Updated core competencies in pharmacoepidemiology to inform contemporary curricula and training for academia, government, and industry.

PURPOSE: The first paper to specify the core content of pharmacoepidemiology as a profession was published by an ISPE (International Society for Pharmacoepidemiology) workgroup in 2012 (Jones JK et al. PDS 2012; 21[7]:677-689). Due to the broader and evolving scope of pharmacoepidemiology, ISPE considers it important to proactively identify, update and expand the list of core competencies to inform curricula of education programs; thus, better positioning pharmacoepidemiologists across academic, government (including regulatory), and industry positions. The aim of this project was to update the list of core competencies in pharmacoepidemiology. METHODS: To ensure applicability of findings to multiple areas, a working group was established consisting of ISPE members with positions in academia, industry, government, and other settings. All competencies outlined by Jones et al. were extracted from the initial manuscript and presented to the working group for review. Expert-based judgments were collated and used to identify consensus. It was noted that some competencies could contribute to multiple groups and could be directly or indirectly related to a group. RESULTS: Five core domains were proposed: (1) Epidemiology, (2) Clinical Pharmacology, (3) Regulatory Science, (4) Statistics and data science, and (5) Communication and other professional skills. In total, 55 individual competencies were proposed, of which 25 were new competencies. No competencies from the original work were dropped but aggregation or amendments were made where considered necessary. CONCLUSIONS: While many core competencies in pharmacoepidemiology have remained the same over the past 10 years, there have also been several updates to reflect new and emerging concepts in the field.

Publishing negative findings and the challenge of avoiding type II errors in studies of suspect teratogens: Example of a recent ondansetron publication.

It is important that negative, as well as positive, studies be published to complete the available picture in areas of scientific inquiry. At the same time, it is critical that the implications of a negative study not be overstated and generalized when major issues of study design and data accuracy may be the reason that no relationship was discovered. The challenge of avoiding type II errors in interpreting negative findings has major public health implications, especially when the relationship of an exposure to birth defects is the concern. This is particularly important when interpreting the report by Fazio et al. (June issue of Reproductive Toxicology) on the relationship of ondansetron exposure to pregnancy outcome and birth defects. This review addresses the study design and conclusions and suggests that an alternative concluding statement would be more apropos, given the limitations of the data.

Gastric pH and Therapeutic Responses to Exsomeprazole in Patients With Functional Dyspepsia: Potential Clinical Implications.

BACKGROUND: Therapy for functional dyspepsia remains a challenge. This study aimed to evaluate esomeprazole (E) versus placebo (P) regarding (1) the effectiveness in providing relief of abdominal pain or discomfort during 16 weeks of therapy in patients with functional dyspepsia having moderate or severe symptoms; (2) the effects on gastric acid suppression and (3) the relationship between symptom relief and gastric pH. METHODS: Enrolled patients were randomized to E (n = 38) or P (n = 35) in a double-blind, placebo-controlled trial. Outcomes were measured at four 4-week intervals. Drug dose titrated at each visit, based on relief of abdominal symptoms. The 24-hour gastric pH was monitored at baseline, 4 and 8 weeks. RESULTS: After 4 weeks, 71% of E patients (40mg) reported satisfactory symptom relief versus 34% of P patients (P < 0.001). When the dose for nonresponders (NR) was titrated to 40mg twice daily, the E relief rate increased to 82% versus 56% in P group (P < 0.05). During the next 4 weeks, with dose decreased by half in responders, E response rate declined to 69% versus 48% in P group (P < 0.10). When the dose was increased for NR during the last 4 weeks, E rate increased to 83% versus 57% in P group (P < 0.05). At 4 and 8 weeks for E responders and NR, patients׳ pH >4 value increased significantly compared to baseline. CONCLUSIONS: (1) Though E 40mg once daily is superior to P, some patients benefit from 40mg twice daily; (2) E, 40mg once daily, profoundly inhibits gastric acid secretion; (3) intragastric pH monitoring before and after therapy may help address the relationship between symptomatic relief and gastric acid secretion and (4) some patients respond to monitored titrated placebo therapy.

Stimulation of Mucin, Mucus, and Viscosity during Lubiprostone in Patients with Chronic Constipation may Potentially Lead to Increase of Lubrication.

