The future of population-based postmarket drug risk assessment: a regulator's perspective.

The US Food and Drug Administration emphasizes the role of regulatory science in the fulfillment of its mission to promote and protect public health and foster innovation. With respect to the evaluation of drug effects in the real world, regulatory science plays an important role in drug risk assessment and management. This article discusses opportunities and challenges with population-based drug risk assessment as well as related regulatory science knowledge gaps in the following areas: (i) population-based data sources and methods to evaluate drug safety issues; (ii) evidence-based thresholds to account for uncertainty in postmarket data; (iii) approaches to optimize the integration and interpretation of evidence from different sources; and (iv) approaches to evaluate the real-world impact of regulatory decisions. Regulators should continue the ongoing dialogue with multiple stakeholders to strengthen regulatory safety science and address these and other critical knowledge gaps.

Mortality in infants with congenital diaphragmatic hernia: a study of the United States National Database.

OBJECTIVE: To examine the effect of regionalization of care on outcomes of neonates with congenital diaphragmatic hernia (CDH). STUDY DESIGN: We analyzed the National Inpatient Sample and the 'Kids' database for the years 1997 to 2004. Infants with CDH were grouped based on whether they underwent surgical repair at the hospital of birth, or at another facility. Groups were compared using chi-square, t-test and logistic regression. RESULT: A total of 2140 infants were included: 41% were females, 42% were Caucasians, 48% were transported, 20% reported the use of extracorporeal membrane oxygenation (ECMO)and 33% died. Only 79% underwent operative repair, in which 85% survived after surgery. Survival among operated patients who used ECMO was 40%. Transported infants used more ECMO than non-transported ones (25 vs 15%; adjusted odds ratio (OR) 1.46; confidence interval 1.1 to 1.9, P=0.007), and had higher mortality after surgery (16 vs 13%; adjusted OR 1.46; confidence interval 1.1 to 2, P=0.02). CONCLUSION: The utilization of neonatal transport of CDH patients is associated with increased mortality and increased need for ECMO. This study supports the need for regionalization of care, and favors maternal transport before delivery of CDH newborns.

Massage with kinesthetic stimulation improves weight gain in preterm infants.

OBJECTIVE: The aim of this study was to evaluate the effects of massage with or without kinesthetic stimulation on weight gain and length of hospital stay in the preterm infant. STUDY DESIGN: A prospective randomized clinical trial was conducted evaluating the effects of massage with or without kinesthetic stimulation (KS) on weight gain and length of stay (LOS) in medically stable premature (<1500 g and/or and <1000 g) was also performed. RESULT: A total of 60 premature infants were recruited for this study; 20 infants in each group. Average daily weight gain and LOS were similar between the groups after controlling for covariates. For infants with BW>1000 g, average daily weight gain was increased in the intervention groups compared to control. This effect was mainly attributable to the M/KS group. CONCLUSION: Massage with KS is a relatively simple and inexpensive intervention that can improve weight gain in selected preterm infants. Length of hospital stay is not impacted by massage with or without KS. Further studies are needed to evaluate the effect of massage in the extremely low BW(<1000 g) infant.

Structure modification in knee osteoarthritis: methodology and outcome parameters.

UNLABELLED: Managing osteoarthritis (OA) with structure-modifying agents (SMAs) is an important emerging topic receiving increased attention from both lay individuals and health care professionals as a promising alternative in the management of OA. OBJECTIVE: To review the methodology and outcome parameters purported to be used in the assessment of the structure-modifying potential of various interventions. DESIGN: A Medline search was performed to select the relevant published articles. This review does not go into detail about various aspects of the design and conduct of structure-modifying studies; however, a vast number of relevant references are provided and may be accessed by interested readers. RESULTS: Enhancing the feasibility of SMAs trials aimed at documenting efficacy can be accomplished by carefully selecting: (1) the outcome parameters, (2) the imaging methodology, and (3) the patient population. Most of the relevant issues that need to be considered by investigators before embarking on a study of this nature have been addressed in this article. CONCLUSION: Most of the evidence to date focuses on the superiority of the radiographic-based techniques in measuring joint space narrowing among a homogeneous population of OA patients. More research is warranted before other techniques such as ultrasound, chondroscopy, and magnetic resonance imaging, can be proven to be reliable.

Oral treatment with a nutraceutical (Cosequin) for ameliorating signs of navicular syndrome in horses.

