The Concurrent and Longitudinal Relationship between Perinatal Sleep Difficulties and Depression in a Large Sample of High-Risk Women in South Africa.

INTRODUCTION: Perinatal depression and sleep difficulties are common among studies conducted in high income countries (HIC). This study examines the relationship between sleep difficulties and depression during the perinatal period and over an eight-year follow-up period in South Africa, a middle income country. METHOD: A population cohort of 1238 pregnant women (mean age = 26.33) in 24 township neighborhoods in South Africa were recruited and reassessed six times over the next 8 years post birth with follow-up rates of 96-83%. The relationship between maternal depressed mood and sleep difficulties was examined over time, as well as the relationship of sleep with other socioeconomic, environmental, and psychiatric risk factors. RESULTS: Thirty-five percent of the women reported sleep difficulties during the perinatal period; whereas only 8% reported sleep difficulties at 8-year follow-up. Perinatal sleep difficulties were associated with lower income, lower educational attainment, less access to electricity, more food insecurity, higher rates of interpersonal violence and HIV, alcohol consumption, and depressed mood at 8 years. However, the severity of depressed mood was the strongest predictor of sleep problems longitudinally and cross-sectionally, after accounting for all other risk factors. CONCLUSIONS: We found that the severity of depressed mood is highly associated with sleep difficulties from pregnancy to 8 years post-birth and in a linear relationship, so that higher depressed mood is associated with more sleep problems. TRIAL REGISTRATION: ClinicalTrials.gov registration: # NCT00996528.

Sleep is understudied among people living in poverty in LMIC's. To our knowledge this is the first study to (a) investigate the relationship between sleep difficulties and depression in a sample of high-risk, black women living in poverty in a LMIC and (b) study the relationship between sleep and depression continuously from the perinatal period through 8 years post-partum in a LMIC. The study finds that sleep difficulties and depression are highly correlated during this period even after accounting for other socioeconomic, environmental and psychiatric risk factors in this high-risk population.

Association between maternal body mass index during pregnancy, short-term morbidity, and increased health service costs: a population-based study.

OBJECTIVE: To investigate the impact of maternal body mass index (BMI, kg/m(2)) on clinical complications, inpatient admissions, and additional short-term costs to the National Health Service (NHS) in Scotland. DESIGN: Retrospective cohort study using an unselected population database. SETTING: Obstetric units in Scotland, 2003-2010. POPULATION: A total of 124,280 singleton deliveries in 109,592 women with a maternal BMI recorded prior to 16 weeks of gestation. METHODS: Population-based retrospective cohort study of singleton deliveries, with multivariable analysis used to assess short-term morbidity and health service costs. MAIN OUTCOME MEASURES: Maternal and offspring outcomes, number and duration of hospital admissions, and healthcare costs. RESULTS: Using multivariable analysis, in comparison with women of normal weight, women who were overweight, obese, or severely obese had an increased risk of essential hypertension [1.87 (1.18-2.96), 11.90 (7.18-19.72), and 36.10 (18.33-71.10)], pregnancy-induced hypertension [1.76 (1.60-1.95), 2.98 (2.65-3.36), and 4.48 (3.57-5.63)], gestational diabetes [3.39 (2.30-4.99), 11.90 (7.54-18.79), and 67.40 (37.84-120.03)], emergency caesarean section [1.94 (1.71-2.21), 3.40 (2.91-3.96), and 14.34 (9.38-21.94)], and elective caesarean section [2.06 (1.84-2.30), 4.61 (4.06-5.24), and 17.92 (13.20-24.34)]. Compared with women of normal weight, women who were underweight, overweight, obese, or severely obese were associated with an 8, 16, 45, and 88% increase in the number of admissions, respectively, and women who were overweight, obese, or severely obese were associated with a 4, 9, and 12% increase in the duration of stay (all P < 0.001). The additional maternity costs [mean (95% CI), adjusted analyses] for women who were underweight, overweight, obese, or severely obese were £102.27 (£48.49-156.06), £59.89 (£41.61-78.17), £202.46 (£178.61-226.31), and £350.75 (£284.82-416.69), respectively. CONCLUSIONS: Maternal BMI influences maternal and neonatal morbidity, the number and duration of maternal and neonatal admissions, and health service costs.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor PF-734200 added to metformin in Type 2 diabetes.