OBJECTIVES: The purpose of this clinical trial was to explore whether lubiprostone increases the rate of mucus and mucin secretion and its viscosity in chronic constipation (CC) patients. The secretion of chloride (CS) into the gastrointestinal tract lumen is pivotal in the body's ability to process non-digestible food components. CS sets the optimal rate of hydration for non-digestible food components, their fluidity, and their adequate propulsion along the alimentary tract. Chloride is also instrumental in the secretion of alimentary tract mucus, and the formation of a gel-like, viscous mucus-buffer layer. This layer acts as the first line and vanguard of the mucosal barrier. This barrier is essential in mucosal lubrication and protection. Lubiprostone, a novel chloride channel stimulator ClC-2, is currently approved for the treatment of CC. Its impact on mucus, mucus secretion, and viscosity is not established. METHODS: A double-blind, crossover trial was approved by the IRBs at the Kansas University Medical Center (Kansas City, KS) (study site) and at the Texas Tech University HSC (El Paso, TX) (analysis site). The study included 20 patients (17 females (F); mean age: 37 years) with symptoms of CC diagnosed according to the Rome III criteria. Patients were randomized to 1 week of therapy with lubiprostone or placebo followed by a 1 week washout and 1 week of the alternative therapy. Gastric juice was collected basally and during stimulation with pentagastrin (6 µg/kg body weight subcutaneously) at the end of weeks 1 and 3. Pentagastrin stimulation mimics food stimulation. The mucus content in gastric juice was assessed gravimetrically. The mucin content was measured after its purification using ultracentrifugation. The viscosity of the gastric secretion was measured using a digital viscometer. RESULTS: In comparison with placebo, the volume of gastric secretion in patients with CC during administration of lubiprostone increased significantly by 50% (86.3 vs. 57.5 ml/h) (P<0.001) in basal conditions and increased by 25% (210.0 vs. 167.6 ml/h) (P=0.024) during stimulation with pentagastrin. The rate of gastric mucus secretion during therapy with lubiprostone was 91% higher (257.3 vs. 135 mg/h) (P=0.001) in basal conditions and 28% higher (348.1 vs. 270.8 mg/h) (NS) in stimulated conditions, although the latter was not statistically significant. The rate of gastric mucin secretion during lubiprostone therapy was 85% higher (98.4 vs. 65.5 mg/h) (P=0.011) in basal conditions and 38% (98.3 vs. 71.7 mg/h) (NS) higher in stimulated conditions. In basal conditions, the viscosity of gastric secretion during administration of lubiprostone increased by 240% at the lowest (P<0.001) and by 106% at the highest shear rate (P<0.001). In stimulated conditions, it increased by 226% (P<0.01) at the lowest shear rate and by 67% (P<0.01) at the highest shear rate. CONCLUSIONS: The significantly higher content of gastric mucus and mucin during therapy in basal conditions with lubiprostone in patients with CC suggests and supports the potentially leading role of lubiprostone and ClC-2 stimulation in their secretion. This increased stimulation results in profoundly increased viscosity, which in turn facilitates and/or accelerates the transit and evacuation of non-digestible food components. Although increases in mucus and mucin were observed in stimulated conditions, neither increase was statistically significant. Based on this experiment, we hypothesize that, in CC patients, the significantly increased rate of mucus and its major component, mucin secretion, during lubiprostone administration may partially explain its clinical effectiveness and also have additional clinically important effects. We propose that since the increased mucus production enhances the protective quality of the mucosal barrier, it also boosts its potential to withstand luminal aggressive components such as acid/pepsin duet, Helicobacter pylori and/or nonsteroidal anti-inflammatory drugs/aspirin, or a combination of all. Further trials are needed to test this hypothesis. As this was crossover clinical trial, the patients serve as their own controls. No interaction was found with body mass index (BMI) and treatment. The observed relationships of BMI and mucus and mucin secretions and gastric juice volume are important considerations in the design of future trials, particularly if a crossover design is not used.

Depression as a predictor of length of stay in patients admitted to the cardiovascular intensive care unit at a university medical center.