Fourteen horses with a progressive forelimb lameness of 3 to 12 months' duration, diagnosed as navicular syndrome, were selected from clinical cases admitted to Auburn University Equine Hospital for evaluation of the efficacy of an orally administered nutraceutical (Cosequin, Nutramax Laboratories, Inc., Edgewood, MD) for ameliorating clinical signs associated with naturally occurring navicular syndrome. Horses were randomly allocated to treatment with the nutraceutical or a placebo. Treatment was five scoops (16.5 g) of powder twice daily in the feed. The test group (n = 8) received a patented nutraceutical consisting of 9 g of FCHG49 (a highly purified glucosamine HCl), 3 g of TRH122 (a specific purified low-molecular-weight sodium chondroitin sulfate), and 600 mg of manganese ascorbate. The placebo group (n = 6) received an indistinguishable oral powder containing only excipients. Owners and the investigator were unaware of group assignments. The same investigator assessed lameness and overall clinical condition at enrollment and after 4 and 8 weeks of treatment. Lameness was assessed by an algofunctional lameness index, comprising a combined sum score of standing posture, hoof tester examination, and lameness scores at various levels of work. Overall clinical efficacy was rated on a visual analogue scale. Owners assessed lameness via a preassigned questionnaire, incorporating an algofunctional lameness index and overall clinical condition at weekly intervals. Radiographic examinations of the navicular bones were performed at enrollment and after 8 weeks of treatment. The median algofunctional lameness index and overall clinical condition scores assigned the investigator were significantly improved (P = .05) for horses treated with the nutraceutical compared with placebo-treated horses. The degree of improvement in algofunctional lameness index assigned by owners after 8 weeks was also significant (P = .045) between the treatment groups. Radiographic scores after treatment were not significantly different between the groups (P > .05).

In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate.

Supplements of glucosamine hydrochloride, low molecular weight chondroitin sulfate, and manganese ascorbate were tested separately and in combination for their ability to retard progression of cartilage degeneration in a rabbit instability model of osteoarthrosis. Computerized quantitative histologic evaluation of safranin O stained sections of the medial femoral condyles measured the grade and extent of tissue involvement of lesions. Severe lesions (Mankin grade greater than 7) were absent in all animals supplemented with a dietary mixture of glucosamine, chondroitin sulfate, and manganese ascorbate. Total linear involvement (mm of lesioned surface) and total grade (mean grade x number of lesions per animal) were reduced significantly in animals given the combination compared with controls (59% and 74% respectively). Animals supplemented with glucosamine, chondroitin sulfate, or manganese ascorbate alone had less moderate and severe tissue involvement than controls but not to the extent of the combined group. In vitro, a combination of glucosamine hydrochloride and chondroitin sulfate acted synergistically in stimulating glycosaminoglycan synthesis (96.6%). Chondroitin sulfate and manganese ascorbate but not glucosamine were effective in inhibiting degradative enzyme activity. These data suggest that the disease modifying effect (the ability to retard progression of cartilage degeneration) of a mixture of glucosamine, chondroitin sulfate, and manganese ascorbate is more efficacious than either agent alone.

Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis.

OBJECTIVES: The objective of this study was to evaluate the oral combination of glucosamine HCl, sodium chondroitin sulfate and manganese ascorbate for the treatment of osteoarthritis (OA) of the knee. DESIGN: A randomized placebo-controlled study design was implemented. We recruited 93 patients with OA of the knee from a single center. The intervention group received 1000 mg FCHG49 glucosamine HCl, 800 mg TRH122 low molecular weight sodium chondroitin sulfate and 152 mg manganese ascorbate twice daily (Cosamin DS). Patients were evaluated initially and then every 2 months for 6 months. The primary outcome was the Lesquene Index of severity of osteoarthritis of the knee (ISK). RESULTS: Patients with radiographically mild or moderate OA (N=72) in the intervention group showed significant improvement in the ISK at 4 and 6 months (P=0.003 and P=0.04, respectively). The response rate to the medication was 52% vs a 28% response rate to placebo. Patients with radiographically severe osteoarthritis (N=21) did not show significant improvements in the ISK. There was a 17% incidence of adverse events in the intervention group and 19% in the placebo group. CONCLUSIONS: The studied combination of glucosamine HCl, sodium chondroitin sulfate and manganese ascorbate was found to be effective for the treatment of radiographically mild to moderate OA of the knee as measured by the ISK. This is the first U.S. study of these agents.

The epidemiology of schistosomiasis in Egypt: Minya Governorate.