AIMS: PF-734200 is a potent and selective oral dipeptidyl peptidase-4 (DPP-4) inhibitor. This study assessed the efficacy and safety of PF-734200 at dose rates of 20 and 30 mg/day in subjects with Type 2 diabetes mellitus inadequately controlled on metformin monotherapy. METHODS: This was a placebo-controlled, double-blind, randomized, multicentre, 12 week study. Subjects with Type 2 diabetes mellitus were eligible if screening glycosylated haemoglobin (HbA(1c) ) was 7-11% (53.0-96.7 mmol/mol) and they had been receiving metformin monotherapy for ≥2 months. Subjects receiving metformin and an insulin secretagogue or metformin and thiazolidinedione needed to have a screening HbA(1c) of 6.5-9.5% (47.5-80.3 mmol/mol), measured prior to discontinuing the insulin secretagogue or thiazolidinedione. The primary end-point of the study was a change from baseline to week 12 in HbA(1c) levels. RESULTS: Baseline characteristics for 289 subjects randomized to PF-734200 or placebo groups were similar (mean age 56.5 years, mean body mass index 32.2 kg/m(2) and mean HbA(1c) 8.2%, 66.1 mmol/mol). In the predefined per protocol data set, least-squares mean HbA(1c) at week 12 was reduced by 0.79 (8.6 mmol/mol 95% confidence interval -1.10 to -0.49, -12.0 to -5.4 mmol/mol) and 0.92% (10.1 mmol/mol; -1.23 to -0.61, -13.4 to -6.7 mmol/mol) in the 20 and 30 mg groups, respectively, compared with placebo. Differences from placebo were statistically significant (P<0.0001), but the differences between the 20 and 30 mg groups were not. The intent-to-treat analysis yielded similar findings. CONCLUSIONS: The HbA(1c) was significantly and meaningfully reduced by both doses of PF-734200, but 20 mg appears to be the more appropriate therapeutic dose for Type 2 diabetes mellitus, contingent upon confirmation by long-term controlled studies.

A placebo-controlled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin.

AIM: To test the hypothesis that glycaemic control with exenatide added to thiazolidinediones (TZDs) with or without metformin was superior to placebo. METHODS: A 26-week, multi-country (Canada, Mexico, Romania, South Africa and the USA), randomized, double-blind, placebo-controlled study compared exenatide twice-daily vs. placebo in 165 subjects suboptimally controlled with TZDs with or without metformin [HbA(1c) 8.2% (s.d. 0.9), fasting serum glucose 9.1 (2.6) mmol/l, body weight 93.9 (17.8) kg, diabetes duration 6.4 (4.3) years]. After a 2-week, single-blind, lead-in period, subjects were randomly assigned (2 : 1) to add exenatide or placebo to current regimens. The primary endpoint was HbA(1c) change at endpoint (Week 26 or last-observation-carried-forward). RESULTS: Only 8 subjects were treated with concomitant TZD alone. Exenatide reduced HbA(1c) significantly more than placebo [-0.84% (s.e. 0.20) vs. -0.10% (0.23), treatment difference -0.74% (0.16), p < 0.001)]. Mean reductions in body weight were similar in both treatments at endpoint [exenatide, -1.4 (s.e. 0.6) kg vs. placebo, -0.8 (0.7) kg, p = 0.176)]. Nearly 71% of subjects had both a reduction in HbA(1c) and body weight with exenatide compared with 54% with placebo. The most common adverse events (exenatide vs. placebo) were nausea (12% vs. 2%, p = 0.037), vomiting (8% vs. 0%, p = 0.031) and headache (4% vs. 4%). Confirmed (blood glucose <3.0 mmol/l) minor hypoglycaemia was experienced by 4 and 2% of subjects treated with exenatide and placebo, respectively. Incidence of hypoglycaemia was not significantly different between groups. CONCLUSIONS: Exenatide added to TZDs alone or in combination with metformin significantly improved glycaemic control as determined by significant improvement in HbA(1c) without associated hypoglycaemia.

