable logistic regression models were used to prospectively predict all-cause and mental health-related hospitalizations in the follow-up year. RESULTS Adherence rates were computed for 3395 schizophrenic patients with a mean age of 42.9 years, of which 52.5% (n = 1782) were females, and 52.8% (n = 1793) were white. The proportion of days covered (PDC) and continuous measure of medication gaps measures of adherence had equal C-statistics of 0.571 in predicting both all-cause and mental health-related hospitalizations. The medication possession ratio (MPR) continuous multiple interval measure of oversupply were the second best measures with equal C-statistics of 0.568 and 0.567 for any-cause and mental health-related hospitalizations. The multivariate adjusted models had higher C-statistics but provided the same rank order results. CONCLUSIONS MPR and PDC were among the best predictors of any-cause and mental health-related hospitalization, and are recommended as the preferred adherence measures when a single measure is sought for use with administrative claims data for patients not on polypharmacy.

The Mentor Alpha 1 Penile Prosthesis With Reservoir Lock-out Valve: Effective Prevention of Auto-inflation With Improved Capability For Ectopic Reservoir Placement

PURPOSE Auto-inflation is a common and annoying complication of 3-piece penile prostheses. In the published literature the rate is approximately 11% with a 2% operative revision rate. We report the results of a review of 160 Alpha 1 and NB implants (Mentor Corp., Santa Barbara, California) with the new lock-out valve located on the reservoir to treat impotence. We compared it with 339 Alpha 1 implants with the standard reservoir. We also investigated the lock-out reservoir for ectopic nonretropubic implantation. MATERIALS AND METHODS We compared 339 Alpha prostheses with the standard reservoir that were implanted between January 1, 1998 through December 31, 1999 and 160 with the new lock-out valve placed since January 2000 with at least 6 months of followup. Implants were further stratified as first time (virgin) or revision-replacement of a previous implant. In 8 patients with a scarred or obliterated retroperitoneal space the lock-out reservoir was placed superior to the transversalis fascia and beneath the abdominal musculature. RESULTS Kaplan-Meier estimated 1-year survival was not significantly different in terms of mechanical failure (p = 0.57 and 0.85) revision for any cause (p = 0.92 and 0.92), patient dissatisfaction (p = 0.35 and 0.11) or infection (p = 0.64 and 0.94) for all implants and virgin implants only, respectively. Only 2 patients (1.3%) with a lock-out valve complained of auto-inflation initially and the problem resolved in each after instruction on how to operate the device. Of the patients in the earlier series 11% complained of auto-inflation and 2% required operative correction. None of the 8 patients with an ectopic reservoir location complained of auto-inflation. CONCLUSIONS Our results indicate that the lock-out valve prevents early auto-inflation. Addition of the lock-out valve does not impact the revision rate compared with the same implant with a standard reservoir. In patients with a scarred retropubic space the lock-out valve offers the penile implant surgeon a decreased probability of auto-inflation with ectopic reservoir placement.