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OBJECTIVE. The goal was to determine the diagnostic utility of the National Cholesterol Education Program pediatric guidelines. METHODS. With the use of pediatric lipid data from the Cincinnati Clinic of the Lipid Research Clinics Prevalence Study and lipid and cardiovascular disease data collected for the same subjects as adults in the Princeton Follow-up Study, the sensitivity and specificity of the National Cholesterol Education Program pediatric guidelines were calculated overall and according to age. Furthermore, whether use of parental cardiovascular disease history during childhood influenced the sensitivity 6and specificity was assessed. RESULTS. Overall sensitivities were 43% to 46% and specificities were 82% to 86% for total and low-density lipoprotein cholesterol levels. There was considerable variation in sensitivities according to age, with the lowest sensitivities at ages 14 to 16 years and the highest sensitivities at ages 5 to 10 years and 17 to 19 years. Results were similar whether or not the population was restricted to children with a positive parental history of cardiovascular disease. CONCLUSIONS. Results of our analyses suggest that the sensitivity and specificity for evaluating total cholesterol or low-density lipoprotein cholesterol levels that are elevated in adulthood are not improved by selecting children with a positive parental history. These data also show the strong role that age (particularly the pubertal years between 10 and 15 years of age) plays in lipid measurements for children and adolescents. Continued prospective and longitudinal studies designed with age as well as other risk parameters are needed to determine the best guidelines for clinical screening in the future. www.pediatrics.org/cgi/doi/10.1542/ peds.2005-2968 doi:10.1542/peds.2005-2968 Key Words low-density lipoprotein cholesterol, adolescent, child, sensitivity, specificity, lipoproteins Abbreviations NCEP--National Cholesterol Education Program CVD--cardiovascular disease LDL--low-density lipoprotein PFS--Princeton Follow-up Study LRC--Lipid Research Clinics, CURRENTLY, CHILDREN AND adolescents are important targets for cardiovascular disease (CVD) risk factor screening. The proportions of pediatricians and all physicians who screen children for serum cholesterol levels are 88% [...]

Background: Plasmodium vivax malaria requires a 2-week course of primaquine (PQ) for radical cure. Evidence suggests that the hepatic isoenzyme cytochrome P450 2D6 (CYP2D6) is the key enzyme required to convert PQ into its active metabolite.Methods: CYP2D6 genotypes and phenotypes of 550 service personnel were determined, and the pharmacokinetics (PK) of a 30-mg oral dose of PQ was measured in 45 volunteers. Blood and urine samples were collected, with PQ and metabolites were measured using ultraperformance liquid chromatography with mass spectrometry.Results: Seventy-six CYP2D6 genotypes were characterized for 530 service personnel. Of the 515 personnel for whom a single phenotype was predicted, 58% had a normal metabolizer (NM) phenotype, 35% had an intermediate metabolizer (IM) phenotype, 5% had a poor metabolizer (PM) phenotype, and 2% had an ultrametabolizer phenotype. The median PQ area under the concentration time curve from 0 to ∞ was lower for the NM phenotype as compared to the IM or PM phenotypes. The novel 5,6-ortho-quinone was detected in urine but not plasma from all personnel with the NM phenotype.Conclusion: The plasma PK profile suggests PQ metabolism is decreased in personnel with the IM or PM phenotypes as compared to those with the NM phenotype. The finding of 5,6-ortho-quinone, the stable surrogate for the unstable 5-hydroxyprimaquine metabolite, almost exclusively in personnel with the NM phenotype, compared with sporadic or no production in those with the IM or PM phenotypes, provides further evidence for the role of CYP2D6 in radical cure.Clinical Trials Registration: NCT02960568. [ABSTRACT FROM AUTHOR]

Background: Paromomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis. Methods: We conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse. Results: The clinical cure of the index lesion for paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus. Conclusions: Superiority of paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials. [ABSTRACT FROM AUTHOR]

Background: A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. Methods: We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. Results: The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period. Significance: This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials. [ABSTRACT FROM AUTHOR]

