Genetic diversification patterns in swine influenza A virus (H1N2) in vaccinated and nonvaccinated animals.

Influenza A viruses (IAVs) are characterized by having a segmented genome, low proofreading polymerases, and a wide host range. Consequently, IAVs are constantly evolving in nature causing a threat to animal and human health. In 2009 a new human pandemic IAV strain arose in Mexico because of a reassortment between two strains previously circulating in pigs; Eurasian "avian-like" (EA) swine H1N1 and "human-like" H1N2, highlighting the importance of swine as adaptation host of avian to human IAVs. Nowadays, although of limited use, a trivalent vaccine, which include in its formulation H1N1, H3N2, and, H1N2 swine IAV (SIAV) subtypes, is one of the most applied strategies to reduce SIAV circulation in farms. Protection provided by vaccines is not complete, allowing virus circulation, potentially favoring viral evolution. The evolutionary dynamics of SIAV quasispecies were studied in samples collected at different times from 8 vaccinated and 8 nonvaccinated pigs, challenged with H1N2 SIAV. In total, 32 SIAV genomes were sequenced by next-generation sequencing, and subsequent variant-calling genomic analysis was carried out. Herein, a total of 364 de novo single nucleotide variants (SNV) were found along all genetic segments in both experimental groups. The nonsynonymous substitutions proportion found was greater in vaccinated animals suggesting that H1N2 SIAV was under positive selection in this scenario. The impact of each substitution with an allele frequency greater than 5% was hypothesized according to previous literature, particularly in the surface glycoproteins hemagglutinin and neuraminidase. The H1N2 SIAV quasispecies evolution capacity was evidenced, observing different evolutionary trends in vaccinated and nonvaccinated animals.

Vaccination against swine influenza in pigs causes different drift evolutionary patterns upon swine influenza virus experimental infection and reduces the likelihood of genomic reassortments.

Influenza A viruses (IAVs) can infect a wide variety of bird and mammal species. Their genome is characterized by 8 RNA single stranded segments. The low proofreading activity of their polymerases and the genomic reassortment between different IAVs subtypes allow them to continuously evolve, constituting a constant threat to human and animal health. In 2009, a pandemic of an IAV highlighted the importance of the swine host in IAVs adaptation between humans and birds. The swine population and the incidence of swine IAV is constantly growing. In previous studies, despite vaccination, swine IAV growth and evolution were proven in vaccinated and challenged animals. However, how vaccination can drive the evolutionary dynamics of swine IAV after coinfection with two subtypes is poorly studied. In the present study, vaccinated and nonvaccinated pigs were challenged by direct contact with H1N1 and H3N2 independent swine IAVs seeder pigs. Nasal swab samples were daily recovered and broncho-alveolar lavage fluid (BALF) was also collected at necropsy day from each pig for swine IAV detection and whole genome sequencing. In total, 39 swine IAV whole genome sequences were obtained by next generation sequencing from samples collected from both experimental groups. Subsequently, genomic, and evolutionary analyses were carried out to detect both, genomic reassortments and single nucleotide variants (SNV). Regarding the segments found per sample, the simultaneous presence of segments from both subtypes was much lower in vaccinated animals, indicating that the vaccine reduced the likelihood of genomic reassortment events. In relation to swine IAV intra-host diversity, a total of 239 and 74 SNV were detected within H1N1 and H3N2 subtypes, respectively. Different proportions of synonymous and nonsynonymous substitutions were found, indicating that vaccine may be influencing the main mechanism that shape swine IAV evolution, detecting natural, neutral, and purifying selection in the different analyzed scenarios. SNV were detected along the whole swine IAV genome with important nonsynonymous substitutions on polymerases, surface glycoproteins and nonstructural proteins, which may have an impact on virus replication, immune system escaping and virulence of virus, respectively. The present study further emphasized the vast evolutionary capacity of swine IAV, under natural infection and vaccination pressure scenarios.

The role of opioid transmission in music-induced pleasure.

