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Innovative cross-over study designs were explored in non-human primate (NHP) studies to determine the value of this approach for the evaluation of drug efficacy against tuberculosis (TB). Firstly, the pharmacokinetics (PK) of each of the drugs Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) and Ethambutol (E), that are standardly used for the treatment of tuberculosis, was established in the blood of macaques after oral dosing as a monotherapy or in combination. Two studies were conducted to evaluate the pharmacokinetics and pharmacodynamics of different drug combinations using cross-over designs. The first employed a balanced, three-period Pigeon design with an extra period; this ensured that treatment by period interactions and carry-over could be detected comparing the treatments HR, HZ and HRZ using H37Rv as the challenge strain of

We investigated limitations in young infants' visual short-term memory (VSTM). We used a one-shot change detection task to ask whether 4- and 8.5-month-old infants (N=59) automatically encode fixated items in VSTM. Our task included trials that consisted of the following sequence: first a brief (500ms) presentation with a sample array of two items, next a brief (300ms) delay period with a blank screen, and finally a test array (2,000ms) identical to the sample array except that the color of one of the two items is changed. In Experiment 1, we induced infants to fixate one item by rotating it during the sample (the other item remained stationary). In Experiment 2, none of the items rotated. In both experiments, 4-month-old infants looked equally at the fixated item when it did and did not change color, providing no evidence that they encoded in VSTM the fixated item. In contrast, 8.5-month-old infants in Experiment 1 preferred the fixated item when it changed color from sample to test. Thus, 4-month-old infants do not appear to automatically encode fixated items in VSTM.

This article belongs to the Special Issue Drug Candidates and Drug Delivery Systems for Tuberculosis Treatment. Innovative cross-over study designs were explored in non-human primate (NHP) studies to determine the value of this approach for the evaluation of drug efficacy against tuberculosis (TB). Firstly, the pharmacokinetics (PK) of each of the drugs Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) and Ethambutol (E), that are standardly used for the treatment of tuberculosis, was established in the blood of macaques after oral dosing as a monotherapy or in combination. Two studies were conducted to evaluate the pharmacokinetics and pharmacodynamics of different drug combinations using cross-over designs. The first employed a balanced, three-period Pigeon design with an extra period; this ensured that treatment by period interactions and carry-over could be detected comparing the treatments HR, HZ and HRZ using H37Rv as the challenge strain of Mycobacterium tuberculosis (M. tb). Although the design accounted for considerable variability between animals, the three regimens evaluated could not be distinguished using any of the alternative endpoints assessed. However, the degree of pathology achieved using H37Rv in the model during this study was less than expected. Based on these findings, a second experiment using a classical AB/BA design comparing HE with HRZ was conducted using the M. tb Erdman strain. More extensive pathology was observed, and differences in computerized tomography (CT) scores and bacteriology counts in the lungs were detected, although due to the small group sizes, clearer differences were not distinguished. Type 1 T helper (Th1) cell response profiles were characterized using the IFN-(Gamma) ELISPOT assay and revealed differences between drug treatments that corresponded to decreases in disease burden. Therefore, the studies performed support the utility of the NHP model for the determination of PK/PD of TB drugs, although further work is required to optimize the use of cross-over study designs. Grant award from EU Commission IMI Joint Undertaking-11537. EU IMI PreDiCT TB-Improving the Pre-Clinical Models and Tools for TB Medicines Research for studies to establish a non-human primate aerosol challenge model of TB for the evaluation of TB drug efficacy.

Orientador: Prof. Dr. Marcelo Escudeiro Hernandes Dissertação (mestrado em Matemática)--Universidade Estadual de Maringá, Dep. de Matemática, Programa de Pós-Graduação em Matemática, Área de Concentração: Álgebra, 2020 Resumo: O objetivo principal, neste trabalho, e calcular o fecho de Ratliff-Rush de uma classe especifica de ideais monomiais no anel de polinômios K[x1; : : : ; xn], em que K _e um corpo, utilizando, para isso, um algoritmo definido por Gasanova em [G]. Abstract: The main goal, in this work, is to compute the Ratliff-Rush closure of a specific class of monomial ideals in the polynomial ring K[x1; : : : ; xn], where K is a field, using an algorithm presented by Gasanova in [G].

