Quality of life in adolescents with hepatitis C treated with sofosbuvir and ribavirin.

Chronic HCV infection has been associated with impairment of HRQL in both adults and paediatric patients. Our aim was to assess the HRQL of HCV-positive children treated with SOF + RBV. The data for this post hoc analysis were collected in a phase 2 open-label multinational study that evaluated safety and efficacy of SOF (400 mg/day) plus RBV (weight-based up to 1400 mg/day) for 12 or 24 weeks in adolescents with chronic HCV (GS-US-334-1112). Patients and their parents/guardians completed the PedsQL-4.0-SF-15 questionnaire at baseline, at the end of treatment and in post-treatment follow-up. We included 50 adolescents with HCV genotype 2 and 3 without cirrhosis (14.8 ± 1.9 years; male: 58%; treatment-naïve: 82%; vertically transmitted HCV: 70%). After treatment, 100% of patients with HCV genotype 2 and 95% with genotype 3 achieved SVR-12. During treatment with SOF + RBV, there were no significant decrements in any of patients' self-reported or parent-proxy-reported PRO scores regardless of treatment duration (all P > .05). After treatment cessation, we recorded a statistically significant improvement in patients' self-reported Social Functioning score by post-treatment week 12: on average, +4.8 points on a 0-100 scale (P = .02). By post-treatment week 24, parent-proxy-reported School Functioning score increased by, on average, +13.0 points (P = .0065). In multivariate analysis, history of abdominal pain and psychiatric disorders were predictive of impaired HRQL in adolescents with HCV (P < .05). Adolescents with HCV do not seem to experience any HRQL decrement during treatment with SOF + RBV and experience some improvement of their HRQL scores after achieving SVR.

Antiretroviral Therapy With Efavirenz Accentuates Pregnancy-Associated Reduction of Dihydroartemisinin-Piperaquine Exposure During Malaria Chemoprevention.

Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. We assessed the impacts of pregnancy and efavirenz-based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV-uninfected pregnant women, in 27 HIV-infected pregnant women receiving efavirenz, and in 30 HIV-uninfected nonpregnant women. DHA peak concentration and area under the concentration time curve (AUC0-8hr ) were 50% and 47% lower, respectively, and piperaquine AUC0-21d was 40% lower in pregnant women compared to nonpregnant women. DHA AUC0-8hr and piperaquine AUC0-21d were 27% and 38% lower, respectively, in pregnant women receiving efavirenz compared to HIV-uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed.

Testing the Validity of Single-Particle Maps at Low and High Resolution.

Single-particle electron cryomicroscopy may be used to determine the structure of biological assemblies by aligning and averaging low-contrast projection images recorded in the electron microscope. Recent progress in both experimental and computational methods has led to higher resolution three-dimensional maps, including for more challenging low molecular weight proteins, and this has highlighted the problems of model bias and over-fitting during iterative refinement that can potentially lead to incorrect map features at low or high resolution. This chapter discusses the principles and practice of specific validation tests that demonstrate the consistency of a 3D map with projection images. In addition, the chapter describes tests that detect over-fitting during refinement and lead to more robust assessment of both global and local map resolution. Application of several of these tests together demonstrates the reliability of single-particle maps that underpins their correct biological interpretation.

Metabolic Syndrome Components After Pediatric Liver Transplantation: Prevalence and the Impact of Obesity and Immunosuppression.

Metabolic syndrome is associated with long-term morbidity and mortality after adult liver transplantation (LT). Whether pediatric LT recipients have a higher prevalence of metabolic syndrome remains controversial. In a cross-sectional study, we evaluated pediatric LT recipients aged 8-30 years using National Health and Nutrition Examination Survey (NHANES) protocols. LT recipients were matched by gender, race/ethnicity, and age with controls from NHANES. Pediatric LT recipients (n = 83), after adjusting for overweight/obesity and glucocorticoid use, had increased prevalence of prehypertension and hypertension, impaired glucose tolerance (IGT; 2-h glucose after oral glucose tolerance test ≥140 mg/dL), and low high-density lipoprotein compared to matched NHANES controls (n = 235) despite a lower prevalence of overweight/obesity. Among LT recipients, the adjusted odds of IGT doubled for every 7.5 years taking calcineurin inhibitors (odds ratio = 2.10, 95% confidence interval 1.06-4.17 per 7.5 years taking calcineurin inhibitors, p = 0.03). Among all subjects with IGT, LT recipients had a lower prevalence of overweight/obesity and less insulin resistance (homeostatic model assessment of insulin resistance) than did controls with IGT. Among normal weight subjects, LT recipients were significantly more likely than controls to have prehypertension/hypertension, IGT, low high-density lipoprotein, and metabolic syndrome. Pediatric LT recipients have unique metabolic syndrome profiles and risk factors and will require tailored screening and management protocols.