Studies conducted in rodents indicate a crucial role of the opioid circuit in mediating objective hedonic reactions to primary rewards. However, it remains unclear whether opioid transmission is also essential to experience pleasure with more abstract rewards, such as music. We addressed this question using a double-blind within-subject pharmacological design in which opioid levels were up- and downregulated by administering an opioid agonist (oxycodone) and antagonist (naltrexone), respectively, before healthy participants (n = 21) listened to music. Participants also performed a monetary incentive delay (MID) task to control for the effectiveness of the treatment and the specificity of the effects. Our results revealed that the pharmacological intervention did not modulate subjective reports of pleasure, nor the occurrence of chills. On the contrary, psychophysiological (objective) measures of emotional arousal, such as skin conductance responses (SCRs), were bidirectionally modulated in both the music and MID tasks. This modulation specifically occurred during reward consumption, with greater pleasure-related SCR following oxycodone than naltrexone. These findings indicate that opioid transmission does not modulate subjective evaluations but rather affects objective reward-related psychophysiological responses. These findings raise new caveats about the role of the opioidergic system in the modulation of pleasure for more abstract or cognitive forms of rewarding experiences, such as music.

Effect of Load Spatial Configuration on the Heating of Chicken Meat Assisted by Radio Frequency at 40.68 MHz.

Food heating assisted by radio frequencies has been industrially applied to post-harvest treatment of grains, legumes and various kind of nuts, to tempering and thawing of meat and fish products and to post-baking of biscuits. The design of food processes based on the application of radiofrequencies was often based on rules of thumb, so much so that their intensification could lead significant improvements. One of the subjects under consideration is the shape of the food items that may influence their heating assisted by radiofrequency. In this work, a joint experimental and numerical study on the effects of the spatial configuration of a food sample (chicken meat shaped as a parallelepiped) on the heating pattern in a custom RF oven (40.68 MHz, 50 Ohm, 10 cm electrodes gap, 300 W) is presented. Minced chicken breast samples were shaped as cubes (4 × 4 × 4 cm3) to be organized in different loads and spatial configurations (horizontal or vertical arrays of 2 to 16 cubes). The samples were heated at two radiofrequency operative power levels (225 W and 300 W). Heating rate, temperature uniformity and heating efficiency were determined during each run. A digital twin of the experimental system and process was developed by building and numerically solving a 3D transient mathematical model, taking into account electromagnetic field distribution in air and samples and heat transfer in the food samples. Once validated, the digital tool was used to analyze the heating behavior of the samples, focusing on the most efficient configurations. Both experiments and simulations showed that, given a fixed gap between the electrodes (10 cm), the vertically oriented samples exhibited a larger heating efficiency with respect to the horizontally oriented ones, pointing out that the gap between the top electrode and the samples plays a major role in the heating efficiency. The efficiency was larger (double or even more; >40% vs. 10−15%) in thicker samples (built with two layers of cubes), closer to the top electrode, independently from nominal power. Nevertheless, temperature uniformity in vertical configurations was poorer (6−7 °C) than in horizontal ones (3 °C).

COVID-19 epidemiological surveillance through pool testing focused on asymptomatic healthcare workers in the city of Bahía Blanca / Vigilancia epidemiológica de covid-19 mediante testeos agrupados focalizada en trabajadores de salud asintomáticos en bahía blanca