Significance Application of antigen-specific immune tolerance in autoimmune disease is a long-sought goal. We studied diseases with abundant information on the autoimmune target: in multiple sclerosis (MS), various myelin antigens are known targets of T cells and antibodies, whereas in neuromyelitis optica (NMO), the aquaporin-4 channel is attacked by T cells and antibodies. We tested whether engineered dendritic cells might induce a tolerogenic immune response in these two conditions. In this in-human clinical study, individual regulatory T cells, secreting IL-10, a key tolerogenic cytokine, were detected after treatment. These results might lead to more extensive trials with this approach in autoimmune conditions where the antigenic target has been identified, including MS, NMO, myasthenia gravis, and Graves disease., There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials.

As a dose-finding phase I study of a new liposomal formulation of doxorubicin (LipD), patients (n = 39; median age: 60 years; range, 41-75; median ECOG performance status, 1; range, 0-2) with refractory cancer had a starting dose of LipD administered at 30 mg/m(2) as a 1-hour intravenous infusion. Cycle duration was 21 days. At the recommended dose (RD), patients received a first cycle of nonliposomal doxorubicin (non-LipD) to evaluate intrapatient pharmacokinetic differences between non-LipD and LipD. The most frequent diagnosis was head and neck tumor (7 patients). Tolerance and safety of dose levels of 30, 40, 50, 60, 70, 80, and 90 mg/m(2) were evaluated. A total of 131 cycles were administered (median per patient, 3; range, 1-6). Of the 39 patients, 8 completed the planned six cycles. Febrile neutropenia was dose limiting and defined the toxic dose of LipD as 70 mg/m(2). Other significant toxicities included asthenia (G2: 31%; G3: 8%), neutropenia (G3: 35%; G4: 29%), thrombopenia (G3: 15%; G4: 2%), anemia (G1-G2: 67%; G3-G4: 5%), mucositis (G1-G2: 32%, G3: 4%), and acute allergic reactions (G1-G2: 36%). Comparison of pharmacokinetic profiles of non-LipD and LipD showed that higher exposure was achieved with LipD. Stable disease was observed in 14 patients. We conclude that the LipD regimen, given as a 1-hour infusion every 3 weeks, is well tolerated and has a favorable pharmacokinetic profile. The recommended dose is 70 mg/m(2) with prophylactic antihistamines and corticoids to preempt allergic reaction.

To estimate the seroprevalence of anti-JCV antibodies, seroconverting rates and evolution of antibody levels in a multiple sclerosis (MS) Spanish cohort.Multicenter, retrospective cross-sectional and longitudinal study. The JCV seroprevalence was analyzed in 711 MS patients by using 1st (STRATIFY-1) and 2nd generation (STRATIFY-2) two-step ELISA over 2.65 (±0.97) years. Seroconversion rate was obtained over 2 samples from 314 patients, and index stability from 301 patients with 3 or more samples available. The effect of each ELISA generation, demographics, clinical characteristics and therapy on seroprevalence was assessed by logistic regression.The overall anti-JCV seroprevalence was 55.3% (51.6-58.9), similar across regions (p=0.073). It increased with age (p0.000) and when STRATIFY-2 was used (60.5%, p=0.001). Neither sex nor immunosuppressive therapy had any influence. Yearly seroconversion rate was 7% (considering only STRATIFY-2). Serological changes were observed in 24/301 patients, 5.7% initially seropositive reverted to seronegative and 7% initially seronegative changed to seropositive and again to seronegative, all these cases had initial index values around the assay's cut-off.JCV seroprevalence in Spanish MS patients was similar to that reported in other European populations. Changes in serostatus are not infrequent and should be considered in clinical decisions.

Nurses continue to experience injuries related to patient handling. These injuries are costly to hospitals in both direct and indirect costs and intangible costs such as staff morale. The need for hospitals to establish safe patient handling programs is growing and is now mandated by legislation in several states. The authors describe the development, implementation, and 6-year outcomes of a lift team that is part of successful safe patient handling program.