Risk factors, prevalence, and intensity of infection with Schistosoma sp. and prevalence and magnitude of morbidity caused by schistosomiasis was assessed in a stratified random sample of 16,433 subjects from 2,409 households in 33 rural communities in Minya Governorate, Egypt. The prevalence of S. haematobium ranged from 1.9% to 32.7% among the communities and averaged 8.9%. The average intensity of infection was a geometric mean egg count (GMEC) of 8.5 per 10 ml of urine and ranged from 1.6 to 30.9. Prevalence was maximum (18-20%) in those 10-20 years of age and higher in males than in females. Intensity of infection followed the same pattern. Infection with S. mansoni was present almost exclusively in a single village, confirming spread of this species up the Nile River and its focality in Minya. Risk factors for S. haematobium infection were an age from 11 to 20; male gender; males bathing in, women washing clothing or utensils in, and children swimming or playing in canals; and a history of, or treatment for, schistosomiasis. Recent history of burning micturition was associated with infection in children but not in adults, while a history of blood in urine correlated with S. haematobium infection in both age groups. Reagent strip-detected hematuria and proteinuria were highly associated, particularly in children, with S. haematobium infection. The presence of hepatomegaly or splenomegaly on physical examination was not associated with S. haematobium ova in the urine. Hepatomegaly, as measured by ultrasonography in the midclavicular line or the midsternal line, or ultrasonography-detected splenomegaly were not present more frequently in infected subjects than in uninfected subjects. Schistosoma ova were not detected more frequently in urine of subjects with ultrasonography-detected periportal fibrosis than in the urine from subjects without this finding. Ultrasonography-detected urinary bladder wall lesions were detected in only 6 (0.3%) subjects and obstructive uropathy was observed in 54 (2.7%) subjects. The absence of an association between prevalence of urinary tract morbidity and S. haematobium infections was surprising. Two possible explanations are 1) that repeated chemotherapy has reduced the prevalence of urinary tract morbidity and 2) that morbidity was not being detected by the ultrasonographic operators.

Results of a survey of small-animal practitioners on the perceived clinical efficacy and safety of an oral nutraceutical.

A mail survey of 3080 practitioners from two sampling frames was used to determine the perceived clinical efficacy and safety of an oral nutraceutical for the treatment of degenerative joint disease (DJD) in small animals. Overall response rate was 82%, of which 64% reported that they were recommending the oral nutraceutical to their clients. There was a high variability reported between the severity of DJD and response to treatment. Sixty-eight percent of practitioners reported lame dogs older than five years to be the most responsive to treatment. Most practitioners (83%) believed response to treatment with the studied product occurred within four weeks. Practitioners using the product rated the clinical efficacy of the product to be either 'good' or 'excellent' in improving mobility, alleviating pain and improving attitude in the majority of the treated animals. No practitioner reported a worsening of pain, mobility or attitude. Self-reported adverse effects were 2% (the most common was gastrointestinal upset). The results of this survey indicated that perceived clinical efficacy of the studied nutraceutical in the treatment of DJD was regarded to be 'good' or 'excellent' by most of the practitioners who use this product and was considered to be safe with minimal side effects. This provides additional information on the product for use in planning future clinical trials.

Determinants of infection with schistosomiasis haematobia using logistic regression.

A population-based stratified random sample of 10,039 inhabitants of rural communities in Minya Governorate, Egypt, were evaluated for risk factors for Schistosoma haematobium infection using multivariate analysis. Data were obtained by personal interview recording demographics, information on exposure to canal water, history of infection, and other risk factors for infection and examining urine samples for S. haematobium ova. Logistic regression analysis was used to adjust for confounders while assessing the role of each risk factor for infection. Using logistic regression allowed detection of several confounders and interactions which influenced other independent variables. Differences in exposure patterns to canal water among age and gender subgroups explained only a small portion of the variation in infection rates, thus favoring the alternative explanation: development of age-acquired immunity. The association of age with reduced prevalence of S. haematobium was the only relationship increasing (odds ratio [OR] = 2.95-4.30) with logistic regression. Male gender was a risk factor for infection but did not increase with logistic regression (OR = 2.33-2.03). The protective effects of education, only noted in schoolage children (OR = 0.59-0.51), were believed to be due to a school-based screening and treatment program.

Hematuria and proteinuria as predictors of Schistosoma haematobium infection.