RESUMEN INTRODUCCIÓN: Uno de los desafíos más relevantes al comienzo de la pandemia consistió en implementar estrategias dirigidas a prevenir la transmisión del virus SARS-CoV-2 y mitigar el impacto de la COVID-19. El propósito de este estudio fue contribuir a reducir la transmisión comunitaria a través de una iniciativa interinstitucional, cuyos objetivos fueron validar un método de detección de ARN del SARS-CoV-2 e implementar y evaluar la vigilancia en trabajadores de salud asintomáticos de instituciones de salud pública de Bahía Blanca. MÉTODOS: Se validó una prueba de detección del gen E del coronavirus mediante RT-PCR a partir de ARN aislado de hisopados nasofaríngeos. Para aumentar la capacidad de testeo se validó la detección del ARN viral en muestras agrupadas (pooles). Se realizó un estudio de cohorte prospectiva entre el 15/09/20 y el 15/09/21. RESULTADOS: La sensibilidad y especificidad de la prueba en muestras individuales fue del 95% (IC 95%: 85%-100%). La sensibilidad de la detección en pooles fue del 73% (IC 95%: 46%-99%) y la especificidad, del 100%. A lo largo de la vigilancia se incluyeron 855 trabajadores y 1764 hisopados, con una incidencia acumulada anual de 2,3% (IC 95%: 1,2%-3,4%). Se detectaron 20 casos asintomáticos positivos. DISCUSIÓN: El tamizaje de trabajadores de salud asintomáticos en la pandemia contribuyó a reducir el riesgo de brotes hospitalarios. Asimismo, se generó un marco de trabajo interdisciplinario aplicable a otros problemas de salud.

ABSTRACT INTRODUCTION: One of the most important challenges at the beginning of the pandemic was to implement strategies to prevent SARS-CoV-2 virus transmission and reduce the impact of COVID-19. The purpose of this study was to contribute to the reduction of community transmission through an interinstitutional initiative, aimed at validating a SARS-CoV-2 RNA detection method, and at implementing and assessing the surveillance of asymptomatic infected healthcare workers (HCWs) at public health institutions in the city of Bahía Blanca. METHODS: To validate a coronavirus RNA detection method, RNA was extracted from nasopharyngeal swabs and identification of the viral E gene was done by RT-PCR. Validation of sample pooling was performed to increase the testing capacity. A prospective cohort study was conducted from 15 September 2020 to 15 September 2021. RESULTS: The sensitivity and specificity of the test in individual samples was 95% (CI 95%: 85%-100%). The sensitivity of the pooling strategy was 73% (CI 95%: 46%-99%) and the specificity was 100%. A total of the 855 HCWs were included in the surveillance and 1764 swabs were performed, with an annual cumulative incidence of 2.3% (CI 95%: 1,2%-3,4%), and 20 positive asymptomatic cases were detected. DISCUSSION: The screening of asymptomatic HCWs during the pandemic contributed to reduce the risk of outbreaks in hospital settings. Moreover, an interdisciplinary team framework applicable to other health problems was generated.

Vigilancia epidemiológica de COVID-19 mediante testeos agrupados focalizada en trabajadores de salud asintomáticos en Bahía Blanca / Epidemiological surveillance of COVID-19 through group testing focused on asymptomatic health workers in Bahía Blanca

INTRODUCCIÓN: Uno de los desafíos más relevantes al comienzo de la pandemia consistió en implementar estrategias dirigidas a prevenir la transmisión del virus SARS-CoV-2 y mitigar el impacto de la COVID-19. El propósito de este estudio fue contribuir a reducir la transmisión comunitaria a través de una iniciativa interinstitucional, cuyos objetivos fueron validar un método de detección de ARN del SARS-CoV-2 e implementar y evaluar la vigilancia en trabajadores de salud asintomáticos de instituciones de salud pública de Bahía Blanca. MÉTODOS: Se validó una prueba de detección del gen E del coronavirus mediante RT-PCR a partir de ARN aislado de hisopados nasofaríngeos. Para aumentar la capacidad de testeo se validó la detección del ARN viral en muestras agrupadas (pooles). Se realizó un estudio de cohorte prospectiva entre el 15/09/20 y el 15/09/21. RESULTADOS: La sensibilidad y especificidad de la prueba en muestras individuales fue del 95% (IC 95%: 85%-100%). La sensibilidad de la detección en pooles fue del 73% (IC 95%: 46%-99%) y la especificidad, del 100%. A lo largo de la vigilancia se incluyeron 855 trabajadores y 1764 hisopados, con una incidencia acumulada anual de 2,3% (IC 95%: 1,2%-3,4%). Se detectaron 20 casos asintomáticos positivos. DISCUSIÓN: El tamizaje de trabajadores de salud asintomáticos en la pandemia contribuyó a reducir el riesgo de brotes hospitalarios. Asimismo, se generó un marco de trabajo interdisciplinario aplicable a otros problemas de salud.