Effects of inhaled human insulin on airway lining fluid composition in adults with diabetes.

Inhaled human insulin (Exubera (human insulin of rDNA origin) Inhalation Powder) causes small, early and reversible changes in pulmonary function in subjects with diabetes mellitus. The present study assessed whether changes occur in cellular and soluble constituents of airway lining fluid consistent with inflammation as a possible cause for Exubera-associated lung function alterations. Two 31-week, open-label, sequential design phase 2 studies were conducted, one with 20 subjects with type 1 and one with 24 subjects with type 2 diabetes. After run-in, all subjects received subcutaneous insulin for 12 weeks, followed after 1 week by 12 weeks of Exubera. Bronchoalveolar lavage fluid cell counts and protein constituents were determined at baseline, after 12 weeks of subcutaneous insulin and after 12 weeks of Exubera. Baseline cellular and soluble constituents of lavage fluid were similar to those reported for nondiabetic adults. Exubera produced no consistent clinically or statistically significant changes in total or differential lavage fluid cell counts or protein concentrations, even though Exubera-associated changes in pulmonary function are known to be fully manifest within 12 weeks. Therefore, 12 weeks of Exubera treatment is not associated with evidence of pulmonary inflammation. The treatment effects on lung function observed in Exubera trials are not caused by lung inflammation.

Assessment of the toxicity of mixtures of copper, 9,10-phenanthrenequinone, and phenanthrene to Daphnia magna: evidence for a reactive oxygen mechanism.

Polycyclic aromatic hydrocarbons and their derivatives are ubiquitous environmental contaminants. They are commonly present in complex mixtures with other contaminants, such as metals. The toxicities of phenanthrene (PHE) and 9,10-phenanthrenequinone (PHQ) with or without Cu were determined using Daphnia magna. Copper was the most toxic among the three chemicals tested, followed by PHQ and then PHE, with 48-h median effective concentrations (EC50s) of 0.96, 1.72, and 5.33 microM, respectively. Copper at 0.31 microM, or approximately the 5% effective concentration, decreased the EC50 of PHQ from 1.72 to 0.28 microM. Likewise, PHQ at 1.2 microM, or approximately the 10% effective concentration, significantly lowered the EC50 of Cu from 0.96 to 0.30 microM. This synergistic effect was not observed, however, in mixtures of Cu and PHE based on the response addition model. Assimilation of Cu wasfound to be similar with or without PHQ at increasing external concentrations of Cu, indicating that the increased toxicity of their mixtures is physiologically based. The ability of Cu plus PHQ to generate reactive oxygen species (ROS) was measured as well. Copper alone caused elevated ROS levels at a low concentration (0.63 microM). With PHQ present, however, this elevation in ROS occurred at an even lower Cu level (0.31 microM). Possible attenuation effects of ascorbic acid (vitamin C) on toxicity and ROS production induced by Cu, PHQ, and their mixtures were then examined. Ascorbic acid protected against Cu and Cu-plus-PHQ mixture-mediated toxicity but did not affect PHQ toxicity. Ascorbic acid also lowered ROS levels in the presence of Cu and Cu plus PHQ. We conclude that there exist potential toxic interactions between metals and modified PAHs and that these interactions can involve ROS formation.

"Doctor my eyes": A natural experiment on the demand for eye care services.

Preventive health care is promoted by many organisations from the World Health Organisation (WHO) to regional and national governments. The degree of cost-sharing between individuals and the health care service affects preventive service use. For instance, out-of-pocket fees that are paid by individuals for curative services reduce preventive care demand. We examine the impact of subsidised preventive care on demand. We motivate our analysis with a theoretical model of inter-temporal substitution in which individuals decide whether to have a health examination in period one and consequently whether to be treated if required in period two. We derive four testable hypotheses. We test these using the subsidised eye care policy introduced in Scotland in 2006. This provides a natural experiment that allows us to identify the effect of the policy on the demand for eye examinations. We also explore socio-economic differences in the response to the policy. The analysis is based on a sample from the British Household Panel Survey of 52,613 observations of people, aged between 16 and 59 years, living in England and Scotland for the period 2001-2008. Using the difference-in-difference methodology, we find that on average the policy did not affect demand for eye examinations. We find that demand for eye examinations only increased among high income households, and consequently, inequalities in eye-care services demand have widened in Scotland since the introduction of the policy.

Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.

OBJECTIVES: To investigate the efficacy of once-daily oral oseltamivir for 6 weeks (Tamiflu) in prophylaxis against laboratory-confirmed clinical influenza in frail older subjects living in homes for seniors and to determine the safety and tolerability of long-term oseltamivir. DESIGN: Double-blind, placebo-controlled, parallel-group, randomized, multicenter study. SETTING: Thirty-one residential homes for seniors across United States and Europe. PARTICIPANTS: Five hundred forty-eight frail older occupants (mean age 81 years, >80% vaccinated). INTERVENTION: Prophylaxis with oseltamivir 75 mg or placebo once daily for 6 weeks, beginning when influenza was detected locally. MEASUREMENTS: The primary efficacy endpoint was laboratory-confirmed clinical influenza. RESULTS: Oseltamivir administration resulted in a 92% reduction in the incidence of laboratory-confirmed clinical influenza compared with placebo (placebo 12/272 (4.4%), oseltamivir 1/276 (0.4%); P = .002). Of subjects vaccinated against influenza, oseltamivir was 91% effective in preventing laboratory-confirmed clinical influenza (placebo 11/218 (5.0%), oseltamivir 1/222 (0.5%); P = .003). Oseltamivir use was associated with a significant reduction in the incidence of secondary complications (placebo 7/272 (2.6%), oseltamivir 1/276 (0.4%); P = .037). Although nearly all subjects were taking concomitant medication both before and during the study, oseltamivir was well tolerated. A similar incidence of adverse events, including gastrointestinal effects, occurred in both groups. There was no suppression of antibody response in oseltamivir recipients. CONCLUSION: Oral oseltamivir 75 mg once daily for 6 weeks effectively prevented clinical influenza in vaccinated frail older subjects using significant concomitant medications in a residential care setting. The treatment was well tolerated and provided additional protection to that afforded by vaccination.

Results of a study to determine the effects of three oral contraceptives on serum lipoprotein levels.

A multicenter, double-blind investigation with random allocations of subjects to Ortho-Novum 1/50 tablets, Ortho-Novum 1/35 tablets, or Modicon tablets (Ortho Pharmaceutical Corporation, Raritan, NJ) was conducted. Each subject remained on the same oral contraceptive (OC) for at least four cycles. Serum high-density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and cholesterol were measured prior to the initiation of OC therapy and were repeated after treatment cycles 2 and 4. There were no significant changes in HDL, LDL, or serum cholesterol levels. Triglyceride levels increased but remained significant only with the lowest dose product. These were no significant differences among the three drugs for the four parameters studied.

Oral contraceptive exposure of amenorrheic women with and without prolactinomas.

The purpose of this study was to determine the extent of oral contraceptive (OC) exposure of women with secondary amenorrhea of hypothalamic-pituitary etiology. In 93 of 126 women with secondary amenorrhea sufficient data were obtained regarding menstrual history and OC exposure: 26 patients had evidence of a prolactinoma, an additional 26 patients had idiopathic hyperprolactinemia without evidence of a pituitary tumor, and 41 had "pure" dysfunction hypothalamic-pituitary amenorrhea. After stratification by age at diagnosis and parity the estimated odds ratio for past oral contraceptive usage showed no differences among the three groups (odds ratios between 0.74 and 1.48). Using the chi-square test the proportion of subjects who had regular menses before oral contraceptive intake and developed anovulation immediately after discontinuance ("post pill amenorrhea") in the three groups also showed no difference (x2 = 0.60, P = 0.74). These data indicate that non-ovulatory patients are likely to have been exposed to OC, and do not indicate that patients with prolactinomas differ in the extent of their OC exposure from other specified groups of patients with secondary.

