Search tips
Search criteria

Results 1-25 (185)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
more »
1.  Children with Chronic Hepatitis B in the US and Canada 
The Journal of pediatrics  2015;167(6):1287-1294.e2.
To test the hypothesis that children with chronic hepatitis B (CHB) living in the US and Canada would also have international origins and characteristic hepatitis B virus (HBV) genotypes and laboratory profiles.
Study design
Clinical characteristics of children enrolled in the HBRN were collected from 7 US and Canadian centers.
Children (n=343) with an age range of 1.0 – 17.8 years were enrolled; 78% of the children were Asian, 55% were adopted and 97% had international origins with either the child or a parent born in one of 31 countries. The majority had hepatitis B virus (HBV) genotype B (43%) or C (32%), and the remainder had genotype A (5%), D (16%), E (4%), or multiple (<1%). Children with genotype B or C were Asian (98% and 96%), more consistently hepatitis B e antigen (HBeAg) positive (95% and 82%), had higher median HBV DNA levels (8.2 and 8.3 log10 IU/mL), and less frequently had elevated alanine aminotransferase values (43% and 57%) compared with children with other genotypes. The percentage of HBeAg positivity and of those with HBV DNA ≥6 log10 IU/mL declined with age.
The majority of children in the HBRN have HBV genotypes which reflect their international origins. Clinical and laboratory data differ substantially by patient age and HBV genotype. Use of these data can help drive the development of optimal strategies to manage and treat children with CHB.
PMCID: PMC4662884  PMID: 26364985
hepatitis B DNA; hepatitis B E antigen; viral genotype; international adoptees
2.  Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria 
ACS Medicinal Chemistry Letters  2015;6(11):1145-1149.
Peroxidic antimalarial agents including the sequiterpene artemisinins and the synthetic 1,2,4-trioxolanes function via initial intraparasitic reduction of an endoperoxide bond. By chemically coupling this reduction to release of a tethered drug species it is possible to confer two distinct pharmacological effects in a parasite-selective fashion, both in vitro and in vivo. Here we demonstrate the trioxolane-mediated delivery of the antimalarial agent mefloquine in a mouse malaria model. Selective partitioning of the trioxolane–mefloquine conjugate in parasitized erythrocytes, combined with effective exclusion of the conjugate from brain significantly reduced brain exposure as compared to mice directly administered mefloquine. These studies suggest the potential of trioxolane-mediated drug delivery to mitigate off-target effects of existing drugs, including the adverse neuropsychiatric effects of mefloquine use in therapeutic and chemoprophylactic settings.
PMCID: PMC4645246  PMID: 26617969
antimalarial; trioxolane; mefloquine; drug delivery
4.  Communicable Diseases: A Global Perspective 
PMCID: PMC5062810  PMID: 27708202
5.  Cryptosporidium and Toxoplasma Parasites Are Inhibited by a Benzoxaborole Targeting Leucyl-tRNA Synthetase 
Antimicrobial Agents and Chemotherapy  2016;60(10):5817-5827.
The apicomplexan parasites Cryptosporidium and Toxoplasma are serious threats to human health. Cryptosporidiosis is a severe diarrheal disease in malnourished children and immunocompromised individuals, with the only FDA-approved drug treatment currently being nitazoxanide. The existing therapies for toxoplasmosis, an important pathology in immunocompromised individuals and pregnant women, also have serious limitations. With the aim of developing alternative therapeutic options to address these health problems, we tested a number of benzoxaboroles, boron-containing compounds shown to be active against various infectious agents, for inhibition of the growth of Cryptosporidium parasites in mammalian cells. A 3-aminomethyl benzoxaborole, AN6426, with activity in the micromolar range and with activity comparable to that of nitazoxanide, was identified and further characterized using biophysical measurements of affinity and crystal structures of complexes with the editing domain of Cryptosporidium leucyl-tRNA synthetase (LeuRS). The same compound was shown to be active against Toxoplasma parasites, with the activity being enhanced in the presence of norvaline, an amino acid that can be mischarged by LeuRS. Our observations are consistent with AN6426 inhibiting protein synthesis in both Cryptosporidium and Toxoplasma by forming a covalent adduct with tRNALeu in the LeuRS editing active site and suggest that further exploitation of the benzoxaborole scaffold is a valid strategy to develop novel, much needed antiparasitic agents.