Population Pharmacokinetics of Intra-articular and Intravenous Administration of Tranexamic Acid in Patients Undergoing Total Knee Replacement.

BACKGROUND: Tranexamic acid (TXA), an antifibrinolytic drug, is usually administered intravenously; however, intra-articular administration has recently been proven to be as effective as intravenous administration. Limited information regarding the pharmacokinetics (PK) of TXA after intra-articular administration has been reported. AIMS: The aim of this study was to develop a population PK model of TXA administered as a single intra-articular dose and as two intravenous doses, and to study the sources of interindividual variability (IIV) in the PK processes of TXA. The developed model was used to simulate PK profiles of TXA at different dosage regimens and in patients with renal impairment. METHODS: Patients who underwent primary unilateral total knee replacement (TKR) received 1 g/10 mL (concentration of 100 mg/mL) of TXA applied directly to the surgical field before wound closure, or 2 g (two doses of 1 g) of intravenous TXA. A population PK model was developed using a nonlinear mixed-effects approach and sources of IIV, such as sex, age, body weight, height, body mass index (BMI), preoperative haemoglobin, preoperative haematocrit, and creatinine clearance. RESULTS: Twenty-four patients were included, 12 in each group. Twenty patients were female, mean age (standard deviation) was 73.7 years (5.6). The disposition of TXA was best described as a two-compartment model with clearance dependent on creatinine clearance. Bootstrap results indicated that the model was stable and robust. The estimated bioavailability for intra-articular administration was 81%. Simulations indicated that 100% of patients would have plasma concentrations associated with partial fibrinolysis at 8 h post-administration with the dosages and routes of administration used in the present study. Intra-articular administration would produce complete inhibition of fibrinolysis in only 12% of patients compared with 72.5% with intravenous administration. No adverse events were reported. CONCLUSIONS: This population PK model demonstrated that a single dose of high-concentration, low-volume intra-articular TXA can achieve antifibrinolytic plasma concentrations of the drug for 8 h, providing both local and systemic effects in patients undergoing TKR. TXA administration to the surgical field could be an alternative to the intravenous; route for patients undergoing TKR; however, clinical studies are needed to assess the toxic local effects of TXA. TRIAL REGISTRATION: Spanish Clinical Studies Registry Number: 2017-004059-22. Date of registration: 12 April 2018.

The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A.

BACKGROUND: The mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist. METHODS: Changes in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects following the acute administration of salvinorin-A are reported. The study included 2 sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design. RESULTS: The electroencephalography measures showed a marked increase in delta and gamma waves and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding single-photon emission computed tomography measures, significant decreases in regional cerebral blood flow were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant regional cerebral blood flow increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs but with an evidently dissociative nature. No dysphoric effects were reported. CONCLUSION: The salvinorin-A-mediated KOR agonism induced dramatic psychotomimetic effects along with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex.

Dopamine modulations of reward-driven music memory consolidation.

Music listening provides one of the most significant abstract rewards for humans because hearing music activates the dopaminergic mesolimbic system. Given the strong link between reward, dopamine, and memory, we aimed here to investigate the hypothesis that dopamine-dependent musical reward can drive memory improvements. Twenty-nine healthy participants of both sexes provided reward ratings of unfamiliar musical excerpts that had to be remembered following a consolidation period under three separate conditions: after the ingestion of a dopaminergic antagonist, a dopaminergic precursor, or a placebo. Linear mixed modeling of the intervention data showed that the effect of reward on memory-i.e., the greater the reward experienced while listening to the musical excerpts, the better the memory recollection performance-was modulated by both dopaminergic signaling and individual differences in reward processing. Greater pleasure was consistently associated with better memory outcomes in participants with high sensitivity to musical reward, but this effect was lost when dopaminergic signaling was disrupted in participants with average or low musical hedonia. Our work highlights the flexibility of the human dopaminergic system, which can enhance memory formation not only through explicit and/or primary reinforcers but also via abstract and aesthetic rewards such as music.