Measures of association between disease and genotype.

This paper is concerned with the statistical aspects of the phenomenon of disease occurring more frequently in individuals with some genotypes than in individuals with others. A correlation coefficient is defined to quantify association between disease and genotype. A distinction is made between the concepts of independence of allele and disease and independence of genotype and disease. This distinction is used to define two components of association which describe separate aspects of association of disease with genotype. One component is a measure of the association of disease with allele; the other a measure of the effect of allele interaction on association of disease and genotype. One aspect of the usefulness of the partition into components which is discussed is in expressing the recurrence risk of disease for a relative of an affected individual. A chi-squared analysis is provided to test hypotheses about the components of association and other hypotheses of genetic interest. This analysis is illustrated using a study done to determine the effect of the sex-linked dwarfing gene in male chickens on resistance to E. coli infection. This analysis shows a significant allele interaction effect on resistance to disease but no association of disease with alleles. In conclusion, some extensions and limitations of the proposed concepts and procedures are discussed.

A statistical methodology for postmarketing surveillance of adverse drug reaction reports.

This paper presents a statistically optimal exact hypothesis testing procedure for detecting changes in sales adjusted adverse drug reaction (ADR) rates between historical and current periods, with a computer program that implements this test appended. We provide discussions and illustrations on how to monitor ADR rates for product lines that consist of several pharmacologically equivalent dosage forms.

Multichannel real-time analysis of the clinical EEG on a dual microprocessor system.

A dual microprocessor system has been developed as an aid to conventional visual analysis of the EEG. Up to eight channels of EEG gathered from any standard EEG strip-chart machine can be processed in real time. The analysis is performed on a dual microprocessor "pipe-line" configuration that is built using Motorola 68000 (16-bit) and 6809 (8-bit) microprocessors. The system is basically software oriented in order to offer processing flexibility. The 16-bit processor is dedicated to the critical task of signal analysis based on a newly developed period-peak algorithm. The 8-bit processor is dedicated to the pre- and post-processing tasks, including statistical generations and display control. Analysis results for each channel are displayed on a video terminal in several convenient graphical formats.

High-performance liquid chromatographic determination of the H+/K+ ATPase inhibitor (BY 1023/SK&F 96,022) and its sulphone metabolite in serum or plasma by direct injection and fully automated pre-column sample clean-up.

A fully automated high-performance liquid chromatographic method is described for the determination of the new H+/K+ ATPase inhibitor BY 1023/SK&F 96,022 and its major metabolite occurring in dog serum. The method uses direct sample injection of up to 200 microliters and a pre-column switching technique. In order to optimize the recovery, pre-column conditions were varied systematically with respect to the pH of the pre-column eluent, its buffering capacity and content of acetonitrile. Optimization resulted in near 100% recovery for both compounds, thus allowing the use of external standardization. The linearity range, precision and detection limits were determined and the method shown to be applicable to both serum and plasma. The method was applied to define the pharmacokinetics in dogs and humans.

Pharmacokinetic and pharmacodynamic assessment of a five-probe metabolic cocktail for CYPs 1A2, 3A4, 2C9, 2D6 and 2E1.