Depression is a predictor of length of stay (LOS) and adverse outcomes in patients with cardiac disease. Our objective was to assess the impact of depression on LOS in a Hispanic population admitted to a cardiovascular intensive care unit (CVICU). This was a prospective study of 151 consecutive patients admitted to the CVICU. Patients were administered the Center for Epidemiologic Studies Depression (CES-D) scale survey within 24 hours of admission. Patients were followed until discharge to determine LOS and adverse outcomes. Depression was more prevalent in Hispanic patients than in nonHispanic patients based on the CES-D scores (41% vs 14%). Using multivariate analysis, the presence of depression was a significant predictor of increased LOS (P = .001). Depression has a significant impact on LOS in a Hispanic population. Appropriate treatment of depression may decrease LOS and has the potential to be cost effective in the current health care environment.

Side effects of oral misoprostol for the prevention of postpartum hemorrhage: results of a community-based randomised controlled trial in rural India.

OBJECTIVE: To investigate the side effects of 600 microg oral misoprostol given for the mother and the newborn to prevent postpartum hemorrhage (PPH). METHODS: One thousand six hundred twenty women delivering at home or subcentres in rural India were randomised to receive misoprostol or placebo in the third stage of labour. Women were evaluated for shivering, fever, nausea, vomiting and diarrhea at 2 and 24 h postpartum. Newborns were evaluated within 24 h for diarrhea, vomiting and fever. Symptoms were graded as absent, mild-to-moderate or severe. RESULTS: Women who received misoprostol had a significantly greater incidence of shivering (52%vs. 17%, p < 0.001) and fever (4.2%vs. 1.1%, p < 0.001) at 2 h postpartum compared with women who received placebo. At 24 h, women in the misoprostol group experienced significantly more shivering (4.6%vs. 1.4%, p < 0.001) and fever (1.4%vs. 0.4%, p < 0.03). There were no differences in nausea, vomiting or diarrhea between the two groups. There were no differences in the incidence of vomiting, diarrhea or fever for newborns. CONCLUSIONS: Misoprostol is associated with a significant increase in postpartum maternal shivering and fever with no side effects for the newborn. Given its proven efficacy for the prevention of PPH, the benefits of misoprostol are greater than the associated risks.

Variation in the postpartum hemorrhage rate in a clinical trial of oral misoprostol.

OBJECTIVE: The main objective of this study was to identify factors associated with variation in the rate of acute postpartum hemorrhage (PPH), defined as blood loss >or= 500 mL within 2 hours of delivery, observed in a randomized clinical trial of misoprostol for the prevention of PPH, conducted in rural India. Although the women in the misoprostol group had a significantly lower probability of having a PPH, we also noted a reduction in the rate of PPH in the placebo group over the course of the study. We hypothesized that this was due to the changing skills of the auxiliary nurse midwives (ANMs) over the course of the study. METHODS: We conducted a post-hoc analysis examining variation in PPH rates over the duration of the trial among the women randomized to the placebo arm (n = 808). Descriptive, correlation analysis and generalized estimating equations (GEE) were used to predict PPH rates. With no direct measure of ANM skills, we used proxy measures, including: (1) the ANM's point of entry into the study (original ANMs at the initiation of the trial were less skilled than replacement ANMs); (2) the study duration, representing exposure of the ANM to ongoing training and monitoring; and (3) duration of the second stage of labor as a measure of improved delivery practices. RESULTS: As the study duration increased, the duration of the second stage of labor decreased (-0.12, p = 0.001) and as the duration of the second stage of labor decreased, the rate of PPH decreased (0.0282; 95% CI 0.0201-0.0363). For each 10-minute increase in the duration of second stage labor increased PPH odds by 7.1% and each 30-day duration of the trial decreased PPH odds by 3.4%. Additionally, a patient delivered by an original ANM was 3.14 times more likely to have a PPH compared to a patient delivered by a replacement ANM. CONCLUSIONS: Declining PPH rates were associated with improved skills and delivery practices that decreased duration of the second stage of labor. These improvements appeared to be consistent with the introduction of the more skilled replacement ANMs as well as ongoing training and monitoring for all ANMs over the duration of the trial.

Factors associated with acute postpartum hemorrhage in low-risk women delivering in rural India.