Under Utilization of Pancreas Transplants in Cystic Fibrosis Recipients in the United Network Organ Sharing (UNOS) Data 1987-2014.

Despite a high prevalence of pancreatic endocrine and exocrine insufficiency in cystic fibrosis (CF), pancreas transplantation is rarely reported. United Network for Organ Sharing (UNOS) data were used to examine utilization of pancreas transplant and posttransplant outcomes in CF patients. Between 1987-2014, CF patients (N = 4600) underwent 17 liver-pancreas, three lung-pancreas, one liver-lung pancreas, four kidney-pancreas, and three pancreas-only transplants. Of the 303 CF patients who received liver transplantation, 20% had CF-related diabetes (CFRD) before transplantation, and nine of those received a liver-pancreas transplant. Of 4241 CF patients who underwent lung transplantation, 33% had CFRD before transplantation, and three of those received a pancreas transplant. Of 49 CF patients who received a liver-lung transplant, 57% had CFRD before transplantation and one received a pancreas transplant. Posttransplantation diabetes developed in 7% of CF pancreas transplant recipients versus 24% of CF liver and 29% of CF lung recipients. UNOS has no data on pancreas exocrine insufficiency. Two-year posttransplantation survival was 88% after liver-pancreas transplant, 33% after lung-pancreas transplant, and 100% after pancreas-kidney and pancreas-only transplants. Diabetes is common pretransplantation and posttransplantation in CF solid organ transplant recipients, but pancreas transplantation remains rare. Further consideration of pancreas transplant in CF patients undergoing other solid organ transplant may be warranted.

Posttransplant metabolic syndrome in the withdrawal of immunosuppression in Pediatric Liver Transplant Recipients (WISP-R) pilot trial.

Posttransplant metabolic syndrome (PTMS)-obesity, hypertension, elevated triglycerides, low HDL and glucose intolerance-is a major contributor to morbidity after adult liver transplant. This analysis of the Withdrawal of Immunosuppression in Pediatric Liver Transplant Recipients (WISP-R) pilot trial is the first prospective study of PTMS after pediatric liver transplant. Twenty children were enrolled in WISP-R, at median age 8.5 years (IQR 6.4-10.8), and weaned from calcineurin-inhibitor monotherapy. The 12 children who tolerated complete immunosuppression withdrawal were compared to matched historical controls. At baseline, 45% of WISP-R subjects and 58% of controls had at least one component of PTMS. Calcineurin-inhibitor withdrawal in the WISP-R subjects did not impact the prevalence of PTMS components compared to controls. At 5 years, despite weaning off of immunosuppression, 92% of the 12 tolerant WISP-R subjects had at least one PTMS component and 58% had at least two; 33% were overweight or obese, 50% had dyslipidemia, 33% glucose intolerance and 42% systolic hypertension. Overweight/obesity increased the risk of hypertension in all children. Compared to controls, WISP-R tolerant subjects had similar GFR at baseline but did have higher GFR at 2, 3 and 4 years. Further study of PTMS and immunosuppression withdrawal after pediatric liver transplant is warranted.

Strain-specific antiviral activity of iminosugars against human influenza A viruses.

OBJECTIVES: Drugs that target host cell processes can be employed to complement drugs that specifically target viruses, and iminosugar compounds that inhibit host α-glucosidases have been reported to show antiviral activity against multiple viruses. Here the effect and mechanism of two iminosugar α-glucosidase inhibitors, N-butyl-deoxynojirimycin (NB-DNJ) and N-nonyl-deoxynojirimycin (NN-DNJ), on human influenza A viruses was examined. METHODS: The viruses examined were a recently circulating seasonal influenza A(H3N2) virus strain A/Brisbane/10/2007, an older H3N2 strain A/Udorn/307/72, and A/Lviv/N6/2009, a strain representative of the currently circulating pandemic influenza A(H1N1)pdm09 virus. RESULTS: The inhibitors had the strongest effect on Brisbane/10 and NN-DNJ was more potent than NB-DNJ. Both compounds showed antiviral activity in cell culture against three human influenza A viruses in a strain-specific manner. Consistent with its action as an α-glucosidase inhibitor, NN-DNJ treatment resulted in an altered glycan processing of influenza haemagglutinin (HA) and neuraminidase (NA), confirmed by MS. NN-DNJ treatment was found to reduce the cell surface expression of the H3 subtype HA. The level of sialidase activity of NA was reduced in infected cells, but the addition of exogenous sialidase to the cells did not complement the NN-DNJ-mediated inhibition of virus replication. Using reassortant viruses, the drug susceptibility profile was determined to correlate with the origin of the HA. CONCLUSIONS: NN-DNJ inhibits influenza A virus replication in a strain-specific manner that is dependent on the HA.