Rupatadine Oral Solution Titration by Body Weight in Paediatric Patients Suffering from Allergic Rhinitis: A Population Pharmacokinetic Study.

BACKGROUND: Allergic rhinitis (AR) and chronic urticaria, both are treated in children with doses of second generation of antihistamines that have been mostly based on extrapolation of data obtained in adults. The objectives of this work were to develop a model to explain the pharmacokinetics (PK) of rupatadine, a second generation antihistamine, administered to children 2-11 years old and to calculate the non-compartmental PK parameters for two groups of age (2-5 and 6-11 years old) based on the individual Bayesian estimates from the selected model. METHODS: Data from two PK studies with rupatadine oral solution (1 mg/mL) were pooled: Study A, an extensive blood sampling study performed in 11 children (6-11 years old) who received a single oral dose of rupatadine; and Study B, a sparse blood sampling study in 40 children (2-5 years old) receiving multiple oral doses. A simultaneous population PK model was developed using data available for all children. Using individual Bayesian estimates from the selected model, steady-state plasma concentrations for both studies were simulated and the non-parametric PK parameters were calculated for two age groups: 2-5 years (subgroup I) and 6-11 years (subgroup II). RESULTS: A two-compartment model with first-order absorption and elimination with clearance depending on body weight, better described the PK of rupatadine for 2-11 year old children. The plasma clearance dependence on weight was linear. The mean (SD) non-compartment PK parameters calculated using simulated plasma profiles at steady state were: Cmax, 2.54 (1.26) vs 1.96 (0.52) ng/mL; AUC0-24h, 10.74 (3.09) vs 10.38 (4.31) ng/mL/h; and t1/2, 12.28 (3.09) vs 15.94 (4.09) h, for children 6-11 and 2-5 years old, respectively. CONCLUSIONS: The PK of rupatadine depends on the weight of paediatric patients but not on their age. The dosage strategy adjusted by body weight in children 2-11 years old (2.5 mL if weight 10-25 kg, and 5 mL if ≥ 25 kg) provides similar exposure between the two groups of age, and to that obtained in adults with the 10 mg dose tablet formulation.

C677T and A1298C MTHFR gene polymorphisms and response to fluoropyrimidine-based chemotherapy in Mestizo patients with metastatic colorectal cancer.

OBJECTIVE: To assess the association between C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and response to first-line fluoropyrimidine-based chemotherapy for metastatic colorectal adenocarcinoma. METHODS: A total of 68 patients were prospectively followed up in San Juan de Dios Hospital (San José, Costa Rica) from January 2019 to November 2020. Patients received first-line therapy with capecitabine or 5-fluorouracil in combination with oxaliplatin or irinotecan. Germline and somatic DNA was extracted from blood samples and paraffin-embedded tissue, respectively. Overall response rate (partial response + complete response) was assessed according to RECIST 1.1 criteria. Cox regression models were performed to identify the effect of MTHFR C677T and A1298C SNPs on progression-free survival (PFS) and overall survival (OS) (NCT registration number: 03852290). RESULTS: Patients harboring one or both T alleles of the MTHFR C677T SNP had better overall response than homozygous wild-type individuals [odds ratio (OR): 3.21; 95% confidence interval (CI), 1.05-9.81; P = 0.03]. No association was found between the MTHFR A1298C genotypes and overall response (OR: 0.75; 95% CI, 0.26-2.20; P = 0.60). Patients with the MTHFR 677 TT and CT genotypes had longer PFS than CC individuals (hazard ratio: 0.53; 95% CI, 0.28-0.98; P = 0.045), even after adjustment for confounders (hazard ratio: 0.50; 95% CI, 0.25-0.98; P = 0.04). We found no association between the MTHFR A1298C SNP and PFS (hazard ratio: 1.35; 95% CI, 0.72-2.55; P = 0.34). None of the SNPs was associated with OS. CONCLUSION: Patients carrying at least one mutant allele of the MTHFR C677T SNP had a better overall response and longer PFS than wild-type homozygous patients.

