Mining Small Routine Clinical Data: A Population Pharmacokinetic Model and Optimal Sampling Times of Capecitabine and its Metabolites

Purpose: The present study was performed to demonstrate that small amounts of routine clinical data allow to generate valuable knowledge. Concretely, the aims of this research were to build a joint population pharmacokinetic model for capecitabine and three of its metabolites (5-DFUR, 5-FU and 5-FUH2) and to determine optimal sampling times for therapeutic drug monitoring. Methods: We used data of 7 treatment cycles of capecitabine in patients with metastatic colorectal cancer. The population pharmacokinetic model was built as a multicompartmental model using NONMEM and was internally validated by visual predictive check. Optimal sampling times were estimated using PFIM 4.0 following D-optimality criterion. Results: The final model was a multicompartmental model which represented the sequential transformations from capecitabine to its metabolites 5-DFUR, 5-FU and 5-FUH2 and was correctly validated. The optimal sampling times were 0.546, 0.892, 1.562, 4.736 and 8 hours after the administration of the drug. For its correct implementation in clinical practice, the values were rounded to 0.5, 1, 1.5, 5 and 8 hours after the administration of the drug. Conclusions: Capecitabine, 5-DFUR, 5-FU and 5-FUH2 can be correctly described by the joint multicompartmental model presented in this work. The aforementioned times are optimal to maximize the information of samples. Useful knowledge can be obtained for clinical practice from small databases

Targeting cattle for malaria elimination: marked reduction of Anopheles arabiensis survival for over six months using a slow-release ivermectin implant formulation

BACKGROUND: Mosquitoes that feed on animals can survive and mediate residual transmission of malaria even after most humans have been protected with insecticidal bednets or indoor residual sprays. Ivermectin is a widely-used drug for treating parasites of humans and animals that is also insecticidal, killing mosquitoes that feed on treated subjects. Mass administration of ivermectin to livestock could be particularly useful for tackling residual malaria transmission by zoophagic vectors that evade human-centred approaches. Ivermectin comes from a different chemical class to active ingredients currently used to treat bednets or spray houses, so it also has potential for mitigating against emergence of insecticide resistance. However, the duration of insecticidal activity obtained with ivermectin is critical to its effectiveness and affordability. RESULTS: A slow-release formulation for ivermectin was implanted into cattle, causing 40 weeks of increased mortality among Anopheles arabiensis that fed on them. For this zoophagic vector of residual malaria transmission across much of Africa, the proportion surviving three days after feeding (typical mean duration of a gonotrophic cycle in field populations) was approximately halved for 25 weeks. CONCLUSIONS: This implantable ivermectin formulation delivers stable and sustained insecticidal activity for approximately 6 months. Residual malaria transmission by zoophagic vectors could be suppressed by targeting livestock with this long-lasting formulation, which would be impractical or unacceptable for mass treatment of human populations

Structural and Mössbauer study of (Sb0.70Te0.30)100-x Snx alloys with x = 0, 2.5, 5.0 and 7.5

(Sb 0.70 Te 0.30 ) 100-x Sn x alloys (with x = 0, 2.5, 5.0 and 7.5 at. %)have been synthesized and characterized in order to determine the crystalline structure and properties of materials obtained upon solidification and to extract information about the location of the Sn atom in the Sb-Te matrix. Powder X-ray diffraction (XRD)has been used to determine the crystalline structure, whereas Mössbauer spectroscopy has been utilized to determine the localization and the local structure of the Sn atom in the Sb-Te matrix through the hyperfine interactions of the 119 Sn probe with its environment. We found that Sb 70 Te 30 crystallizes in a trigonal structure belonging to P-3m1 space group, while the doping with Sn leads to structural distortions of the unit cell that can be described, for all the Sn concentrations, with the C2/m space group. The hyperfine parameters indicate that tin behaves as Sn(II)and has a slightly distorted environment. Finally, in order to extract all the information that the experimental results contain and to determine the preferential site occupied by the Sn impurities in the Sb-Te matrix, we have performed ab-initio calculations within the framework of the Density Functional Theory. The theoretical results enable us to determine the structural and electronic ground state of (Sb 0.70 Te 0.30 ) 100-x Sn x compounds and to confirm that Sn atoms substitute Sb atoms in the Sb-Te host.Fil: Rocca, Javier Alejandro. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long". Universidad de Buenos Aires. Facultad de Ingeniería. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long"; ArgentinaFil: Bilovol, Vitaliy. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long". Universidad de Buenos Aires. Facultad de Ingeniería. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long"; ArgentinaFil: Errandonea, Alfredo Mario. Universidad de Valencia; EspañaFil: Gil Rebaza, Arles Víctor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Mudarra Navarro, Azucena Marisol. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Medina Chanduvi, Hugo Harold. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Errico, Leonardo Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Arcondo, B.. Universidad Nacional del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Fontana, Marcelo. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long". Universidad de Buenos Aires. Facultad de Ingeniería. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long"; ArgentinaFil: Rodríguez Cuellar, O.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long". Universidad de Buenos Aires. Facultad de Ingeniería. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long"; Argentina. Universidad de Buenos Aires; ArgentinaFil: Ureña, María Andrea. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long". Universidad de Buenos Aires. Facultad de Ingeniería. Instituto de Tecnologías y Ciencias de la Ingeniería "Hilario Fernández Long"; Argentin