Decreased risk of graft failure with maternal liver transplantation in patients with biliary atresia.

The presence of maternal cells in offspring may promote tolerance to noninherited maternal antigens (NIMAs). Children with biliary atresia (BA) have increased maternal cells in their livers, which may impact tolerance. We hypothesized that patients with BA would have improved outcomes when receiving a maternal liver. We reviewed all pediatric liver transplants recorded in the SRTR database from 1996 to 2010 and compared BA and non-BA recipients of maternal livers with recipients of paternal livers for the incidences of graft failure and retransplantation. Rejection episodes after parental liver transplantation were examined for patients transplanted at our institution. BA patients receiving a maternal graft had lower rates of graft failure compared to those receiving a paternal graft (3.7% vs. 10.5%, p = 0.02) and, consequently, fewer episodes of retransplantation (2.7% vs. 7.5%, p = 0.04). These differences were not seen among non-BA patients or among BA patients who received female deceased donor grafts. In patients transplanted at our institution, paternal liver transplantation was associated with an increased incidence of refractory rejection compared to maternal liver transplantation only in BA. Our data support the concept that maternal cells in BA recipients promote tolerance to NIMAs and may be important in counseling BA patients who require liver transplantation.

Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria.

Dihydroartemisinin-piperaquine is being increasingly used as a first-line artemisinin combination treatment for malaria. The aim of this study was to describe the pharmacokinetic and pharmacodynamic properties of piperaquine in 236 children with uncomplicated falciparum malaria in Burkina Faso. They received a standard body weight-based oral 3-day fixed-dose dihydroartemisinin-piperaquine regimen. Capillary plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling. The population pharmacokinetics of piperaquine were described accurately by a two-transit-compartment absorption model and a three-compartment distribution model. Body weight was a significant covariate affecting clearance and volume parameters. The individually predicted day 7 capillary plasma concentration of piperaquine was an important predictor (P < 0.0001) of recurrent malaria infection after treatment. Young children (2-5 years of age) received a significantly higher body weight-normalized dose than older children (P = 0.025) but had significantly lower day 7 piperaquine concentrations (P = 0.024) and total piperaquine exposures (P = 0.021), suggesting that an increased dose regimen for young children should be evaluated.

Antiprotozoal activities of some constituents of Markhamia tomentosa (Bignoniaceae).

Phytochemical investigation of an ethyl-acetate extract of the stem bark of Markhamia tomentosa (Bignoniaceae), which had good antimalarial activity in vitro, resulted in the isolation of eight known compounds: 2-acetylnaphtho[2,3-b]furan-4,9-dione (1), 2-acetyl-6-methoxynaphtho[2,3-b]furan-4,9-dione (2), oleanolic acid (3), pomolic acid (4), 3-acetylpomolic acid (5), tormentic acid (6), beta-sitosterol (7) and beta-sitosterol-3-O-beta-D-glucopyranoside (8). The structures of these compounds were established by spectroscopic methods. Each of compounds 1, 2, 4 and 5 was evaluated in vitro for its antiprotozoal activities against the ring stages of two chloroquine-resistant strains of Plasmodium falciparum (K1 and W2), the amastigotes of Leishmania donovani, and the bloodstream trypomastigotes of Trypanosoma brucei rhodesiense (the species responsible for human malaria, visceral leishmaniasis and African trypanosomiasis, respectively). Although compounds 1 and 2 exhibited potent antiprotozoal activities, they also showed high toxicity against a mammalian (L-6) cell line.

Intermittent preventive therapy for malaria in pregnancy: is sulfadoxine-pyrimethamine the right drug?

Pregnant women are at particularly high risk for morbidity and mortality from malaria, and pregnancy can markedly affect drug pharmacokinetics, yet the pharmacokinetics of antimalarial drugs in pregnancy has been little studied. An important malaria-control measure in Africa is intermittent preventive therapy (IPT) with sulfadoxine-pyrimethamine (SP) during pregnancy. We discuss IPT with SP in light of several concerns and highlight recent findings from a pharmacokinetic study of SP in this population.

Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).

OBJECTIVE: To identify genetic causes of COACH syndrome BACKGROUND: COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). METHODS: In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. RESULTS: 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). CONCLUSIONS: Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.

Long-term management of the liver transplant patient: recommendations for the primary care doctor.

No official document has been published for primary care physicians regarding the management of liver transplant patients. With no official source of reference, primary care physicians often question their care of these patients. The following guidelines have been approved by the American Society of Transplantation and represent the position of the association. The data presented are based on formal review and analysis of published literature in the field and the clinical experience of the authors. These guidelines address drug interactions and side effects of immunosuppressive agents, allograft dysfunction, renal dysfunction, metabolic disorders, preventive medicine, malignancies, disability and productivity in the workforce, issues specific to pregnancy and sexual function, and pediatric patient concerns. These guidelines are intended to provide a bridge between transplant centers and primary care physicians in the long-term management of the liver transplant patient.

Long-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigs.

BACKGROUND: The optimal duration of clopidogrel treatment following percutaneous coronary intervention (PCI) and the patient population that would benefit most are still unknown. In a porcine coronary injury model, we tested two different durations of clopidogrel treatment on severely or moderately injured arteries and examined the arterial response to injury. To understand the molecular mechanism, we also investigated the effects on transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1). MATERIALS AND METHODS: In 24 cross-bred pigs, one coronary artery was only moderately injured by percutaneous transluminal coronary angioplasty (PTCA) and one coronary artery was severely injured by PTCA and subsequent beta-irradiation (Brachy group). Animals received 325 mg aspirin daily for 3 months and 75 mg clopidogrel daily for either 28 days [short-term (ST) clopidogrel group] or 3 months [long-term (LT) clopidogrel group]. RESULTS: After 3 months, the number of proliferating cells per cross-section differed significantly between ST and LT in both injury groups (PTCA(ST) 90.2 +/- 10.3 vs. PTCA(LT )19.2 +/- 4.7, P < 0.05; Brachy(ST) 35.8 +/- 8.4 vs. Brachy(LT) 7.5 +/- 2.0, P < 0.05). Similar results were seen for inflammatory cells (CD3(+) cells): PTCA(ST) 23.5 +/- 3.55 vs. PTCA(LT )4.67 +/- 0.92, P < 0.05; Brachy(ST) 83.17 +/- 11.17 vs. Brachy(LT) 20 +/- 4.82, P < 0.05). Long-term administration also reduced the activity of NF-kappaB and AP-1 by 62-64% and 42-58%, respectively. However, the effects of different durations of clopidogrel administration on artery dimensions were not statistically significant. CONCLUSIONS: Regarding inflammation and transcription factor activity at the PCI site, long-term clopidogrel administration is superior to short-term administration, especially in severely injured arteries. Transferring our results to the human situation, patients with more severely diseased arteries may benefit from a prolonged clopidogrel medication after PCI.

Methotrexate combined with isoniazid treatment for latent tuberculosis is well tolerated in patients with rheumatoid arthritis: experience from an urban arthritis clinic.

OBJECTIVES: Reactivation of Mycobacterium tuberculosis (TB) is a significant problem with all available tumour necrosis factor (TNF) antagonists when used to treat rheumatoid arthritis (RA), psoriatic arthritis, psoriasis and other inflammatory diseases. Concerns have been raised regarding the appropriate management of patients with latent TB (LTB) exposure (or active TB infection) before initiating TNF antagonists as the safety data of combined treatment with two potentially hepatotoxic medications, methotrexate (MTX) and isoniazid (INH), is lacking. The goal of this study was to investigate the toxicity of MTX and INH treatment in patients with RA before initiating TNF antagonists. METHODS: To investigate the toxicity of MTX and INH treatment in patients with RA we performed a retrospective chart review of patients seen at the Bellevue Hospital Arthritis Clinic in New York City between 2002 and 2006. Forty-four patients who were concomitantly treated with both drugs were included. The primary outcome investigated was increase in liver function tests (LFT). RESULTS: Transient increases in LFT were seen in 11% of patients, but in no case was this more than twice the upper limit of normal values. All abnormal LFT resolved spontaneously without intervention. In addition, no patient has developed signs or symptoms of TB reactivation. CONCLUSIONS: The use of INH for LTB was well tolerated in patients with RA on a background regimen of MTX. While the risks and benefits of all treatment must always be considered, in our experience the additive risk of INH to MTX in terms of hepatotoxicity was low. None the less it is prudent to follow LFT closely on patients taking this combination.

Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa.

Metabolism of the antimalarial drug amodiaquine (AQ) into its primary metabolite, N-desethylamodiaquine, is mediated by CYP2C8. We studied the frequency of CYP2C8 variants in 275 malaria-infected patients in Burkina Faso, the metabolism of AQ by CYP2C8 variants, and the impact of other drugs on AQ metabolism. The allele frequencies of CYP2C8*2 and CYP2C8*3 were 0.155 and 0.003, respectively. No evidence was seen for influence of CYP2C8 genotype on AQ efficacy or toxicity, but sample size limited these assessments. The variant most common in Africans, CYP2C8(*)2, showed defective metabolism of AQ (threefold higher K(m) and sixfold lower intrinsic clearance), and CYP2C8(*)3 had markedly decreased activity. Considering drugs likely to be coadministered with AQ, the antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent CYP2C8 inhibitors at clinically relevant concentrations. Variable CYP2C8 activity owing to genetic variation and drug interactions may have important clinical implications for the efficacy and toxicity of AQ.

Catheter based intracoronary brachytherapy leads to increased platelet activation.

BACKGROUND: Vascular brachytherapy (VBT) after percutaneous coronary intervention (PCI) is associated with a higher risk of stent thrombosis than conventional treatment. OBJECTIVE: To investigate in vivo periprocedural platelet activation with and without VBT, and to assess a possible direct effect of radiation on platelet activation. DESIGN: Of 50 patients with stable angina, 23 received VBT after PCI, while 27 had PCI only. The 23 patients who received VBT after PCI were pretreated for one month with aspirin and clopidogrel. Platelet activation was assessed by flow cytometry. RESULTS: The two patient groups did not differ in their platelet activation before the intervention. There was a significant increase in activation immediately after VBT, with 21.2% (interquartile range 13.0% to 37.6%) thrombospondin positive and 54.0% (42.3% to 63.6%) CD 63 positive platelets compared with 12.7% (9.8% to 14.9%) thrombospondin positive and 37.9% (33.2% to 45.2%) CD 63 positive platelets before the intervention (p < 0.001 and p < 0.01, respectively). Patients without VBT had no periprocedural difference in platelet activation immediately after PCI. No increase in platelet activation was found after ex vivo irradiation of blood samples obtained from healthy controls. CONCLUSIONS: Catheter based intracoronary VBT carried out according to current standards is highly thrombogenic. The current antithrombotic treatment with aspirin and clopidogrel is not sufficient to suppress platelet activation during the procedure. From in vitro experiments, it appears that platelet activation during brachytherapy is not caused by irradiation but by the procedure of catheter based VBT.

Calibration and validation of a quality assurance system for 90Sr/90Y radiation source trains.

A quality assurance system (OPTIDOS, PTW-Freiburg) developed for dose rate verification of 90Sr/90Y radiation source trains (RSTs) was calibrated and validated. These source trains are used in the 5-F-BetaCath system (Novoste Corp.) for the treatment of endovascular diseases. The calibration factor of the OPTIDOS system was obtained empirically and is valid for 90Sr/90Y dose rate measurements at the specification point which is located at 2 mm distance from the source axis. A total of 187 OPTIDOS dose rate verifications of the 5-F-BetaCath system were performed in different hospitals. The histogram of the deviation between the manufacturer's dose rate specification and the dose rate measured using the OPTIDOS dosimetry system is Gaussian shaped with +/- 3% relative width and a mean shift of about +2% with respect to the corresponding dose rate specification. Additionally, 128 OPTIDOS dose rate verifications of the new jacketed RST (3.5-F-BetaCath, Novoste Corp.) were performed using the same calibration factor as derived for the 5-F-BetaCath system. Distribution of the deviation between the certified and the measured dose rate is nearly identical in comparison to the histogram of the 5-F-BetaCath system. The mean value of the deviations is shifted by -1.5% with respect to the certified dose rate. In order to compare the results of the calibrated OPTIDOS dosimetry system with a standard measuring method, separate dose rate measurements were performed using electron accelerator calibrated radiochromic films in which calibration is traceable to PTB (Physikalisch Technische Bundesanstalt, Germany). Deviation between both the methods is less than 3.1%. These results confirm that the calibrated OPTIDOS dosimetry system can be considered suitable for quality assurance of both types of RST used in the BetaCath systems.