Variabilidad regional en incidencia, características generales y resultados finales de la parada cardiaca extrahospitalaria en España: Registro OHSCAR / Regional variation in the incidence, general characteristics, and outcomes of prehospital cardiac arrest in Spain: the Out-of-Hospital Spanish Cardiac Arrest Registry

OBJETIVOS: Existe gran variabilidad internacional en la incidencia y los resultados en la atención a la parada cardiaca extrahospitalaria (PCRE). El objetivo es conocer si existe variabilidad en la incidencia, características y resultados en supervivencia en la atención a la PCRE por los servicios extrahospitalarios de emergencias (SEM) de España. MÉTODO: Análisis descriptivo, retrospectivo de los datos del registro OHSCAR correspondientes al periodo octubre2013-octubre 2014, que incluye pacientes atendidos por 19 SEM de España con intento de reanimación. Se recogieron los casos atendidos y variables clave sobre la asistencia a una PCRE: incidencia, características del paciente, del evento, de la actuación previa a los equipos de emergencias (EE), de la reanimación realizada, y de los principales tratamientos hospitalarios. Se comparó la situación neurológica al alta hospitalaria de los casos con ingreso hospitalario. RESULTADOS: La incidencia de casos con intento de reanimación y todas las características generales, salvo la distribución por sexo, presentaron diferencias estadísticamente significativas entre los SEM participantes (p < 0,001). Hubo diferencias significativas en los tratamientos hospitalarios recibidos y en los resultados finales, tanto en la proporción de pacientes que llegaron con pulso espontáneo al hospital, 30,5%, rango entre 21,3% y 56,1% (p < 0,001), como en el porcentaje de altas hospitalaria con categoría 1 o 2 de la clasificación Cerebral Perfomance Categories (CPC), sobre el total de ingresados, 31,8%, rango entre 17,2% y 58,3% (p < 0,001). CONCLUSIONES: Existe una importante variabilidad entre los SEM españoles en la incidencia de casos con intento de reanimación, en todas las variables clave y en la supervivencia al alta hospitalaria de la atención a la PCRE

BACKGROUND AND OBJECTIVE: The incidence and outcomes of care for out-of-hospital cardiac arrest (OHCA) vary greatly from country to country. We aimed to study variation in the incidence, characteristics, and outcomes of care for OHCAs given by Spanish prehospital emergency services. METHODS: Descriptive retrospective analysis of data from the Out-of-Hospital Spanish Cardiac Arrest Registry (OHSCAR) from October 2013 to October 2014. Attempts by 19 Spanish emergency services to resuscitate patients were studied. All OHCA cases were reviewed to obtain the following data: incidence, patient and event characteristics, prior emergencies, resuscitation attempts, and the main treatments provided in the hospital. If a patient was admitted, we compared the neurologic status on hospital discharge. RESULTS: Statistically significant differences were detected between emergency services (P< .0001) in the incidence of attempted resuscitation and all general characteristics except sex. Hospital treatments and outcomes also differed significantly: pulse had been restored on arrival of 30.5% of patients (range 21.3% to 56.1%, P< .001), and 31.8% of admitted patients were discharged in cerebral performance categories 1 or 2 (range 17.2% to58.3%,P< .001). CONCLUSION: Differences in the incidence of resuscitation attempts, key variables, and survival at discharge from the hospital are present in OHCA cases attended by prehospital emergency services in different regions of Spain

Regional variation in the incidence, general characteristics, and outcomes of prehospital cardiac arrest in Spain: the Out-of-Hospital Spanish Cardiac Arrest Registry. / Variabilidad regional en incidencia, características generales y resultados finales de la parada cardiaca extrahospitalaria en España: Registro OHSCAR.