Randomized clinical trial of the safety and immunogenicity of the Tdap vaccine in pregnant Mexican women

ABSTRACT Immunization with the tetanus, diphtheria, and pertussis (Tdap) vaccine raises controversies on immunogenicity and possible antibody interference. We performed an experimental, double-blind, parallel group controlled clinical trial to evaluate the safety and immunogenicity of the Tdap vaccine in 204 pregnant women and their children and to determine its interference in antibody production. Pregnant women 18 to 38 y of age with 12 to 24 weeks gestation, a low obstetric risk, and without serious disease were randomly selected. The experimental group received 0.5 mL IM of Tdap and the control group normal saline. Six blood samples were drawn before and after solution application, and from the umbilical cord of the infants and at 2, 4, and 6 months of age. Pertactin and Pertussis toxin antibodies and possible interference of maternal antibodies with the vaccine were determined. In the experimental group, antibodies against Bordetella pertussis pertactin (anti-PRN) (112 E/mL 95% CI 89.9–139.9) and antibodies against pertussis toxin (anti-PT) (24.0 E/mL, 95% CI 18.3–31.4) were elevated in the mother before vaccination. These were higher in the umbilical cord and descended in the infant at 2 months (71.4 (95% CI 56.8–89.7 and 10.9; 95% CI 8.7–13.7, respectively). Anti-PT showed a delay in production. Tdap safety was confirmed with only mild local pain at 24 and 48 hours. Anti-PRN and anti-PT antibodies in the infant descend at 2 months of age. There is a delay in anti-PT in children of immunized mothers. Further studies are needed to elucidate its clinical significance

Altered subcortical emotional salience processing differentiates Parkinson’s patients with and without psychotic symptoms

Objective Current research does not provide a clear explanation for why some patients with Parkinson’s Disease (PD) develop psychotic symptoms. The ‘aberrant salience hypothesis’ of psychosis has been influential and proposes that dopaminergic dysregulation leads to inappropriate attribution of salience to irrelevant/non-informative stimuli, facilitating the formation of hallucinations and delusions. The aim of this study is to investigate whether non-motivational salience is altered in PD patients and possibly linked to the development of psychotic symptoms. Methods We investigated salience processing in 14 PD patients with psychotic symptoms, 23 PD patients without psychotic symptoms and 19 healthy controls. All patients were on dopaminergic medication for their PD. We examined emotional salience using a visual oddball fMRI paradigm that has been used to investigate early stages of schizophrenia spectrum psychosis, controlling for resting cerebral blood flow as assessed with arterial spin labelling fMRI. Results We found significant differences between patient groups in brain responses to emotional salience. PD patients with psychotic symptoms had enhanced brain responses in the striatum, dopaminergic midbrain, hippocampus and amygdala compared to patients without psychotic symptoms. PD patients with psychotic symptoms showed significant correlations between the levels of dopaminergic drugs they were taking and BOLD signalling, as well as psychotic symptom scores. Conclusion Our study suggests that enhanced signalling in the striatum, dopaminergic midbrain, the hippocampus and amygdala is associated with the development of psychotic symptoms in PD, in line with that proposed in the ‘aberrant salience hypothesis’ of psychosis in schizophrenia

Postpartum endometritis and infection following incomplete or complete abortion: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data

Need for developing case definitions and guidelines for data collection, analysis, and presentation for postpartum endometritis and infection following incomplete or complete abortion as adverse events following maternal immunization

Chorioamnionitis: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data

Chorioamnionitis is a term encompassing a broad spectrum of disease during pregnancy that is characterized by inflammation and/or infection of intrauterine structures such as the placenta, the chorion and amnion. The clinical presentation of chorioamnionitis can vary based on clinical, microbiologic, and histologic factors which interact and overlap to varying degrees

Valorization of the essential oil from Drypetes gossweileri S. Moore (Putranjivaceae): in vitro, in vivo, and in silico nematicidal activity