PMCID: PMC5038320  PMID: 27431220
6.  Characterizing microscopic and submicroscopic malaria parasitaemia at three sites with varied transmission intensity in Uganda 
Malaria Journal  2016;15:470.
Parasite prevalence is a key metric used to quantify the burden of malaria and assess the impact of control strategies. Most published estimates of parasite prevalence are based on microscopy and likely underestimate true prevalence.
Thick smear microscopy was performed in cohorts of children (aged 6 month to 10 years) and adults every 90 days over 2 years, at three sites of varying transmission intensity in Uganda. Microscopy-negative samples were tested for sub-microscopic parasitaemia using loop-mediated isothermal amplification (LAMP). Generalized estimating equation models were used to evaluate associations between age and parasitaemia, factors associated with sub-microscopic infection and associations between parasitaemia and haemoglobin.
A total of 9260 samples were collected from 1245 participants. Parasite prevalence among children across the three sites was 7.4, 9.4 and 28.8 % by microscopy and 21.3, 31.8 and 69.0 % by microscopy plus LAMP. Parasite prevalence among adults across the three sites was 3.1, 3.0 and 5.2 % by microscopy and 18.8, 24.2 and 53.5 % by microscopy plus LAMP. Among those with parasitaemia, adults and persons recently treated with anti-malarial therapy had the highest prevalence of sub-microscopic infection. Children with sub-microscopic or microscopic parasitaemia had lower mean haemoglobin levels compared to children with no detectable parasites.
Across a range of transmission intensities in Uganda, microscopy vastly underestimated parasite prevalence, especially among adults.
PMCID: PMC5024471  PMID: 27628178
Malaria; Parasitaemia; LAMP; Sub-microscopic infection
7.  Quality of Life and its Determinants in a Multi-Center Cohort of Children with Alagille Syndrome 
The Journal of pediatrics  2015;167(2):390-396.e3.
To assess health-related quality of life (HRQOL) in children with Alagille syndrome (ALGS) in comparison with healthy and other liver disease cohorts, and to identify determinants of HRQOL in patients with ALGS.
Study design
Within the Childhood Liver Disease Research Network prospective study of cholestasis, Pediatric Quality of Life Inventory™ (PedsQL) questionnaires were administered to 70 ALGS, 95 alpha-1-antitrypsin deficiency (A1ATD) and 49 children with other causes of chronic intrahepatic cholestasis (IHC) aged 5-18 years. Parent-proxy PedsQL scores were recorded for children aged 2-18 (98 ALGS, 123 A1ATD, 68 IHC).
Mean ages and total bilirubin (mg/dL) were: ALGS 9.4y; 4.4, A1ATD 9.5y; 0.7, IHC 10.3y; 2.9. ALGS child PedsQL scores were lower than in healthy children and children with A1ATD (mean 73 vs. 83 p=0.001). Children with ALGS and IHC were similar, except in physical scores (73 vs. 79 p=0.05). ALGS parents perceived their children to have worse HRQOL than A1ATD (p<=0.001) and marginally lower compared with IHC. Univariate analysis revealed ALGS child-reported scores were positively associated with better growth and inversely with total bilirubin. Growth failure, elevated INR and an intra-cardiac defect were predictive of poor parental scores (p<=0.05). In multivariate analysis, only weight z-score remained significant for child and parent-reported scores.
HRQOL is impaired in ALGS compared with healthy and children with A1ATD, similar to IHC and is associated with growth failure, which is a potentially treatable cause of impaired HRQOL.
PMCID: PMC4516587  PMID: 26059338
health-related quality of life; cholestasis
8.  Azithromycin for Malaria? 
PMCID: PMC4944689  PMID: 27215296
9.  Baseline Analysis of a Young Alpha-1-AT Deficiency Liver Disease Cohort Reveals Frequent Portal Hypertension 
Alpha-1-antitrypsin deficiency (A1AT) is a common genetic disease with unpredictable and highly variable course. The Childhood Liver Disease Research and Education Network (ChiLDREN) is an NIH, multi-center, longitudinal consortium studying pediatric liver diseases, with the objective of prospectively defining natural history and identifying disease modifiers.
