High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1)

This study aimed to characterize possible relationships between polymorphisms in the drug transporter genes organic anion transporting polypeptide-C (OATP-C, SLCO1B1), OATP-B (SLCO2B1), multidrug resistance-associated protein 2 (MRP2, ABCC2) and multidrug resistance transporter (MDR1, ABCB1) and the pharmacokinetics of pravastatin. We studied 41 healthy Caucasian volunteers who had previously participated in pharmacokinetic studies with pravastatin. Six volunteers had a very high pravastatin AUC value and were defined as outliers according to statistical criteria. The OATP-C gene was sequenced completely in all subjects, and they were also genotyped for selected single nucleotide polymorphisms (SNP) in the OATP-B, MDR1 and MRP2 genes. Of the six outliers, five were heterozygous for the OATP-C 521T>C (Val174Ala) SNP (allele frequency 42%) and three were heterozygous for a new SNP in the promoter region of OATP-C (-11187G>A, allele frequency 25%). Among the remaining 35 subjects, two were homozygous and six were heterozygous carriers of the 521T>C SNP (allele frequency 14%, P = 0.0384 versus outliers) and three were heterozygous carriers of the -11187G>A SNP (allele frequency 4%, P = 0.0380 versus outliers). In subjects with the -11187GA or 521TC genotype, the mean pravastatin AUC0-12 was 98% (P = 0.0061) or 106% (P = 0.0034) higher, respectively, compared to subjects with the reference genotype. These results were substantiated by haplotype analysis. In heterozygous carriers of *15B (containing the 388A>G and 521T>C variants), the mean pravastatin AUC0-12 was 93% (P = 0.024) higher compared to non-carriers and, in heterozygous carriers of *17 (containing the -11187G>A, 388A>G and 521T>C variants), it was 130% (P = 0.0053) higher compared to non-carriers. No significant associations were found between OATP-B, MRP2 or MDR1 polymorphisms and the pharmacokinetics of pravastatin. These results suggest that haplotypes are more informative in predicting the OATP-C phenotype than single SNPs.     

Measuring factors underlying intendedness of women's first and later pregnancies

CONTEXT: Unintended pregnancy is associated with poor health outcomes for mothers and infants, and is indicative of gaps in family planning services. Conventional measures of pregnancy intendedness do not reflect the multiple factors affecting a woman's pregnancy-related intentions and attitudes. METHODS: Data collected between March 2002 and February 2003 from 701 women in a public family planning clinic and 671 women in a public prenatal clinic in New Orleans were analyzed to examine factors underlying intendedness (including attitudes toward pregnancy and motivations to achieve or avoid pregnancy). RESULTS: In factor analyses, variables measuring pregnancy intendedness were represented by a single latent factor, pregnancy desirability. For first pregnancy, variables that best captured desirability were those measuring happiness, effort in achieving the pregnancy, extent of looking forward to telling friends, whether the pregnancy was intended (i.e., came at the right time or later), and whether the woman wanted to have a baby with her partner. For last or current pregnancies that were second or higher order ones, they were happiness, pregnancy wantedness, effort in achieving the pregnancy, whether the pregnancy was planned and whether the woman wanted to have a baby with her partner. Among women younger than 18 at first pregnancy, happiness and whether a woman wanted a baby with her partner were the only items that captured pregnancy desirability. CONCLUSIONS: Future surveys on pregnancy intendedness could reduce the number of questions used to capture pregnancy desirability. This should help standardize surveillance systems and permit better assessment of trends in pregnancy desirability over time.     

Editorial: Wishful thinking

As a supplement to our lead editorial, the editors of the new journal, Epidemiologic Perspectives & Innovations, provide a partial list of specific analyses and topic areas they would like to see submitted to the journal.     

The harmful consequences of elevating the doctor-patient relationship to be a primary goal of the general practice consultation

Introduction In the UK, it has been estimated that an ‘average’GP will undertake 8000 face to face clinical interactions annually.¹The consultation has come to be identified as the cornerstoneof general practice,² and to be seen more than an occasion forthe medical work of diagnosis and treatment.³ Beginning withthe work of Balint,⁴ it has also come to be seen as a ‘meeting’of individuals in which (often undifferentiated) symptoms areexpected to be understood and accommodated in relation to theirsocial and psychological contexts. Much effort in educationand research has been invested in giving the consultation thisdeeper meaning and wider range of potential practice.⁵ Thus,whilst the doctor–patient relationship is a given in today'sprimary care, achieving a satisfactory doctor–patientrelationship has also been elevated to be an outcome or goalof every consultation. In many ways, exploring that     

Evaluation of a school-based intervention for HIV/AIDS prevention among Belizean adolescents

The purpose of this study was to evaluate the impact of a cognitive-behavioral peer-facilitated school-based HIV/AIDS education program on knowledge, attitudes and behavior among primary and secondary students in Belize. Students (N = 150) were recruited from six schools in Belize City. A quasi-experimental research design was used to assess the impact of a 3-month intervention. Seventy-five students received the intervention and 75 students served as controls. The intervention was guided by constructs from the Theory of Reasoned Action and Social Cognitive Theory. At the follow-up assessment, the intervention group showed higher HIV knowledge, were more likely to report condom use, had more positive attitudes toward condoms and were more likely to report future intentions to use condoms than the students in the control group. Overall, the findings indicate that the intervention had a positive impact on participants. Given the increasing rate of HIV/AIDS in Belize, especially among adolescents, this study has important implications for the country of Belize.     