An investigation of a population-based stratified random sample of 11,970 inhabitants of Minya Governorate in Egypt included examining urine specimens for Schistosoma haematobium ova using the filtration technique and for hematuria and proteinuria using reagent strips. Age- and gender-specific sensitivity, specificity, predictive values, and likelihood ratios of reagent strip-detected hematuria and proteinuria as indicators of S. haematobium infection were assessed. Results showed that in this population with a 9.0% infection rate, sensitivity (from 45.9 to 70.9) and specificity (from 65.9 to 86.3) were much lower than in previous reports. The most clinically valuable parameters, positive predictive value (PPV), negative predictive value (NPV) and likelihood ratio (LR), were highest with the presence of hematuria > or = +++ and proteinuria > or = ++, especially in males less than 20 years of age. Using the LR allowed effective altering of the pretest probability of infection among age and gender subgroups. The study concluded that reagent strip-detected hematuria and proteinuria, although valuable, are less reliable predictors of S. haematobium within communities than previously reported and their usefulness is improved with stratification by age and gender. In addition, predictive values and likelihood ratios provide practical information for predicting the presence or absence of infection within population subgroups.

Comparative evaluation of the use of artificial neural networks for modelling the epidemiology of schistosomiasis mansoni.

There has been a marked increase in the application of approaches based on artificial intelligence (AI) in the field of computer science and medical diagnosis, but AI is still relatively unused in epidemiological settings. In this study we report results of the application of neural networks (NN; a special category of AI) to schistosomiasis. It was possible to design an NN structure which can process and fit epidemiological data collected from 251 schoolchildren in Egypt using the first year's data to predict second and third years' infection rates. Data collected over 3 years included age, gender, exposure to canal water and agricultural activities, medical history and examination, and stool and urine parasitology. Schistosoma mansoni infection rates were 50%, 78% and 66% at the baseline and the 2 follow-up periods, respectively. NN modelling was based on the standard back-propagation algorithm, in which we built a suitable configuration of the network, using the first year's data, that optimized performance. It was implemented on an IBM compatible computer using commercially available software. The performance of the NN model in the first year compared favourably with logistic regression (NN sensitivity = 83% (95% confidence interval [CI] 78-88%) and positive predictive value (PPV) = 63% (95% CI 57-69%); logistic regression sensitivity = 66% (95% CI 60%-72%) and PPV = 59% (95% CI 53%-65%). The NN model generalized the criteria for predicting infection over time better than logistic regression and showed more stability over time, as it retained its sensitivity and specificity and had better false positive and negative profiles than logistic regression. The potential of NN-based models to analyse and predict wide-scale control programme data, which are inevitably based on unstable egg excretion rates and insensitive laboratory techniques, is promising but still untapped.

Relationship between blood lead and dietary iron intake in preschool children. A cross-sectional study.

The relationship between dietary iron intake and blood lead levels in urban preschool children was investigated in a cross-sectional study of 299 children from 9 months to 5 years old. Mothers of children attending the University of Maryland Pediatric Ambulatory Clinic volunteered for the children and themselves to join the study. The data collected included nutritional status, socioeconomic status, medical history, and potential sources of lead exposure. Blood samples from all participants were evaluated for levels of blood lead, serum iron (ferritin), free erythrocyte protoporphyrin, calcium, and hematocrit. The average blood lead level (standard deviation) in the studied population was 11.4 (7.3) micrograms/dL. With multiple linear and logistic regression analyses to adjust for covariates, a negative association (P = 0.03) between blood lead and dietary iron intake was found. This finding is consistent with similar results from experimental studies. It is concluded that there is evidence that higher dietary iron intake is associated with lower blood lead among urban preschool children in the studied population.

Application of neural networks to the real-time diagnosis of acute toxoplasmic infection in immunocompetent patients.

Neural networks constitute a relatively new, radically different approach to the interpretation and recognition of subtle diagnostic patterns in multivariate data. In this study the use of neural networks with a single serum sample for rapid real-time recognition of recent toxoplasmic infection was investigated. A neural-network model was implemented on the basis of data obtained by four serological methods--dye test, indirect fluorescence assay, indirect hemagglutination assay, and IgM immunosorbent agglutination assay--and was "trained" to extract features of acute infection by application to an analysis of 65 immunocompetent patients, 10 of whom were in fact acutely infected. The trained model correctly classified all 10 cases of acute infection. On its application to 61 additional infected patients, this method correctly identified seven cases as potentially acute. Our study shows that neural networks can discern diagnostic patterns from variables that individually have limited utility in the diagnosis of acute toxoplasmosis.