Longitudinal, cohort study of A1AT patients birth through 25 years diagnosed with liver disease, type PIZZ or PISZ. Medical history, physical exam, laboratory, imaging, and standardized survey tool data were collected during the provision of standard of care.
In this report of the cohort at baseline, 269 subjects were enrolled between Nov. 2008 and Oct. 2012 (208 with their native livers and 61 post-liver transplant). Subjects with mild disease (native livers and no portal hypertension [PHT]) compared to severe disease (with PHT or post-liver transplant) were not different in age at presentation. 57% of subjects with mild disease and 76% with severe disease were jaundiced at presentation (p=0.0024). 29% of subjects with native livers had PHT, but age at diagnosis and growth were not different between the no PHT and PHT groups (p>0.05). Subjects with native livers and PHT were more likely to have elevated bilirubin, ALT, AST, INR, and GGTP than the no PHT group (p≪0.001), but overlap was large. Chemistries alone could not identify PHT.
Many A1AT subjects presenting with elevated liver tests and jaundice improve spontaneously. Subjects with PHT have few symptoms and normal growth. Longitudinal cohort follow up will identify genetic and environmental disease modifiers. NCT00571272.
PMCID: PMC4692167  PMID: 25651489
cirrhosis; liver transplant; liver enzymes; metabolic liver disease; jaundice
10.  Benzoxaborole Antimalarial Agents. Part 4. Discovery of Potent 6-(2-(Alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles 
Journal of Medicinal Chemistry  2015;58(13):5344-5354.
A series of 6-hetaryloxy benzoxaborole compounds was designed and synthesized for a structure–activity relationship (SAR) investigation to assess the changes in antimalarial activity which result from 6-aryloxy structural variation, substituent modification on the pyrazine ring, and optimization of the side chain ester group. This SAR study discovered highly potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 27–34) with IC50s = 0.2–22 nM against cultured Plasmodium falciparum W2 and 3D7 strains. Compound 9 also demonstrated excellent in vivo efficacy against P. berghei in infected mice (ED90 = 7.0 mg/kg).
PMCID: PMC4500456  PMID: 26067904
11.  Malaria Transmission, Infection, and Disease at Three Sites with Varied Transmission Intensity in Uganda: Implications for Malaria Control 
The intensification of control interventions has led to marked reductions in malaria burden in some settings, but not others. To provide a comprehensive description of malaria epidemiology in Uganda, we conducted surveillance studies over 24 months in 100 houses randomly selected from each of three subcounties: Walukuba (peri-urban), Kihihi (rural), and Nagongera (rural). Annual entomological inoculation rate (aEIR) was estimated from monthly Centers for Disease Control and Prevention (CDC) light trap mosquito collections. Children aged 0.5–10 years were provided long-lasting insecticidal nets (LLINs) and followed for measures of parasite prevalence, anemia and malaria incidence. Estimates of aEIR were 2.8, 32.0, and 310 infectious bites per year, and estimates of parasite prevalence 7.4%, 9.3%, and 28.7% for Walukuba, Kihihi, and Nagongera, respectively. Over the 2-year study, malaria incidence per person-years decreased in Walukuba (0.51 versus 0.31, P = 0.001) and increased in Kihihi (0.97 versus 1.93, P < 0.001) and Nagongera (2.33 versus 3.30, P < 0.001). Of 2,582 episodes of malaria, only 8 (0.3%) met criteria for severe disease. The prevalence of anemia was low and not associated with transmission intensity. In our cohorts, where LLINs and prompt effective treatment were provided, the risk of complicated malaria and anemia was extremely low. However, malaria incidence was high and increased over time at the two rural sites, suggesting improved community-wide coverage of LLIN and additional malaria control interventions are needed in Uganda.