A diagnostic decision rule for management of children with meningeal signs

In a previous study we devised a diagnostic decision rule to improve management of children with meningeal signs, suspected of having bacterial meningitis. The decision rule aimed to guide decisions on (1) whether a lumbar puncture is necessary in children with meningeal signs, and (2) which children need hospitalisation and empirical antibiotic treatment for bacterial meningitis. In this study we assessed the validity of this rule in an external population of four (paediatric) hospitals in The Netherlands. The decision rule included two scoring algorithms using symptoms, signs and quickly available blood and cerebrospinal fluid (CSF) laboratory tests. To evaluate the discriminative value of both algorithms, the absolute numbers of correctly diagnosed patients and the area under the receiver operator characteristic curve were estimated, and compared with the results from the original population (n = 360). In a 18 month period, we included 226 children, median age 2.2 years, who visited the emergency department with meningeal signs. Bacterial meningitis was present in 25 (11%). Using the scoring algorithms patients could be categorised in groups of increasing risk of bacterial meningitis. The discriminative values of the clinical and CSF algorithm in this new population were similar to those in the original population. In the total population of 586 children with meningeal signs, the rule selected 205 children (35%) who did not need a lumbar puncture and 366 children who did not need empirical treatment (62%). In conclusion, this diagnostic rule performed well in a new population of children with meningeal signs. This diagnostic decision rule is a valuable tool for the clinician when deciding to treat these children for bacterial meningitis and thus improving their management.     

Hypertonic hyperglycemia progresses to diabetes faster than normotonic

To explore whether elevated plasma glucose might progress to diabetes via a mechanism that involves plasma hypertonicity, we evaluated the independent and joint effects of these variables on diabetes risk. Community-dwelling older adults (70+years), who reported no previous diagnosis of diabetes and had glucose levels below 200 mg/dl in the 1992 Duke EPESE survey, were re-interviewed in 1996 for diabetes status (n=979). Plasma tonicity at baseline was estimated from serum glucose, sodium, and potassium measures. In logistic regression models that controlled for glucose, as well as age, sex, race, weight status, activity level, serum creatinine, history of heart disease, stroke and cancer, plasma hypertonicity (300 mOsm/l) was independently associated with increased odds of developing diabetes (OR=2.0, 95% CI: 0.9–4.2). Hypertonicity magnified the effects of elevated glucose (125 mg/dl), such that individuals with both exposures were over four times more likely to develop diabetes than those with elevated glucose only (OR=4.9, 95%CI: 1.7–14.3), adjusting for all covariates. When tonicity was replaced by its determinant variables, glucose, sodium and potassium, in the multivariable models, independent effects of sodium were also observed. Further work is needed to pursue plasma hypertonicity as a factor in the progression of elevated plasma glucose to diabetes.     

Time-dependent bias was common in survival analyses published in leading clinical journals

OBJECTIVE: In survival analysis, "baseline immeasurable" time-dependent factors cannot be recorded at baseline, and change value after patient observation starts. Time-dependent bias can occur if such variables are not analyzed appropriately. This study sought to determine the prevalence of such time-dependent bias in highly-cited medical journals. STUDY DESIGN AND SETTING: We searched Medline databases to identify all observational studies that used a survival analysis in American Journal of Medicine, Annals of Internal Medicine, Archives of Internal Medicine, British Medical Journal, Chest, Circulation, Journal of the American Medical Association, Lancet, and New England Journal of Medicine between 1998 and 2002. Studies with "baseline immeasurable" time-dependent factors were susceptible to time-dependent bias if a time-dependent covariate analysis was not used. RESULTS: Of 682 eligible studies, 127 (18.6%, 95% CI 15.8-21.8%) contained a "baseline immeasurable" time-dependent factor and 52 (7.6% [5.8-9.9%] of all survival analyses/40.9% [32.3-50.0%] of studies with a time-dependent factor) were susceptible to time-dependent bias. In 35 studies (5.1% [3.7-7.1%]/27.6% [20.5-35.9%]), the bias affected a variable highlighted in the study abstract and correction of the bias could have qualitatively changed the study's conclusion in over half of studies. CONCLUSION: In medical journals, time-dependent bias is concerningly common and frequently affects key factors and the study's conclusion.     

Employment, employment-related problems, and drug use at drug court entry

The literature indicates that employment may be an important factor for retaining substance misusing clients in treatment. Given the link between employment problems and treatment retention for Drug Court clients, the current project builds upon the existing services provided by Drug Courts in order to develop and implement an innovative model that focuses on obtaining, maintaining, and upgrading employment for Drug Court participants. The purpose of this article is to (1) describe the employment intervention used in Kentucky Drug Courts, which is grounded in established job readiness and life skill training approaches; and (2) profile those participants who were employed full-time prior to Drug Court and those who were not. Findings suggest that those employed full-time were more likely to have higher incomes and more earned income from legitimate job sources, although there were no differences in the types of employment (major jobs included food service and construction). In addition, study findings suggest that full-time employment was not "protective" since there were few differences in drug use and criminal activity by employment status. Employment interventions need to be examined to determine their utility for enhancing employment and keeping drug users in treatment. This article focuses on the initial 400 participants, who began entering the study in March, 2000.