Background: Tafenoquine is a long half-life primaquine analog being developed for malaria prophylaxis. The US Army recently performed a unified analysis of efficacy in preparation for a regulatory submission, utilizing legacy data from three placebo-controlled studies conducted in the late 1990s and early 2000s. The subjects were residents of Africa who were naturally exposed to Plasmodium falciparum for 12-26 weeks. Methods: The prophylactic efficacy of tafenoquine and mefloquine (included in some studies as a comparator) was calculated using incidence density among subjects who had completed the three-day loading doses of study drug, had at least one maintenance dose and had at least one blood smear assessed during the prophylactic period. The three placebo-controlled studies were analysed separately and then in two pooled analyses: one for tafenoquine versus placebo (three studies) and one for tafenoquine and mefloquine versus placebo (two studies). Results: The pooled protective efficacy (PE) of a tafenoquine regimen with three daily loading doses plus weekly maintenance at 200-mg for 10 weeks or longer (referred to as 200-mg weekly hereafter) relative to placebo in three placebo-controlled studies was 93.1 % [95 % confidence interval (CI) 89.1-95.6 %; total N = 492]. The pooled PEs of regimens of tafenoquine 200-mg weekly and mefloquine 250-mg weekly relative to placebo in two placebo-controlled studies (total N = 519) were 93.5 % (95 % CI 88.6-96.2 %) and 94.5 % (95 % CI 88.7-97.3 %), respectively. Three daily loading plus weekly maintenance doses of 50- and 100-mg, but not 25-mg, exhibited similar PEs. The PEs of tafenoquine regimens of a three-day loading dose at 400-mg with and without follow-up weekly maintenance doses at 400-mg were 93.7 % (95 % CI 85.4-97.3 %) and 81.0 % (95 % CI 66.8-89.1 %), respectively. Conclusions: Tafenoquine provided the same level of prophylactic efficacy as mefloquine in residents of Africa. These data support the prophylactic efficacy of tafenoquine and mefloquine that has already been demonstrated in the intended malaria naive population. [ABSTRACT FROM AUTHOR]

Background In 2000/2001, the Australian Defense Forces (ADF), in collaboration with SmithKline Beecham and the United States Army, conducted a field trial to evaluate the safety, tolerability and efficacy of tafenoquine and mefloquine/primaquine for the prophylaxis of malaria amongst non-immune Australian soldiers deployed to East Timor (now called Timor Leste) for peacekeeping operations. The lack of a concurrent placebo control arm prevented an internal estimate of the malaria attack rate and so the protective efficacy of the study regimens was not determined at the time. Methods In a retrospective analysis of the trial results, the all species malaria attack rate was estimated for the prophylactic phase of the study which was defined as the period between administration of the first prophylactic dose and the first dose of post-deployment medication. First, the Plasmodium vivax attack rate was estimated during the prophylactic phase of the deployment by adjusting the observed P. vivax relapse rate during postdeployment to account for the known anti-relapse efficacies (or effectiveness) of the study medications (determined from prior studies). The all species malaria attack rate (P. vivax and Plasmodium falciparum) was then determined by adjusting the P. vivax attack rate based on the ratio of P. falciparum to P. vivax observed during prior ADF deployments to Timor Leste. This estimated all species malaria attack rate was then used as the 'constant estimated attack rate' in the calculation of the protective efficacy of tafenoquine and mefloquine during the prophylactic phase of the deployment. Results The estimated attack rate during the prophylactic phase of the study was determined to be 7.88%. The protective efficacies of tafenoquine and mefloquine, with corresponding 95% confidence intervals (95% CI), were determined to be 100% (93%-100%) and 100% (79%- 100%) respectively. Conclusions The protective efficacy of tafenoquine (200 mg per day for three days, followed by weekly 200 mg maintenance doses) is similar to that of the weekly standard of care (mefloquine, 250 mg). [ABSTRACT FROM AUTHOR]