PMCID: PMC4426576  PMID: 25778501
12.  The Effect of Storage and Extraction Methods on Amplification of Plasmodium falciparum DNA from Dried Blood Spots 
Extraction and amplification of DNA from dried blood spots (DBS) collected in field studies is commonly used for detection of Plasmodium falciparum. However, there have been few systematic efforts to determine the effects of storage and extraction methods on the sensitivity of DNA amplification. We investigated the effects of storage conditions, length of storage, and DNA extraction methods on amplification via three PCR-based assays using field samples and laboratory controls. Samples stored as DBS for 2 or more years at ambient temperature showed a significant loss of sensitivity that increased with time; after 10 years only 10% samples with parasite densities > 1,000 parasites/μL were detectable by nested polymerase chain reaction (PCR). Conversely, DBS and extracted DNA stored at −20°C showed no loss of sensitivity with time. Samples with low parasite densities amplified more successfully with saponin/Chelex compared with spin-column-based extraction, though the latter method performed better on samples with higher parasite densities stored for 2 years at ambient temperature. DNA extracted via both methods was stable after 20 freeze-thaw cycles. Our results suggest that DBS should be stored at −20°C or extracted immediately, especially if anticipating 2 or more years of storage.
PMCID: PMC4426578  PMID: 25758652
13.  Factors Determining Delta-Bilirubin Levels in Biliary Atresia Infants Running head: Delta-Bilirubin in Biliary Atresia 
Delta bilirubin (Bδ) forms when bilirubin conjugates covalently bind to albumin by way of non-enzymatic transesterification in patients with cholestasis. Cholestatic infants with biliary atresia form Bδ. The aim of this study was to investigate the factors determining serum Bδ concentrations in infants with biliary atresia.
Study subjects were infants enrolled into a prospective study (PROBE: NCT00061828) of biliary atresia. We acquired data of concurrently measured serum bilirubin analytes (total bilirubin (TB), conjugated bilirubin (Bc), and unconjugated bilirubin (Bu)) and applied graphical methods and linear mixed effects model to study factors contributing to Bδ variability.
Bδ level increased with increasing levels of Bc and TB. In addition, the length of time cholestasis persisted partially determined the level of Bδ. One mg/dL increase in Bc is related to approximately 0.36 mg/dL increase in Bδ (p < 0.0001); every 100 days of cholestasis is associated with an approximately 1.0 mg/dL increase in Bδ (p < 0.0001) given the same level of Bc. Serum albumin levels are not significantly related to Bδ (p=0.89).
Bδ levels in infants with BA increase with increasing levels of Bc and longer duration of cholestasis. Understanding the relationship between Bδ, Bc, total bilirubin and direct-reacting bilirubin levels can help in interpretation of the clinical extent of cholestasis in infants and children with biliary atresia assisting in the diagnosis and management of these infants.
PMCID: PMC4409472  PMID: 25564820
delta bilirubin; conjugated bilirubin; biliary atresia
14.  Absence of Putative Artemisinin Resistance Mutations Among Plasmodium falciparum in Sub-Saharan Africa: A Molecular Epidemiologic Study 
The Journal of Infectious Diseases  2014;211(5):680-688.
Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin resistance genotypes in African parasite populations is unknown. We developed an assay to quantify rare polymorphisms in parasite populations that uses a pooled deep-sequencing approach to score allele frequencies, validated it by evaluating mixtures of laboratory parasite strains, and then used it to screen P. falciparum parasites from >1100 African infections collected since 2002 from 14 sites across sub-Saharan Africa. We found no mutations in African parasite populations that are associated with artemisinin resistance in Southeast Asian parasites. However, we observed 15 coding mutations, including 12 novel mutations, and limited allele sharing between parasite populations, consistent with a large reservoir of naturally occurring K13-propeller variation. Although polymorphisms associated with artemisinin resistance in P. falciparum in Southeast Asia are not prevalent in sub-Saharan Africa, numerous K13-propeller coding polymorphisms circulate in Africa. Although their distributions do not support a widespread selective sweep for an artemisinin-resistant phenotype, the impact of these mutations on artemisinin susceptibility is unknown and will require further characterization. Rapid, scalable molecular surveillance offers a useful adjunct in tracking and containing artemisinin resistance.
