Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Ensayo preclínico de la vacuna candid #1 producida en Argentina contra la fiebre hemorrágica Argentina

Se comparó en cobayos la seguridad, inmunogenicidad y eficacia protectora de un lote de vacuna Candid #1(C#1) fabricada en Estados Unidos de América (EE.UU.) y distintos lotes de la misma vacuna fabricados en Argentina (Arg). El lote TSI 5-1-92 (EE.UU.) y los lotes Exp Nº 3, 7A y 8A (Arg) fueron inoculados (0.5 ml, IM) en cobayos de 250-400 g. Para cada ensayo diez animales recibieron solución fisiológica y sirvieron como control. Todos fueron desafiados con la cepa patógena P23790 de virus Junin. Se registró: a) temperatura rectal, b) peso corporal, c) presencia de anticuerpos neutralizantes (AcNT) pre y post-vacunación, d) respuesta al desafío. Todos los animales vacunados desarrollaron AcNT anti virus Junin (rango = 40- 81920 y sobrevivieron al desafío. En cada grupo control 8/10 animales murieron (día 23.3 ± 5.4 post-desafío). Los cobayos resultaron idénticamente protegidos de una descarga letal de virus Junin por la vacuna importada y los diferentes lotes de C#1 producidos en Argentina.Preclinical assay of Candid #1 vaccine against Argentine Hemorrhagic Fever made in Argentina. Candid #1 vaccine against Argentine Hemorrhagic Fever produced in USA versus lots of the same vaccine made in Argentina were compared in guinea pigs regarding safety, immunogenicity and protective efficacy against a challenge with pathogenic Junin virus. Lots Nº Exp 3, 7A and 8A of Argentine origin as well as lot TSI 5-1-92 from USA were inoculated in guinea pigs of 250-400 g in two consecutive assays. Ten animals inoculated with saline performed as normal controls in each experiment. Parameters studied were: a) temperature; b) body weight; c) neutralizing antibodies to Junin virus; d) response to viral challenge. Animals gained weight and remained normothermic up to the challenge. Guinea pigs that received Candid #1 from any manufacturer elicited neutralizing antibodies to Junin virus (titles from 40 to 81920) and survived to challenge whilst 8/10 animals died in each control group. Data presented demonstrated that Candid #1 vaccines from USA or Argentine manufacturers were equally safe, immunogenic and protective in guinea pigs.Fil: Ambrosio, Ana M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Saavedra, María del Carmen. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Riera, Laura M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Sottosanti, María J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina

Neutralization test for lymphocytic choriomeningitis virus for distinguishing between two arenavirus infections in Argentina

Fil: Ambrosio, Ana M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Riera, Laura. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Saavedra, María del Carmen. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Sottosanti, María J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.The active coexistence of two pathogenic arenaviruses, Junin (JUNV) and lymphocytic choriomeningitis (LCMV), in the same region of Argentina, has been known since the early 70's, and records of clinical and subclinical human infections by one and/or the other agent have been continuously produced for the last 25 years. Anti-LCMV antibody is currently searched only by indirect immunofluorescence, a test that shows cross reactions among a number of arenaviruses yielding, in the cases of LCMV and JUNV consecutive infections, a concomitant seroconversion for both viruses, as an inconclusive diagnostic result. In contrast, neutralization (NT) tests reveal arenavirus antibodies directed to unique epitopes on these virus envelopes, thus allowing to disclose the sequence in the cases of consecutive infections. In this paper, the characteristics of neutralization (NT) test for LCMV in cell cultures are described, as well as its performance in the field diagnosis of LCMV human infections. The native LCMV strain Cba An 13065 was inoculated on L-929 cell (ATCC CCL 1), and procedures were followed to perform a constant virus-variable serum NT test. Final points of sera titrations were expressed as the maximal serum dilution that yielded 75% of pfu inhibition. This NT test was assayed on paired serum samples of 36 patients with confirmed Argentine hemorrhagic fever (AHF) (a disease caused by JUNV), who had had a known previous contact with LCMV through IFI. The use of this one test led to confusing diagnosis of the disease due to concomitant seroconversion for JUNV and LCMV. By using NT test, it was shown that: some of them were possibly not infected by LCMV, and that 30/36 cases (83.3%) had a pre-existing level of LCMV antibody, with titers in the range of 5 to 640, remaining unchanged 60 days after the clinical AHF. This shows that NT antibodies to LCMV are not influenced by the outcome of the immune response to JUNV, thus confirming the efficiency of NT test as identificator among arenaviruses. To assess the performance of this NT test in individuals having only IFI antibodies to LCMV, 126 serum samples obtained through serological surveillance in a rural area of Argentina, were used. It was found that NT had improved coincidence with IFI as IFI titers increased. Interpretations were based on the pan-arenavirus antibody response obtained by using IFI as the only test. Results presented herein prove that the described NT test is a valuable tool for the detection of LCMV infections, particularly when a previous infection with LCMV has to be demonstrated during the acute phase of Argentine hemorrhagic fever