OBJECTIVE: Postpartum hemorrhage (PPH), a major cause of maternal mortality and morbidity in low-income countries, can occur unpredictably. This study examined the sociodemographic, clinical, and perinatal characteristics of low-risk women who experienced PPH. METHODS: This analysis was conducted using data on 1620 women from a randomized trial testing oral misoprostol for prevention of PPH in rural India. RESULTS: Of the women, 9.2% experienced PPH. No maternal or sociodemographic factors and few perinatal factors differed between women with PPH and those without, other than treatment with misoprostol. Having fewer than 4 prenatal visits and lack of iron supplementation increased the risk for PPH (P<0.001 and P=0.037, respectively). Several factors unknown until the second stage of labor (perineal tear and birth weight) were also associated (P=0.003). CONCLUSIONS: Among women at low risk for PPH, there were few factors associated with further risk. Given that PPH can occur without warning, rural communities should consider ways to increase both primary prevention (iron supplementation, AMTSL) and secondary prevention of PPH (availability of obstetric first aid, availability of transport, and availability of emergency obstetric care).

Significant enhancement of esophageal pre-epithelial defense by tegaserod: implications for an esophagoprotective effect.

BACKGROUND & AIMS: Tegaserod, a serotonin 5-hydroxytryptamine (5-HT)4 receptor agonist, is thought to stimulate intestinal secretions. The aim of the current study was to assess the effect of tegaserod vs placebo on salivary and esophageal protective factors in patients with gastroesophageal reflux disease (GERD). METHODS: This study was a randomized, double-blind, placebo-controlled, cross-over trial in 38 GERD patients treated with tegaserod 6 mg twice a day vs placebo. Salivary samples were collected basally and during mastication. In addition, in 32 GERD patients, salivary and esophageal secretions also were collected during infusion of NaCl, HCl/pepsin, and NaCl in a consecutive fashion using a specially designed esophageal catheter. Saliva and esophageal perfusates were assessed for the pH, volume, content of buffers, protein, mucin, epidermal growth factor (EGF), transforming growth factor alpha (TGFalpha), and prostaglandin E (PGE)2 and analyzed statistically. RESULTS: Salivary flow rates during administration of tegaserod increased over corresponding values during both basal conditions (P < .01) and mastication (P < .001). The rate of secretion of salivary bicarbonate and nonbicarbonate buffers also increased in basal conditions (P < .001 and P < .01, respectively) and during mastication (P < .05 and P = .05). Salivary EGF increased during mastication (P < .05), whereas PGE2 and TGF alpha increased in basal conditions (P < .05 and P < .01). Esophageal perfusate volumes increased during administration of tegaserod in basal conditions (P < .05), whereas esophageal EGF secretion increased after mucosal exposure to HCl/pepsin and subsequent final perfusion with NaCl (P < .05). CONCLUSIONS: Significant stimulatory impact of 5-HT4 agonist on several salivary protective factors as well as esophageal EGF secretion may have esophagoprotective implications in patients with GERD and may help to address new therapies in the future.

Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial.

BACKGROUND: Postpartum haemorrhage is a major cause of maternal mortality in the developing world. Although effective methods for prevention and treatment of such haemorrhage exist--such as the uterotonic drug oxytocin--most are not feasible in resource-poor settings where many births occur at home. We aimed to investigate whether oral misoprostol, a potential alternative to oxytocin, could prevent postpartum haemorrhage in a community home-birth setting. METHODS: In a placebo-controlled trial undertaken between September, 2002, and December, 2005, 1620 women in rural India were randomised to receive oral misoprostol (n=812) or placebo (n=808) after delivery. 25 auxiliary nurse midwives undertook the deliveries, administered the study drug, and measured blood loss. The primary outcome was the incidence of acute postpartum haemorrhage (defined as > or =500 mL bleeding) within 2 h of delivery. Analysis was by intention-to-treat. The trial was registered with the US clinical trials database (http://www. clinicaltrials.gov) as number NCT00097123. FINDINGS: Oral misoprostol was associated with a significant reduction in the rate of acute postpartum haemorrhage (12.0% to 6.4%, p<0.0001; relative risk 0.53 [95% CI 0.39-0.74]) and acute severe postpartum haemorrhage (1.2% to 0.2%, p<0.0001; 0.20 [0.04-0.91]. One case of postpartum haemorrhage was prevented for every 18 women treated. Misoprostol was also associated with a decrease in mean postpartum blood loss (262.3 mL to 214.3 mL, p<0.0001). Postpartum haemorrhage rates fell over time in both groups but remained significantly higher in the placebo group. Women taking misoprostol had a higher rate of transitory symptoms of chills and fever than the control. INTERPRETATION: Oral misoprostol was associated with significant decreases in the rate of acute postpartum haemorrhage and mean blood loss. The drug's low cost, ease of administration, stability, and a positive safety profile make it a good option in resource-poor settings.

