Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III).

BACKGROUND: Therapies to prevent recurrence of Clostridioides difficile infection (CDI) in pediatric patients are needed. Bezlotoxumab is a fully human monoclonal antibody approved for prevention of recurrent CDI in adults. We assessed the pharmacokinetics, safety, tolerability, and efficacy of bezlotoxumab in pediatric patients. METHODS: MODIFY III was a multicenter, double-blind, placebo-controlled study of bezlotoxumab in children (1 to <18 years) receiving antibacterial treatment for CDI. Participants were randomized 3:1 to receive a single infusion of bezlotoxumab (10 mg/kg) or placebo and were stratified by age at randomization (cohort 1: 12 to <18 years, cohort 2: 1 to <12 years). The primary objective was to characterize bezlotoxumab pharmacokinetics to support dose selection for pediatric patients; the primary endpoint was the area under the bezlotoxumab serum concentration-time curve (AUC0-inf). Safety, tolerability, and efficacy were monitored for 12 weeks post-infusion. RESULTS: A total of 148 participants were randomized and 143 were treated: 107 with bezlotoxumab and 36 with placebo (cohort 1 n = 60, cohort 2 n = 83; median age 9.0 years); 52.4% of participants were male and 80.4% were white. Geometric mean ratios (90% CI) for bezlotoxumab AUC0-inf were 1.06 (0.95, 1.18) and 0.82 (0.75, 0.89) h * µg/mL for cohorts 1 and 2, respectively. Bezlotoxumab 10 mg/kg was generally well-tolerated with an adverse event profile similar to placebo, including no treatment discontinuations due to adverse events. CDI recurrence was low and comparable for bezlotoxumab (11.2%) and placebo (14.7%). CONCLUSIONS: The results of this study support the bezlotoxumab dose of 10 mg/kg for pediatric patients. TRIAL REGISTRATION: NCT03182907 at ClinicalTrials.gov.

Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper.

Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignancies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CAR-T constructs are in research for both hematological and non-hematological diseases. Most of the patients receiving CAR-T therapy will develop fever at some point after infusion, mainly due to cytokine release syndrome (CRS). The onset of CRS is often indistinguishable from an infection, which makes management of these patients challenging. In addition to the lymphodepleting chemotherapy and CAR T cells, the treatment of complications with corticosteroids and/or tocilizumab increases the risk of infection in these patients. Data regarding incidence, risk factors and prevention of infections in patients receiving CAR-T cell therapy are scarce. To assist in patient care, a multidisciplinary team from hospitals designated by the Spanish Ministry of Health to perform CAR-T therapy prepared these recommendations. We reviewed the literature on the incidence, risk factors, and management of infections in adult and pediatric patients receiving CAR-T cell treatment. Recommendations cover different areas: monitoring and treatment of hypogammaglobulinemia, prevention, prophylaxis, and management of bacterial, viral, and fungal infections as well as vaccination prior and after CAR-T cell therapy.

Analysis of SUMOylation in the RENT Complex by Fusion to a SUMO-Specific Protease Domain.

Protein sumoylation is a reversible posttranslational modification that controls multiple processes during cell cycle progression. Frequently, SUMO synergistically targets various subunits in a protein complex to modulate its function, leading to what has been defined as protein group sumoylation. Different subunits in the RENT (regulator of nucleolar silencing and telophase) complex, including Net1, Sir2, and Cdc14, can be coupled to SUMO, making it difficult to ascertain the role of this modification. Here we describe a method to downregulate sumoylation in RENT, consisting in the fusion of a catalytic domain of the Ulp1 SUMO protease (Ulp Domain; UD) to the C-terminus of members in the complex using epitope tags as linkers. Targeting of the UD to specific loci can be simplified by transformation of PCR-amplified cassettes. The presence of the UD in the complex allows the concurrent downregulation of sumoylated species in the RENT complex, what can be easily monitored by pull-down of SUMO conjugates. This methodology can be applied to other protein complexes exhibiting group sumoylation.

Hepatotoxicidad en el lactante sano expuesto a nevirapina durante el embarazo / Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy

INTRODUCCIÓN: En nuestro medio, el uso de nevirapina en la embarazada infectada por el VIH se desaconseja por su potencial hepatotoxicidad. Existen pocos datos sobre dicha toxicidad en el neonato no infectado por el VIH y expuesto a este fármaco durante la gestación. Se pretende determinar el grado de hepatotoxicidad en el recién nacido expuesto a nevirapina y VIH durante la gestación. MÉTODOS: Estudio transversal observacional multicéntrico en una cohorte de recién nacidos hijos de madre VIH positivas no infectados en los que se revisó la primera determinación de alanina aminotransferasa antes de las 6 semanas de vida. Se establecieron 2 grupos según hubieran estado expuestos o no a nevirapina durante la gestación. La hepatotoxicidad se clasificó según el AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). RESULTADOS: Se incluyeron 160 recién nacidos de 159 gestaciones (88 expuestos a tratamientos combinados con nevirapina y 71 a inhibidores de proteasa). No se observó ningún caso de hepatotoxicidad según laGrading Table del DAIDS, pero se registraron 2 casos de ALT superior a los valores de normalidad (2,8%, IC 95%: 0,3-9,8) en los no expuestos a nevirapina y uno (1,1%, IC 95%: 0,0-6,1) en el grupo expuesto (p = 0,585). CONCLUSIONES: La ausencia de diferencias entre ambos grupos sugiere que los regímenes de tratamiento antirretroviral de gran actividad que incluyen nevirapina durante la gestación no asocian un riesgo aumentado de hepatopatía en el lactante con respecto a otros regímenes

BACKGROUND: The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. METHODS: A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6 weeks of age, was collected. Patients were allocated to 2 groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). RESULTS: This study included 160 newborns from 159 pregnancies (88 exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95% CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95% CI: 0.0-6.1%) in the group exposed to nevirapine (P = .585). CONCLUSION: The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations

[Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy]. / Hepatotoxicidad en el lactante sano expuesto a nevirapina durante el embarazo.

BACKGROUND: The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. METHODS: A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). RESULTS: This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585). CONCLUSION: The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations.

Off-label use of maraviroc in HIV-1-infected paediatric patients in clinical practice.

Maraviroc (MVC) is not approved for HIV-1-infected paediatric patients. This is the first assessment of the use of MVC-based salvage therapy in vertically HIV-1-infected paediatric patients in clinical settings. The results suggest that MVC-based salvage therapy is useful in children and adolescents with extensive resistance profile leading to maintained virological suppression in up to 88% of the patients with CCR5-tropic virus. The likelihood of treatment success might increase when MVC is combined with other active drugs.

ATPase-dependent control of the Mms21 SUMO ligase during DNA repair.

Modification of proteins by SUMO is essential for the maintenance of genome integrity. During DNA replication, the Mms21-branch of the SUMO pathway counteracts recombination intermediates at damaged replication forks, thus facilitating sister chromatid disjunction. The Mms21 SUMO ligase docks to the arm region of the Smc5 protein in the Smc5/6 complex; together, they cooperate during recombinational DNA repair. Yet how the activity of the SUMO ligase is controlled remains unknown. Here we show that the SUMO ligase and the chromosome disjunction functions of Mms21 depend on its docking to an intact and active Smc5/6 complex, indicating that the Smc5/6-Mms21 complex operates as a large SUMO ligase in vivo. In spite of the physical distance separating the E3 and the nucleotide-binding domains in Smc5/6, Mms21-dependent sumoylation requires binding of ATP to Smc5, a step that is part of the ligase mechanism that assists Ubc9 function. The communication is enabled by the presence of a conserved disruption in the coiled coil domain of Smc5, pointing to potential conformational changes for SUMO ligase activation. In accordance, scanning force microscopy of the Smc5-Mms21 heterodimer shows that the molecule is physically remodeled in an ATP-dependent manner. Our results demonstrate that the ATP-binding activity of the Smc5/6 complex is coordinated with its SUMO ligase, through the coiled coil domain of Smc5 and the physical remodeling of the molecule, to promote sumoylation and chromosome disjunction during DNA repair.

Infeccions de transmissió sexual en els adolescents / No disponible

No disponible

[Trends of HIV mother-to-child transmission in Catalonia, Spain, between 1987 and 2003]. / Evolución de la transmisión vertical del VIH en Cataluña durante el período 1987-2003.

BACKGROUND AND OBJECTIVE: To describe and to analyze the evolution of the mother-to-child transmission (MTCT) of the human immunodeficiency virus (HIV), the clinical and epidemiological characteristics and the use of antiretrovirals (ARV) in the HIV infected pregnant women and their new-borns alive between 1987 and 2003 in Catalonia. MATERIAL AND METHOD: The available clinical-epidemiological and treatment data were obtained from 4 reference hospitals that take care of most of the children born to HIV infected mothers in Catalonia. Two of the hospitals had a data base designed to the follow up of their patients, whereas in the other 2 data were gathered by reviewing clinical registries. For the analysis, 3 periods, based on the recommendations of treatment ARV during pregnancy, were settled down: 1987-1993; 1994-1996, and 1997-2003. RESULTS: 1,105 mother-infant pairs were studied. HIV MTCT was reduced from 20.4% to 3.5% from first to third period of study (p < 0.001). The median age of the mothers increased from 24.6 to 30.5 years of age (p < 0.001). The proportion of women infected by sexual transmission increased from 17.2% to 58.8% (p < 0.001), whereas that of parenteral transmission decreased from the 79.2% to 43.5% (p < 0.001). In the last period, 74.1% of mother-child pairs received complete ARV prophylaxis regimens and 21.6% partial ones. The rate of elective caesarean-section went up from 32.2% to 58.2% (p < 0.001). CONCLUSIONS: The rates of MTCT in our setting have followed the same trend as in other countries of our surroundings. The observed changes reflect the variations in the characteristics of the epidemic in the general population. The implementation of the recommendations on ARV prophylaxis has begun early and it has extended progressively without getting to be total. Additional strategies for the universal coverage of the screening test during pregnancy are still needed.