Neutralization test for lymphocytic choriomeningitis virus for distinguishing between two arenavirus infections in Argentina

Fil: Ambrosio, Ana M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Riera, Laura. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Saavedra, María del Carmen. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Sottosanti, María J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.The active coexistence of two pathogenic arenaviruses, Junin (JUNV) and lymphocytic choriomeningitis (LCMV), in the same region of Argentina, has been known since the early 70's, and records of clinical and subclinical human infections by one and/or the other agent have been continuously produced for the last 25 years. Anti-LCMV antibody is currently searched only by indirect immunofluorescence, a test that shows cross reactions among a number of arenaviruses yielding, in the cases of LCMV and JUNV consecutive infections, a concomitant seroconversion for both viruses, as an inconclusive diagnostic result. In contrast, neutralization (NT) tests reveal arenavirus antibodies directed to unique epitopes on these virus envelopes, thus allowing to disclose the sequence in the cases of consecutive infections. In this paper, the characteristics of neutralization (NT) test for LCMV in cell cultures are described, as well as its performance in the field diagnosis of LCMV human infections. The native LCMV strain Cba An 13065 was inoculated on L-929 cell (ATCC CCL 1), and procedures were followed to perform a constant virus-variable serum NT test. Final points of sera titrations were expressed as the maximal serum dilution that yielded 75% of pfu inhibition. This NT test was assayed on paired serum samples of 36 patients with confirmed Argentine hemorrhagic fever (AHF) (a disease caused by JUNV), who had had a known previous contact with LCMV through IFI. The use of this one test led to confusing diagnosis of the disease due to concomitant seroconversion for JUNV and LCMV. By using NT test, it was shown that: some of them were possibly not infected by LCMV, and that 30/36 cases (83.3%) had a pre-existing level of LCMV antibody, with titers in the range of 5 to 640, remaining unchanged 60 days after the clinical AHF. This shows that NT antibodies to LCMV are not influenced by the outcome of the immune response to JUNV, thus confirming the efficiency of NT test as identificator among arenaviruses. To assess the performance of this NT test in individuals having only IFI antibodies to LCMV, 126 serum samples obtained through serological surveillance in a rural area of Argentina, were used. It was found that NT had improved coincidence with IFI as IFI titers increased. Interpretations were based on the pan-arenavirus antibody response obtained by using IFI as the only test. Results presented herein prove that the described NT test is a valuable tool for the detection of LCMV infections, particularly when a previous infection with LCMV has to be demonstrated during the acute phase of Argentine hemorrhagic fever

Italian monitoring registries: a tool for a safer use of innovative drugs? Data from the national pharmacovigilance system

Our aim was to investigate the ADR reports of drugs with a monitoring registry (MR drugs), in particular those related to abuse/misuse, medication error, overdose, which might indicate an unsafe use. We compared these reports with those of similar drugs without a registry (non-MR drugs), thus verifying whether the registries could be useful tools for a safer use of innovative drugs

Ensayo preclínico de la vacuna candid #1 producida en Argentina contra la fiebre hemorrágica Argentina