PMCID: PMC4402372  PMID: 25180240
falciparum malaria; artemisinin resistance; drug resistance; molecular epidemiology
15.  Stereotactic guidance for navigated percutaneous sacroiliac joint fusion 
Journal of Biomedical Research  2015;30(2):162-167.
Arthrodesis of the sacroiliac joint (SIJ) for surgical treatment of SIJ dysfunction has regained interest among spine specialists. Current techniques described in the literature most often utilize intraoperative fluoroscopy to aid in implant placement; however, image guidance for SIJ fusion may allow for minimally invasive percutaneous instrumentation with more precise implant placement. In the following cases, we performed percutaneous stereotactic navigated sacroiliac instrumentation using O-arm® multidimensional surgical imaging with StealthStation® navigation (Medtronic, Inc. Minneapolis, MN). Patients were positioned prone and an image-guidance reference frame was placed contralateral to the surgical site. O-arm® integrated with StealthStation® allowed immediate auto-registration. The skin incision was planned with an image-guidance probe. An image-guided awl, drill and tap were utilized to choose a starting point and trajectory. Threaded titanium cage(s) packed with autograft and/or allograft were then placed. O-arm® image-guidance allowed for implant placement in the SIJ with a small skin incision. However, we could not track the cage depth position with our current system, and in one patient, the SIJ cage had to be revised secondary to the anterior breach of sacrum.
PMCID: PMC4820893
sacroiliac joint; arthrodesis; technique; image guidance
16.  Lack of Artemisinin Resistance in Plasmodium falciparum in Uganda Based on Parasitological and Molecular Assays 
We evaluated markers of artemisinin resistance in Plasmodium falciparum isolated in Kampala in 2014. By standard in vitro assays, all isolates were highly sensitive to dihydroartemisinin (DHA). By the ring-stage survival assay, after a 6-h DHA pulse, parasitemia was undetectable in 40 of 43 cultures at 72 h. Two of 53 isolates had nonsynonymous K13-propeller gene polymorphisms but did not have the mutations associated with resistance in Asia. Thus, we did not see evidence for artemisinin resistance in Uganda.
PMCID: PMC4505276  PMID: 26033725
17.  Treatment of Bile Acid Amidation Defects with Glycocholic Acid 
Hepatology (Baltimore, Md.)  2014;61(1):268-274.
Bile acid amidation defects were predicted to present with fat/fat soluble vitamin malabsorption with minimal cholestasis. We identified and treated 5 patients (1 male/4 females) from 4 families with defective bile acid amidation due to a genetically confirmed deficiency in bile acid CoA:amino acid N-acyl transferase (BAAT) with the conjugated bile acid, glycocholic acid (GCA). Fast atom bombardment-mass spectrometry analysis of urine and bile at baseline revealed predominantly unconjugated cholic acid and absence of the usual glycine and taurine conjugated primary bile acids. Treatment with 15 mg/kg GCA resulted in total duodenal bile acid concentrations of 23.3 ± 19.1 mmol/L (mean ± SD) and 63.5 ± 4.0% of the bile acids were secreted in bile in the conjugated form of which GCA represented 59.6 ± 9.3% of the total biliary bile acids. Unconjugated cholic acid continued to be present in high concentrations in bile because of partial intestinal deconjugation of orally administered GCA. Serum total bile acid concentrations did not significantly differ between pretreatment and post-treatment samples and serum contained predominantly unconjugated cholic acid. These findings confirmed efficient intestinal absorption, hepatic extraction and biliary secretion of the administered GCA. Oral tolerance tests for vitamin D2 (1000 IU vitamin D2/kg) and tocopherol (100 IU/kg tocopherol acetate) demonstrated improvement in fat-soluble vitamin absorption after GCA treatment. Growth improved in 3/3 growth-delayed prepubertal patients. Conclusions: Oral glycocholic acid therapy is safe and effective in improving growth and fat-soluble vitamin absorption in children and adolescents with inborn errors of bile acid metabolism due to amidation defects.