Evolución de la transmisión vertical del VIH en Cataluña durante el período 1987-2003 / Trends of HIV mother-to-child transmission in Catalonia, Spain, between 1987 and 2003

FUNDAMENTO Y OBJETIVO: Describir y analizar la evolución de la transmisión vertical (TV) del virusde la inmunodeficiencia humana (VIH), las características clinicoepidemiológicas y el uso deantirretrovirales (ARV) en las gestantes infectadas por el VIH y sus recién nacidos vivos entre1987 y 2003 en Cataluña.MATERIAL Y MÉTODO: Se obtuvieron los datos clinicoepidemiológicos y de tratamiento disponiblesde los 4 hospitales de referencia que más hijos de madres infectadas atienden en Cataluña.Dos de ellos disponían de una base de datos propia, diseñada para el seguimiento de sus pacientes,mientras que en los otros 2 los datos se recogieron mediante revisión de historias clínicas.Para el análisis se establecieron 3 períodos en función de las recomendaciones de tratamientoARV durante el embarazo: 1987-1993; 1994-1996, y 1997-2003.RESULTADOS: Se estudió a 1.105 parejas madres-hijo. La tasa de TV se redujo del 20,4 al 3,5% entreel primer y el tercer períodos de estudio (p < 0,001). La mediana de edad de las madres se incrementódesde los 24,6 a los 30,5 años (p < 0,001). La proporción de mujeres infectadas por transmisiónsexual pasó del 17,2 al 58,8% (p < 0,001), mientras que la de transmisión parenteral pasó del 79,2al 43,5% (p < 0,001). En el último período un 74,1% de parejas madre-hijo recibió profilaxis ARVcompleta y un 21,6% parcial. Las cesáreas programadas pasaron del 32,2 al 58,2% (p < 0,001).CONCLUSIONES: Las tasas de TV en nuestro medio han seguido la misma tendencia que en otrospaíses de nuestro entorno. Los cambios observados reflejan las variaciones en las característicasde la epidemia en la población general. La adopción de las recomendaciones de la profilaxisARV se ha iniciado con prontitud y se ha extendido progresivamente sin llegar a ser total. Sonaún necesarias estrategias para la universalización de la prueba de cribado durante el embarazo

BACKGROUND AND OBJECTIVE: To describe and to analyze the evolution of the mother-to-child transmission(MTCT) of the human immunodeficiency virus (HIV), the clinical and epidemiologicalcharacteristics and the use of antiretrovirals (ARV) in the HIV infected pregnant women andtheir new-borns alive between 1987 and 2003 in Catalonia.MATERIAL AND METHOD: The available clinical-epidemiological and treatment data were obtainedfrom 4 reference hospitals that take care of most of the children born to HIV infected mothersin Catalonia. Two of the hospitals had a data base designed to the follow up of their patients,whereas in the other 2 data were gathered by reviewing clinical registries. For the analysis, 3periods, based on the recommendations of treatment ARV during pregnancy, were settleddown: 1987-1993; 1994-1996, and 1997-2003.RESULTS: 1,105 mother-infant pairs were studied. HIV MTCT was reduced from 20.4% to 3.5%from first to third period of study (p < 0.001). The median age of the mothers increased from24.6 to 30.5 years of age (p < 0.001). The proportion of women infected by sexual transmissionincreased from 17.2% to 58.8% (p < 0.001), whereas that of parenteral transmission decreasedfrom the 79.2% to 43.5% (p < 0.001). In the last period, 74.1% of mother-child pairs receivedcomplete ARV prophylaxis regimens and 21.6% partial ones. The rate of elective caesarean-sectionwent up from 32.2% to 58.2% (p < 0.001).CONCLUSIONS: The rates of MTCT in our setting have followed the same trend as in other countriesof our surroundings. The observed changes reflect the variations in the characteristics of the epidemicin the general population. The implementation of the recommendations on ARV prophylaxishas begun early and it has extended progressively without getting to be total. Additional strategiesfor the universal coverage of the screening test during pregnancy are still needed