The chemical composition, insect antifeedant, in vtro/in vivo nematicidal activity, phytotoxicity, and in silico nematicidal activity of the essential oil (EO) of the African medicinal plant Drypetes gossweileri were studied. Chemical analysis using GC/MS indicated that benzyl isothiocyanate (96.23%) was the major compound, followed by benzyl cyanide (1.38%). The biocidal effects of this oil were tested against insect pests and root-knot nematodes. All the insect species tested were significantly affected by the oil according to their feeding adaptations (Spodoptera littoralis and Myzus persicae were less affected than Rhopalosiphum padi) with efficient doses (EC50) of 29.4 8.3 μg/cm2, 14.744 8.3 μg/cm2, and 8.3 μg/cm2, respectively. The oil was highly effective against juveniles J2 of the nematode Meloidogyne javanica, with LC50–LC90 values of 0.007 mg/mL–0.0113 mg/mL. D. gossweileri EO at minimum lethal concentrations (MLC) and below strongly inhibited egg hatching in vitro, whereas soil treatment caused a strong suppression of nematode population, infection frequency, and multiplication rate. The EO inhibited ryegrass (Lolium perenne) germination at 0.4 mg/mL, while at 0.1 mg/mL, its effects on germination, root and leaf growth were moderate (32.4%, 8.4%, and 18.3%, respectively). The tomato (Solanum lycopersicum) germination was not affected by the EO, but the root growth was reduced (56% at 0.1 mg/mL) at a dose 10 times higher than the LD50 calculated for M. javanica J2 mortality. Molecular docking of the nematicidal effects of the oil using PyRx revealed a strong interaction between potassium chloride transporting KCC3 (PDB ID: 7D90) and benzyl cyanide at a distance of 2.20 A° with GLN C:350, followed by benzyl isothiocyanate at a distance of 2.78 A° with ARG B:294. The in vivo nematicidal effects of D. gossweileri EO on M. javanica penetration and reproduction in tomato roots further support the potential of this EO as a nematicidal agent with insect antifeedant effects, which could be used by local farmers for crop protection

Metabolomic-Based Noninvasive Serum Test to Diagnose Nonalcoholic Steatohepatitis: Results From Discovery and Validation Cohorts

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy-proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 +/- 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 +/- 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 +/- 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy.Supported by the National Institutes of Health Blueprint for Neuroscience Research (R01AT001576 to S.C.L., J.M.M.), Agencia Estatal de Investigacion of the Ministerio de Economia, Industria y Competitividad (SAF2014-52097R to J.M.M.), CIBER Hepatic and Digestive Diseases and Instituto de Salud Carlos III (PIE14/0003 to J.M.M.), Etorgai 2015-Gobierno Vasco (ER-2015/00015 to R.M., I.M.A., C.A., A.C.), Plan de Promocion de la Innovacion 2015-Diputacion Foral de Bizkaia (6/12/IN/2015/00131 to A.C., C.A.), National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK81410 to A.J.S.), and Czech Ministry of Health (RVO VFN64165 to L.V.)

Abnormal reward prediction-error signalling in antipsychotic naive individuals with first-episode psychosis or clinical risk for psychosis.

Ongoing research suggests preliminary, though not entirely consistent, evidence of neural abnormalities in signalling prediction errors in schizophrenia. Supporting theories suggest mechanistic links between the disruption of these processes and the generation of psychotic symptoms. However, it is unknown at what stage in the pathogenesis of psychosis these impairments in prediction-error signalling develop. One major confound in prior studies is the use of medicated patients with strongly varying disease durations. Our study aims to investigate the involvement of the meso-cortico-striatal circuitry during reward prediction-error signalling in earliest stages of psychosis. We studied patients with first-episode psychosis (FEP) and help-seeking individuals at-risk for psychosis due to sub-threshold prodromal psychotic symptoms. Patients with either FEP (n = 14), or at-risk for developing psychosis (n = 30), and healthy volunteers (n = 39) performed a reinforcement learning task during fMRI scanning. ANOVA revealed significant (p < 0.05 family-wise error corrected) prediction-error signalling differences between groups in the dopaminergic midbrain and right middle frontal gyrus (dorsolateral prefrontal cortex, DLPFC). FEP patients showed disrupted reward prediction-error signalling compared to controls in both regions. At-risk patients showed intermediate activation in the midbrain that significantly differed from controls and from FEP patients, but DLPFC activation that did not differ from controls. Our study confirms that FEP patients have abnormal meso-cortical signalling of reward-prediction errors, whereas reward-prediction-error dysfunction in the at-risk patients appears to show a more nuanced pattern of activation with a degree of midbrain impairment but preserved cortical function