The impact of a school entry law on adolescent immunization rates.

PURPOSE: Middle school entry laws increase coverage with recommended vaccines, but their effect on vaccines that are not required is unknown. We compared vaccination coverage for hepatitis B, tetanus and diphtheria (Td), and measles, mumps and rubella (MMR) in areas of states with discordant middle school, hepatitis B school entry laws, and evaluated the relationship between demographic characteristics and adolescent immunization rates. METHODS: Retrospective design with purposive school sampling, using location of residence to determine study group. In each school, immunization records from a random sample of up to 75 students in ninth grade (affected by a new hepatitis B law) and 12th grade (not affected by the law) from 11 schools in two areas discordant for the law were analyzed. All areas had long standing two-dose MMR and Td requirements. RESULTS: Ninth graders in schools with the law had hepatitis B rates higher (72.8%) than those without the law (18.6%) (U = 2.0, p < .01). There were no significant differences between grades or schools for MMR and Td. However, even in the presence of the law, rates were significantly lower in schools with lower socioeconomic indicators. CONCLUSIONS: Middle school immunization laws are effective at raising adolescent hepatitis B, but in this study there wasn't enough power to discern the effect on rates for other vaccines or the influence of demographic variables on rates. Results suggested that laws did not appear to completely overcome disparities. For school mandates to be more effective, additional efforts, presumably on enforcement, especially in areas with lower socioeconomic indicators, are needed.

Initiating a novel therapy in preventing postpartum hemorrhage in rural India: a joint collaboration between the United States and India.

BACKGROUND: Maternal mortality rates in India are estimated at 560/100,000 live births and postpartum hemorrhage (PPH) accounts for 35-56% of these deaths. Given that 50% of births in rural India occur at home, oral Misoprostol administered by minimally trained midwives may be an effective uterotonic agent for preventing PPH when the use of other uterotonics is not feasible. While the import for testing the effectiveness of this intervention may be readily obvious, the elements essential for the conduct of a scientific study in rural areas served by indigenous health workers may not be as evident. METHODS: We present the design as well as the preparation and development of an ongoing NICHD sponsored U.S.-Indian collaborative randomized, placebo-controlled, clinical trial (RCT) conducted in four Primary Health Center areas of Belgaum District, Karnataka, India. The primary goal of the trial is to assess the effectiveness of Misoprostol 600 microg orally in reducing the incidence of acute PPH (> or = 500 mL) in women delivering at home or in neighboring sub-centers. 1600 pregnant women will be randomized to receive Misoprostol or placebo immediately post-delivery of the infant. However, beyond testing the scientific merit of the RCT, this study also tests the feasibility of having indigenous midwives regularly using Misoprostol in rural areas as well as the willingness of these communities to accept this intervention. In addition, this paper also explores the international and community collaborations necessary for the conduct of this study. FINDINGS: It is necessary to have several critical elements in place, including international collaboration between the Indian and US research sites, funding through a private/public collaboration and trained scientists, as well as commitment from the community for the successful conduct of such a study. In the development and implementation of a RCT, careful attention must be paid to the training of field personnel involved in the delivery process and developing a data collection and monitoring system to ensure that information gathered is valid. CONCLUSIONS: A joint U.S.-Indian collaboration to test the efficacy and the feasibility of an innovative method to reduce PPH can serve as collaborative model to develop additional interventions to improve maternal mortality and morbidity. If Misoprostol is shown to be sufficiently safe and efficacious in the prevention of PPH, the appropriate government agencies will be encouraged to make the drug available to midwives (ANMs) and rurally located physicians for whom parenteral medications are either not permitted or impractical and/or unavailable. Such a project can serve as a model applicable to rural settings throughout the developing world for improving delivery practices and reducing maternal mortality and morbidity. These are important public health concerns in India and other developing nations.