PMCID: PMC4280294  PMID: 25163551
18.  Drug Delivery to the Malaria Parasite Using an Arterolane-Like Scaffold 
ChemMedChem  2014;10(1):47-51.
The antimalarial agents artemisinin and arterolane act via initial reduction of a peroxide bond in a process likely mediated by ferrous iron sources in the parasite. Here, we report the synthesis and antiplasmodial activity of arterolane-like 1,2,4-trioxolanes specifically designed to release a tethered drug species within the malaria parasite. Compared to our earlier drug delivery scaffolds, these new arterolane-inspired systems are of significantly reduced molecular weight and possess superior metabolic stability. We also demonstrate the use of the aminonucleoside antibiotic puromycin as a chemo/biomarker to validate successful drug release in live P. falciparum parasites.
PMCID: PMC4420023  PMID: 25314098
antimalarials; drug delivery; targeted prodrugs; trioxolanes; puromycin
19.  Estimating malaria parasite prevalence from community surveys in Uganda: a comparison of microscopy, rapid diagnostic tests and polymerase chain reaction 
Malaria Journal  2015;14:528.
Household surveys are important tools for monitoring the malaria disease burden and measuring impact of malaria control interventions with parasite prevalence as the primary metric. However, estimates of parasite prevalence are dependent on a number of factors including the method used to detect parasites, age of the population sampled, and level of immunity. To better understand the influence of diagnostics, age, and endemicity on estimates of parasite prevalence and how these change over time, community-based surveys were performed for two consecutive years in three settings and the sensitivities of microscopy and immunochromatographic rapid diagnostic tests (RDTs) were assessed, considering polymerase chain reaction (PCR) as the gold standard.
Surveys were conducted over the same two-month period in 2012 and 2013 in each of three sub-counties in Uganda: Nagongera in Tororo District (January–February), Walukuba in Jinja District (March–April), and Kihihi in Kanungu District (May–June). In each sub-county, 200 households were randomly enrolled and a household questionnaire capturing information on demographics, use of malaria prevention methods, and proxy indicators of wealth was administered to the head of the household. Finger-prick blood samples were obtained for RDTs, measurement of hemoglobin, thick and thin blood smears, and to store samples on filter paper.
A total of 1200 households were surveyed and 4433 participants were included in the analysis. Compared to PCR, the sensitivity of microscopy was low (65.3 % in Nagongera, 49.6 % in Walukuba and 40.9 % in Kihihi) and decreased with increasing age. The specificity of microscopy was over 98 % at all sites and did not vary with age or year. Relative differences in parasite prevalence across different age groups, study sites, and years were similar for microscopy and PCR. The sensitivity of RDTs was similar across the three sites (range 77.2–82.8 %), was consistently higher than microscopy (p < 0.001 for all pairwise comparisons), and decreased with increasing age. The specificity of RDTs was lower than microscopy (76.3 % in Nagongera, 86.3 % in Walukuba, and 83.5 % in Kihihi) and varied significantly by year and age. Relative differences in parasite prevalence across age groups and study years differed for RDTs compared to microscopy and PCR.
Malaria prevalence estimates varied with diagnostic test, age, and transmission intensity. It is important to consider the effects of these parameters when designing and interpreting community-based surveys.
PMCID: PMC4696244  PMID: 26714465
Malaria; Parasite prevalence; Community surveys; Surveillance; Diagnostics; Rapid diagnostic tests; Microscopy
20.  Total Serum Bilirubin Predicts Fat-Soluble Vitamin Deficiency Better Than Serum Bile Acids in Infants with Biliary Atresia 
Fat soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acids. We hypothesized that serum bile acids (SBA) would predict biochemical FSV deficiency better than serum total bilirubin level (TB) in infants with biliary atresia.
Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia (START) after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA and vitamin levels at 1, 3 and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and non-parametric correlations were made between specific vitamin measurement levels and either TB or SBA.
The degree of correlation for any particular vitamin at a specific time point was higher with TB than SBA (higher for TB in 31 circumstances versus 3 circumstances for SBA). Receiver operating characteristic (ROC) shows that TB performed better than SBA (AUC 0.998 vs. 0.821). Including both TB and SBA did not perform better than TB alone (AUC 0.998).