Se comparó en cobayos la seguridad, inmunogenicidad y eficacia protectora de un lote de vacuna Candid #1(C#1) fabricada en Estados Unidos de América (EE.UU.) y distintos lotes de la misma vacuna fabricados en Argentina (Arg). El lote TSI 5-1-92 (EE.UU.) y los lotes Exp Nº 3, 7A y 8A (Arg) fueron inoculados (0.5 ml, IM) en cobayos de 250-400 g. Para cada ensayo diez animales recibieron solución fisiológica y sirvieron como control. Todos fueron desafiados con la cepa patógena P23790 de virus Junin. Se registró: a) temperatura rectal, b) peso corporal, c) presencia de anticuerpos neutralizantes (AcNT) pre y post-vacunación, d) respuesta al desafío. Todos los animales vacunados desarrollaron AcNT anti virus Junin (rango = 40- 81920 y sobrevivieron al desafío. En cada grupo control 8/10 animales murieron (día 23.3 ± 5.4 post-desafío). Los cobayos resultaron idénticamente protegidos de una descarga letal de virus Junin por la vacuna importada y los diferentes lotes de C#1 producidos en Argentina.Preclinical assay of Candid #1 vaccine against Argentine Hemorrhagic Fever made in Argentina. Candid #1 vaccine against Argentine Hemorrhagic Fever produced in USA versus lots of the same vaccine made in Argentina were compared in guinea pigs regarding safety, immunogenicity and protective efficacy against a challenge with pathogenic Junin virus. Lots Nº Exp 3, 7A and 8A of Argentine origin as well as lot TSI 5-1-92 from USA were inoculated in guinea pigs of 250-400 g in two consecutive assays. Ten animals inoculated with saline performed as normal controls in each experiment. Parameters studied were: a) temperature; b) body weight; c) neutralizing antibodies to Junin virus; d) response to viral challenge. Animals gained weight and remained normothermic up to the challenge. Guinea pigs that received Candid #1 from any manufacturer elicited neutralizing antibodies to Junin virus (titles from 40 to 81920) and survived to challenge whilst 8/10 animals died in each control group. Data presented demonstrated that Candid #1 vaccines from USA or Argentine manufacturers were equally safe, immunogenic and protective in guinea pigs.Fil: Ambrosio, Ana M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Saavedra, María del Carmen. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Riera, Laura M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Sottosanti, María J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina

IgG subclasses in human immune response to wild and attenuated (vaccine) Junin virus infection

Fil: Saavedra, María del Carmen. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Sottosanti, Josefa María. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Riera, Laura. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Fil: Ambrosio, Ana María. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina.Different proportions of IgG subclasses have previously been reported to distinguish the immune response elicited by primary and recurrent viral infections, as well as viral vaccines. The goal of this study was to study the IgG subclasses composition in the immune response of patients with Argentine hemorrhagic fever, and vaccinees with Candid #1 strain of Junin virus. Twenty-four individuals inoculated with Candid #1 vaccine and 67 patients with Argentine hemorrhagic fever were studied. Blood samples were drawn at 30, 60, and/or 180 days post-inoculation with Candid #1 and 30, 60, and 90 days after clinical onset of the disease. Specific anti-Junin virus IgG subclasses were titrated with specific human monoclonal antibody fluorescence isothiocyanate conjugate (FITC) by immunofluorescent assay (IFA). IgG(1) anti-Junin virus was found in every subject studied and IgG(3) was also detected in some patients with a severe form of Argentine hemorrhagic fever. IgG(2) and IgG(4) were not detected in any serum sample studied. The mean titer of specific IgG(1) in vaccinees was significantly lower than in patients with Argentine hemorrhagic fever (P 0.05). The results of this study demonstrated a central role of IgG(1) in human recovery from infection with every strain of Junin virus, an observation stressed by the immune response to Candid #1 vaccine, which resulted in no difference in IgG subclasses composition from that found in mild cases of Argentine hemorrhagic fever

Safety of Antiplatelet Agents: Analysis of ‘Real-World’ Data from the Italian National Pharmacovigilance Network