It is not established whether there is an association between erythrocyte aggregation and AB0 blood type, as glycophorins carry sialic acid which is responsible for the negative erythrocyte surface charge and the antigenicity for AB0 blood groups. We have determined erythrocyte aggregation by means of the Myrenne aggregometer in 114 healthy volunteers, along with plasma lipids, fibrinogen and AB0 blood groups. No differences in erythrocyte aggregation (EA0 and EA1) were observed when subjects with 0 (n = 45) and non-0 (n=69) blood group were compared (P = 0.624 and P = 0.838, respectively). Fibrinogen was statistically lower in 0 group compared with non-0 group (P = 0.012). Erythrocyte aggregation (EA0 and EA1) correlated significantly with both lipids and fibrinogen (P0.01). When erythrocyte aggregation was dichotomized as EA1or = 8, no association was found with 0 and non-0 blood groups (P0.05) but it was associated with high lipid levels: T-Chol220 mg/dl, TG175 mg/dl and high fibrinogen levels300 mg/dl (P = 0.035; P = 0.030; P = 0.010, respectively). Erythrocyte aggregation does not seem to be associated with blood groups, but rather with plasma lipids and fibrinogen.

Purpose: Plitidepsin, given as a 1-hour weekly i.v. infusion for 3 consecutive weeks during a 4-week treatment cycle, was investigated in patients with solid tumors to determine the maximum tolerated dose and the recommended dose (RD) using this administration schedule. Experimental Design: Consecutive cohorts of patients with metastatic solid tumors or non–Hodgkin's lymphomas were to be treated at escalating doses of plitidepsin in a conventional phase I study including pharmacokinetic analyses of plitidepsin in plasma, whole blood, and blood cell pellets. Results: Forty-nine patients with solid tumors were enrolled, and 48 were treated with plitidepsin (doses from 0.133 to 3.6 mg/m2/week). Dose-limiting toxicities (defining 3.6 mg/m2/week as the maximum tolerated dose) included myalgia, increased creatine phosphokinase levels, and sustained grade 3/4 increases of hepatic enzyme levels. The RD was established at 3.2 mg/m2/week. The most common toxicities were fatigue, vomiting/nausea, anorexia, injection site reaction, and pain, mostly of mild or moderate severity. Muscular toxicity manifested by mild-moderate myalgia, weakness, and/or creatine phosphokinase elevations occurred in ∼25% of patients and seemed to be dose related. Transient transaminase elevations were frequent but achieved grade 3 or 4 in only ∼10% of patients. Plitidepsin lacked significant hematologic toxicity. No complete or partial tumor responses were observed; however, five patients had disease stabilization (including one patient with medullary thyroid carcinoma with an unconfirmed partial response and one patient with renal carcinoma with major tumor shrinkage in lung metastases). Pharmacokinetic results for the RD indicated a long plasma half-life give value (16.8 ± 7.7 hour) and a high volume of distribution value (525.2 ± 219.3 L). Conclusions: The recommended dose for plitidepsin given as a weekly 1-hour schedule was 3.2 mg/m2/week. Muscular and liver toxicity were dose limiting at 3.6 mg/m2/week. Additional evaluation of this dose dense schedule is warranted.

The aim of this study was to determine the safety and feasibility profile of paclitaxel (PTX) and docetaxel (DTX) in combination and the pharmacokinetic and pharmacodynamic interaction between these two drugs in two different alternated sequences of administration. The starting dose was PTX (100 mg/m2) as a 3-h IV infusion followed by DTX (50 mg/m2) as 1-h IV infusion or the alternative sequence in every other patient. The sequence was alternated in the second course in each patient treated. Cycle duration was 21 days. Twenty patients received 103 cycles of treatment through three dose levels. Febrile neutropenia and grade 4 neutropenia lasting longer than 7 days were dose-limiting and defined the toxic dose of DTX (50 mg/m2) and PTX (135 mg/m2) in patients with prior treatment and the recommended dose in patients without prior treatment. Non-hematological toxicities included asthenia, neuropathy, arthralgia/myalgia and stomatitis. Pharmacokinetics of DTX were significantly affected by the sequence. Nadir ANC was more profound when DTX was administered first (P = 0.022). There were one complete response and six partial responses, giving an overall response rate of 35%. DTX (50 mg/m2) followed by PTX (135 mg/m2) can be administered safely and it is an active regimen. The pharmacokinetics of PTX are not influenced by DTX but DTX pharmacokinetics depend on the sequence of administration, which influences its haematological toxicity profile.