We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as PFIC, alpha-one antitrypsin deficiency and Alagille syndrome where the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.
PMCID: PMC4243585  PMID: 25419594
fat –soluble vitamin; cholestasis; serum bile acid; biliary atresia; bilirubin
21.  Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children 
Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.
PMCID: PMC4432194  PMID: 25753626
22.  Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial 
AIDS (London, England)  2014;28(18):2701-2709.
Trimethoprim-sulfamethoxazole (TS) prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children.
Open-label, randomized controlled trial.
Tororo, Uganda, a rural area with intense, year-round, malaria transmission.
200 infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age).
No chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily TS, or monthly dihydroartemisinin-piperaquine (DP) given from randomization to 24 months of age.
Main outcome measures
The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrheal illness, or respiratory tract infection; prevalence of anemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped.
During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% (95% CI, 53-80%, p<0.001) for DP, 49% (95% CI, 23-66%, p=0.001) for TS, and 9% for SP (95% CI, −35 to 38%, p=0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the DP arm.
Monthly chemoprevention with DP was safe and associated with a significant reduction in malaria in young HIV-exposed children.
PMCID: PMC4487368  PMID: 25493596
HIV-exposed uninfected infants; malaria chemoprevention; dihydroartemsinin piperaquine; trimethoprim sulfamethoxazole prophylaxis; sulfadoxine pyrimethamine
23.  Determination of the antimalarial drug piperaquine in small volume pediatric plasma samples by LC–MS/MS 
Bioanalysis  2014;6(23):3081-3089.
Determination of piperaquine (PQ) in pediatric plasma requires a method with a small sample volume.
We report a sensitive LC–MS/MS method for quantitation of PQ with only 25 µI human plasma. Using a deuterated internal standard (PQ-d6), an analytical PFP column, APCI+ as the ion source and MRM (535/288 for PQ and 541/294 for the IS) for detection, the method has a linear calibration range of 1.5–250 ng/ml with a runtime of 3.0 min per sample. The method was applied to plasma samples from children.
The developed LC–MS/MS method is suitable for pediatric studies with small volume plasma samples collected via capillary tubes. One limitation was the performance of PFP columns varied among different brands.
PMCID: PMC4321809  PMID: 25529877
24.  An evaluation of the impact of donor BMI on survival and post-transplant obesity in pediatric liver transplant recipients 
In adult liver transplant recipients, donor BMI is associated with post-transplant obesity but not graft or patient survival. Given the U.S. obesity epidemic and already-limited supply of liver donors, clarifying whether donor BMI affects pediatric outcomes is important.
UNOS data on pediatric U.S. liver transplants 1990-2010 was evaluated. Data on transplants 2004-2010 (n=3788) was used for survival analysis with Kaplan-Meier and Cox proportional hazards models and for post-transplant obesity analysis with generalized estimating equations.
For children receiving adult donor livers, donor BMI 25-35 kg/m2 was not associated with graft or patient survival in univariate or multivariate analyses. Donor BMI>35 kg/m2 increased the risk of graft loss (HR 2.54, 95%CI 1.29-5.01, p=0.007) and death (HR 3.56, 95%CI 1.64-7.72, p=0.001). For pediatric donors, donor BMI was not associated with graft loss or mortality in univariate or multivariate analysis. Donor overweight/obesity was not a risk factor for post-transplant obesity.
Overweight/obesity is common among liver transplant donors. This analysis suggests that for adult donors, BMI 25-35 should not by itself be a contraindication to liver donation. Severe obesity (BMI>35) in adult donors increased the risk of graft loss and mortality, even after adjustment for recipient, donor, and transplant risk factors. Post-transplant obesity was not associated with donor BMI in this analysis. Further research is needed to clarify the impact of donor obesity on pediatric liver transplant recipients.
PMCID: PMC4559411  PMID: 22467594
overweight; obesity; pediatrics; liver transplant; long-term complications
25.  Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network 
Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs.
PMCID: PMC4574275  PMID: 26259943

Results 1-25 (185)