Introduction: According to the Italian National Report on drug use, thienopyridines (ticlopidine, clopidogrel and prasugrel) and ticagrelor represent the most prescribed antiplatelet agents, beside aspirin. The aim of this study was to analyse the safety profile of these drugs using data from spontaneous reporting of suspected adverse reactions (ADRs). Methods: Suspected ADRs for ticlopidine, clopidogrel, prasugrel and ticagrelor, reported on the Italian National Pharmacovigilance Network between January 2009 and December 2016, were included in the analysis. All suspected ADRs were classified by frequency, seriousness, outcome, age and system organ class. Results: Clopidogrel showed the highest absolute number of suspected ADRs, followed by ticlopidine. However, these data need to be contextualized in view of the differences in marketing authorization dates, prescription rates and a characterization of the relative seriousness of ADRs per each drug. After the correction for prescription rate, ticagrelor showed the highest reporting trend and ticlopidine the lowest. Most ADRs occurred in the elderly, in particular for ticlopidine. Bleeding represents one of the most reported events (ticlopidine 40%, clopidogrel 26%, prasugrel 42%, ticagrelor 30%) and aspirin was the most frequently associated suspected drug. The majority of ADRs had complete recovery and were non-serious, except for ticlopidine (serious ADRs 53%). Prasugrel showed the highest percentage of ‘life-threatening’ events and ‘death’. Conclusions: Based on the analysis conducted on spontaneous ADRs reporting system in Italy, the safety profile of antiplatelet drugs seems favourable. However, the overall risk-benefit ratio of these drugs needs to be reassessed taking into account the appropriateness of use in particular populations at risk, such as the elderly. Based on this information, we believe that more attention from clinicians and/or an implementation of regulatory measures could be useful for clinical practice

Ibuprofen-associated hypothermia in children: analysis of the Italian spontaneous reporting database

Purpose: An analysis of Italian spontaneous adverse drug reactions (ADR) reporting database highlighted a potential association between hypothermia and ibuprofen in children. Hypothermia is defined as a core body temperature of 35\ua0\ub0C (95\ua0\ub0F). Ibuprofen is the most prescribed NSAID for the treatment of fever and moderate pain in children. We aimed to analyze the cases of ibuprofen-associated hypothermia retrieved in the Italian database in order to contribute to the discussion on this potential association. Methods: We extracted all suspected cases of ibuprofen-associated hypothermia from the Italian spontaneous reporting database and from VigiBase up to December 2015. We considered the proportional reporting ratio (PRR) as a measure of disproportionality for the Italian cases and the information component (IC) for the reports from VigiBase. We performed a case-by-case analysis to exclude duplicates. Results: Nineteen cases of hypothermia associated with ibuprofen use were retrieved from the Italian spontaneous reporting database (PRR 19.8, CI 95\ua0%, 12.0\u201332.9). The reports concerned ten females and nine males with an average age of 2.5\ua0years. Up to 31 December 2015, 168 cases of hypothermia associated with ibuprofen were reported to VigiBase, with an IC of 2.05 (IC025, 1.82). Among these, 126 cases involved children (49\ua0% males) with an average age of 4.4\ua0years. Conclusions: Although the risk of this ADR is unknown so far, the widespread use of this drug recommends the need for further studies to better characterize this possible association. Clinicians and pharmacists but also parents should be aware that this risk is theoretical as not yet been confirmed

Isolation of lymphocytic choriomeningitis virus from human individuals

Fil: Saavedra, Maria del Carmen. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Ambrosio, Ana M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Riera, Laura. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Levis, Silvana. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Sottosanti, Josefa. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Sabattini, Marta. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Los antecedentes del virus de la coriomeningitis linfocitaria (vLCM) en Argentina se basan en la detección de anticuerpos en roedores y seres humanos y en el aislamiento de sólo una cepa viral a partir de un roedor Mus domesticusen el sur de la provincia de Córdoba. El objetivo de este trabajo fue registrar los casos diagnosticados por serología como LCM y realizar el aislamiento y tipificación de cepas humanas del vLCM en Argentina. Durante los últimos 19 años se diagnosticaron por inmunofluorescencia indirecta (IFI) y/o enzimoinmunoensayo (ELISA) 15 casos de LCM y, al incorporar la prueba de neutralización (NT), éstos fueron clasificados como ocho confirmados, tres probables y cuatro negativos. La distribución geográfica de los casos abarcó tres provincias: Córdoba, Bs.As. y Santa Fe. El aislamiento viral se intentó en cinco pacientes clasificados como confirmados, resultando dos aislamientos positivos (P5226 y P8573), que fueron identificados como vLCM por IFI y NT. La importancia del aislamiento de cepas de vLCM en esta zona, radica en que su coexistencia con otros arenavirus, como los virus Junin y Oliveros podría generar modificaciones en la virulencia y/o patogenicidad para humanos asociada a cambios genómicos. Futuros estudios de la variabilidad antigénica, genómica y de virulencia de las cepas de vLCM de la Argentina así como también la búsqueda sistemática de la infección humana, contribuirán a conocer la importancia de este agente viral en nuestro país y derivar en medidas de control