El problema de la p-mediana es un modelo básico de localización en redes donde las longitudes de las aristas (distancias) y los pesos de los vértices (demandas) son conocidos. Consiste en encontrar p puntos de la red de modo que se minimice la distancia total ponderada entre estos puntos y los vértices. Como la mayoría de problemas de localización, se utiliza para tomar decisiones a largo plazo en un entorno incierto. En consecuencia, la hipótesis de que los datos son deterministas no parece apropiada para resolver un problema real. En este trabajo presentamos el problema de la mediana sobre un árbol con incertidumbre en las demandas, resuelto mediante técnicas de optimización robusta. En concreto, hemos supuesto que la incertidumbre viene reflejada por el hecho de que cada demanda puede variar en un rango de valores. Nuestro objetivo es conseguir una solución que, cuando los datos tomen algún valor en el futuro, minimice la demanda no atendida y cuyo coste no esté muy lejos del mínimo coste que hubiésemos obtenido de saber con antelación el auténtico valor de los datos. Puesto que la forma de plantear matemáticamente este objetivo no es única, presentamos y comparamos varias opciones entre las que puede elegir el decisor.

Los problemas de localización tratan de averiguar la ubicación de las instalaciones de una empresa de modo que se minimicen los costes o se maximicen los beneficios. Dos de los modelos más utilizados en localización en redes son el problema de la p-mediana y el problema del p-centro. El primero consiste en minimizar la suma total de las distancias ponderadas, mientras que el segundo trata de minimizar la máxima distancia ponderada desde un centro de servicio hasta sus usuarios asignados. El objetivo del problema de la p-mediana hace que sea eficiente pero no equitativo, mientras que la cota implícita en el problema del p-centro lo convierte en equitativo pero no eficiente. Para combinar ambos aspectos, aparece en la década de los 70 un nuevo problema, el de la p-centdiana, cuya función objetivo es una mezcla de las dos anteriores. En este trabajo presentamos un modelo de programación binaria mixta para el problema generalizado de la p-centdiana sobre una red en el que los pesos asociados al p-centro y a la p-mediana no son necesariamente iguales. El primer paso para resolver el problema es identificar su conjunto dominante finito. En consecuencia, previamente a la descripción del modelo, proponemos un algoritmo que nos permitirá calcular este conjunto.

48 consecutive patients (pts) with muscle-invasive bladder cancer were treated between November 1988 and May 1993. All pts had pure transitional carcinoma, absence of diffuse Tis, and clinic N0M0 stage. 39 pts had T2-3a stages and 9 had T3b-4a. The treatment consisted of RTU, neoadjuvant chemotherapy M-VAC (CT) (2–4 cycles), and radiotherapy (RT) (44 Gy). RT was continued to 64 Gy in pts with biopsy-proven absence of invasive cancer (CR). Cystectomy was performed in pts with residual invasive tumor. 9 pts did not receive RT: 6 with failure to CT underwent immediate cystectomy, and 3 with CR received only CT. The CR rate to neoadjuvant treatment was 75%. After a mean follow-up of 35 months, 24 pts (50%) had preserved bladders free of invasive tumor and functioning well. The actuarial survival and disease free survival at 3 years were, respectively, 49% and 56%. Of the 24 currently surviving pts 87% have their bladder preserved. 5 pts required salvage cystectomy for recurrent invasive cancer or diffuse Tis. 9 pts had recurrent superficial bladder tumors, and 5 of them preserved their bladders after further RTU and BCG. The response to CT had prognostic value for survival (P = .0004). Long-term bladder sparing was significantly associated with absence of hydronephrosis and bladder-confined disease (T2-T3a). Severe complications were: 1 death for fulminant hepatitis after CT, 2 late radiation cystitis that required cystectomy, with one death in postoperatory, and colovesical fistula that needed rectosygmoidectomy. The long-term bladder preservation is feasible in a selected group of pts by multimodality treatment. Most surviving pts had their bladders intact.