Red blood cells (RBC) and reticulocyte parameters were determined on peripheral blood from a subset of patients enrolled in the multicenter study of hydroxyuea (HU) in sickle cell anemia. Multiple blood samples were obtained every 2 weeks. Cellular indices were measured by flow cytometry. Generalized linear models were used to determine the relationship between the longitudinal trajectories of RBC and reticulocyte indices and HU usage. There was a significant relationship between HU usage and most of the RBC and reticulocyte indices. Hydroxyurea produced higher value trajectories than those generated by placebo usage for the hemoglobin (Hb) content of both the RBCs and reticulocytes and for the mean corpuscular volume (MCV) of reticulocytes. These changes were first detected 10 weeks after starting HU and before the increase in Hb F levels. The data suggest that subtle and early markers of response to HU reside in the hemogram. [ABSTRACT FROM AUTHOR]

Abstract: Context: Exploratory findings from the randomized, double-blind, placebo-controlled, multicenter study of hydroxyurea (MSH) in sickle cell anemia (SS). Recurrent acute painful crises may be mild, moderate, or severe in nature and often require treatment at home, in acute care facilities as outpatients, and in the hospital with oral and/or parenteral opioids. Objectives: The objectives of this study were to determine the effects of hydroxyurea (HU) on length of stay (LOS) in hospital and opioid utilization during hospitalization, outpatient acute care contacts, and at home. Methods: Data from patient diaries, follow-up visit forms, and medical contact forms for the 299 patients enrolled in the MSH were analyzed. Types and dosages of at home, acute care, and in-hospital analgesic usage were explored descriptively. Results: At-home analgesics were used on 40% of diary days and 80% of two-week follow-up periods, with oxycodone and codeine the most frequently used. Responders to HU used analgesics on fewer days. During hospitalization, 96% were treated with parenteral opioids, with meperidine the most frequently used; oxycodone was the most commonly used oral medication. The average LOS for responders to HU was about two days less than for other groups, and their cumulative time hospitalized during the trial was significantly less than for nonresponders or placebo groups (P <0.022). They also had the lowest doses of parenteral opioids during acute care crises (P =0.015). Conclusion: Beneficial effects of HU include shortening the duration of hospitalization because of acute painful episodes and reducing the net amount of opioid utilization. [ABSTRACT FROM AUTHOR]

Background: A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use., Methods: We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15 μg, 30 μg, or 60 μg respectively of VMP001, all formulated in 500 μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls., Results: The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period., Significance: This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.

The purpose of this study was to determine the association between hydroxyurea treatment and changes in employment status, if any, among patients with sickle cell anemia enrolled in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH). To that end, we compared the employment status among treatment responders, treatment nonresponders, and placebo groups of patients enrolled in MSH during the clinical trial and follow-up periods. Treatment with hydroxyurea did not significantly (p > .05) affect employment status, but there was a trend for more consistent employment in the hydroxyurea group. Given the fact that patients enrolled in MSH had moderate to severe disease with irreversible complications such as avascular necrosis, if would be attractive to hypothesize that future treatment of young patients with hydroxyurea could prevent or mitigate the incidence of complications of sickle cell anemia and, hence, improve the employment status of treated patients.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) was a randomized double-blind placebo-controlled trial to test whether hydroxyurea could reduce the rate of painful crises in adults who had at least 3 painful crises per year. Because hydroxyurea is known to be carcinogenic, mutagenic, and teratogenic in animals, a major inclusion criterion in MSH was the use of contraceptives both by females and males in order to avoid exposure of the fetus to hydroxyurea. Despite this precautionary measure, some women became pregnant while taking hydroxyurea or their male partners were on hydroxyurea. We followed surviving patients who were enrolled in the original MSH trial for up to 17 years postrandomization. Our findings suggest that exposure of the fetus to hydroxyurea does not cause teratogenic changes in those pregnancies that terminate in live birth whether full-term or premature. This seems to be true whether the parent taking hydroxyurea was the mother or the father. The same argument seems to apply for exposure to opioids. However, it will take a much longer follow-up of many more hydroxyurea-exposed sickle cell disease subjects to establish the results conclusively.