AIMS: The primary objectives of the present study were to establish whether there was a pharmacokinetic or pharmacodynamic interaction between the probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4), when administered in combination as a cocktail. Furthermore, the tolerability of these probe drugs, both alone and in combination as a cocktail was assessed. METHODS: Twelve healthy volunteer subjects (age range 22-48 years) were entered into an open, fixed sequence, 6-limb, single centre study. The randomization was such that all drugs were given individually followed by the full "cocktail" as the last treatment limb. The phenotypic index used to assess the intrinsic activity of the CYP isoforms included metabolite/parent ratios in plasma and urine (CYPs 1A2, 2E1 & 2C9), parent/metabolite ratios in urine (CYP2D6) and plasma AUClast (CYP3A4). Blood pressure and blood glucose measurements were used to assess pharmacodynamic interactions. Tolerability was assessed through reporting of adverse events RESULTS: Overall, there was little evidence that the probe drugs interacted metabolically when co-administered as the cocktail. The ratio of the geometric mean (and 90% confidence interval) of the phenotypic index, obtained after administration of the probe as part of the cocktail and when given alone were: caffeine, 0.86 (0.67-1.10), midazolam, 0.96 (0.74-1.24), tolbutamide, 0.86 (0.72-1.03), debrisoquine 1.04 (0.97-1.12) and chlorzoxazone, 0.95 (0.86-1.05). There was no difference in blood pressure and blood glucose concentrations following the cocktail and dosing of the individual probes. There was no effect on ECG recordings at any time-point. The adverse events reported for individual drug administrations were mild, transient and expected. Overall no more adverse events were reported on the cocktail study days than on the days when the drugs were administered alone. CONCLUSIONS: The five probe drugs when coadministered, in this dosing regimen, demonstrated no evidence of either a metabolic or pharmacodynamic interaction that might confound the conclusions drawn during a cocktail study. The present cocktail methodology has the potential to become a useful tool to aid the detection of clinically important drug-drug interactions during drug development.

Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group.

BACKGROUND: Erectile dysfunction in men is common. We evaluated a system by which alprostadil (prostaglandin E1) is delivered transurethrally to treat this disorder. METHODS: Alprostadil was delivered transurethrally in a double-blind, placebo-controlled study of 1511 men, 27 to 88 years of age, who had chronic erectile dysfunction from various organic causes. The men were first tested in the clinic with up to four doses of the drug (125, 250, 500, and 1000 microg); those who had sufficient responses were randomly assigned to treatment with either the effective dose of alprostadil or placebo for three months at home. RESULTS: During in-clinic testing, 996 men (65.9 percent) had erections sufficient for intercourse. Of these men, 961 reported the results of at least one home treatment; 299 of the 461 treated with alprostadil (64.9 percent) had intercourse successfully at least once, as compared with 93 of the 500 who received placebo (18.6 percent, P<0.001). On average, 7 of 10 alprostadil administrations were followed by intercourse in men responsive to treatment. The efficacy of alprostadil was similar regardless of age or the cause of erectile dysfunction, including vascular disease, diabetes, surgery, and trauma (P<0.001 for all comparisons with placebo). The most common side effect was mild penile pain, which occurred after 10.8 percent of alprostadil treatments, but the pain rarely resulted in refusal to continue in the study. Hypotension occurred in the clinic in 3.3 percent of men receiving alprostadil. Hypotension-related symptoms were uncommon at home. No men had priapism or penile fibrosis. CONCLUSIONS: In men with erectile dysfunction, transurethral alprostadil therapy resulted in erections in the clinic and in intercourse at home.

Portal vein complications after liver transplantation for biliary atresia.

The objective of this report is to review portal complications (PC) after pediatric liver transplantation (LT) for biliary atresia (BA) in the Bicêtre surgical series. From January 1, 1988, to February 28, 1995, 96 children with BA underwent 115 LTs Portal anastomosis was done on either the recipient portal vein (n = 85) or superior mesenteric vein (n = 11). No antiaggregative agents were administered postoperatively. Median follow-up was 50 months (range, 12 to 97). Nineteen PC (16.5%) occurred in 17 recipients: 16 portal thrombosis (PT) and 3 portal stenosis (PS). Fifteen instances of early PT occurred between days 0 and 17 (median, day 2). Emergency thrombectomy was performed in 9 cases (successful in 5). Three children underwent a secondary portosystemic shunt (successful in 2). Three PS were cured by either surgery or balloon dilatation. Four children died, 3 are alive with portal hypertension (PHT), and 10 are alive without PHT. Three-year patient actuarial survival is 82.4% in PC cases and 82% in others (NS). Significant risk factors of PC are young age and weight at the time of LT, small portal vein, and emergency LT. Analysis of our own results and review of the literature suggest that prevention of PC depends primarily on appropriate surgical technique. Reduction of postoperative hypercoagulability may also play an important role: a meta-analysis of 1,257 published pediatric LT show an overall risk of PT of 2.2% in teams using aspirin with or without dipyridamole compared with 7.8% when no antiaggregative agents are given (P = .0001).