OBJECTIVES: The incidence and outcomes of care for out-of-hospital cardiac arrest (OHCA) vary greatly from country to country. We aimed to study variation in the incidence, characteristics, and outcomes of care for OHCAs given by Spanish prehospital emergency services. MATERIAL AND METHODS: Descriptive retrospective analysis of data from the Out-of-Hospital Spanish Cardiac Arrest Registry (OHSCAR) from October 2013 to October 2014. Attempts by 19 Spanish emergency services to resuscitate patients were studied. All OHCA cases were reviewed to obtain the following data: incidence, patient and event characteristics, prior emergencies, resuscitation attempts, and the main treatments provided in the hospital. If a patient was admitted, we compared the neurologic status on hospital discharge. RESULTS: Statistically significant differences were detected between emergency services (P .0001) in the incidence of attempted resuscitation and all general characteristics except sex. Hospital treatments and outcomes also differed significantly: pulse had been restored on arrival of 30.5% of patients (range 21.3% to 56.1%, P .001), and 31.8% of admitted patients were discharged in cerebral performance categories 1 or 2 (range 17.2% to 58.3%, P .001). CONCLUSION: Differences in the incidence of resuscitation attempts, key variables, and survival at discharge from the hospital are present in OHCA cases attended by prehospital emergency services in different regions of Spain.

OBJETIVO: Existe gran variabilidad internacional en la incidencia y los resultados en la atención a la parada cardiaca extrahospitalaria (PCRE). El objetivo es conocer si existe variabilidad en la incidencia, características y resultados en supervivencia en la atención a la PCRE por los servicios extrahospitalarios de emergencias (SEM) de España. METODO: Análisis descriptivo, retrospectivo de los datos del registro OHSCAR correspondientes al periodo octubre 2013-octubre 2014, que incluye pacientes atendidos por 19 SEM de España con intento de reanimación. Se recogieron los casos atendidos y variables clave sobre la asistencia a una PCRE: incidencia, características del paciente, del evento, de la actuación previa a los equipos de emergencias (EE), de la reanimación realizada, y de los principales tratamientos hospitalarios. Se comparó la situación neurológica al alta hospitalaria de los casos con ingreso hospitalario. RESULTADOS: La incidencia de casos con intento de reanimación y todas las características generales, salvo la distribución por sexo, presentaron diferencias estadísticamente significativas entre los SEM participantes (p 0,001). Hubo diferencias significativas en los tratamientos hospitalarios recibidos y en los resultados finales, tanto en la proporción de pacientes que llegaron con pulso espontáneo al hospital, 30,5%, rango entre 21,3% y 56,1% (p 0,001), como en el porcentaje de altas hospitalaria con categoría 1 o 2 de la clasificación Cerebral Perfomance Categories (CPC), sobre el total de ingresados, 31,8%, rango entre 17,2% y 58,3% (p 0,001). CONCLUSIONES: Existe una importante variabilidad entre los SEM españoles en la incidencia de casos con intento de reanimación, en todas las variables clave y en la supervivencia al alta hospitalaria de la atención a la PCRE.

Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV.

BACKGROUND: People living with human immunodeficiency virus are ageing under combination antiretroviral treatments but data on drug exposure in serum and cerebrospinal fluid are limited. Dolutegravir is a widely used second-generation integrase strand transfer inhibitor: conflicting data suggest that neuropsychiatric side effects may present at a higher frequency in patients with higher dolutegravir serum concentrations. METHODS: We performed a retrospective analysis of our therapeutic drug monitoring registry identifying patients receiving once-daily dolutegravir without concomitant interacting drugs and significant clinical conditions. Data were analysed stratifying time after drug dose intake (maximum concentration 0.5-4 and trough concentration 21-27 h). Cerebrospinal fluid samples from patients enrolled in neurological studies and receiving dolutegravir were analysed for dolutegravir cerebrospinal fluid concentrations and cerebrospinal fluid-to-plasma ratios. Serum and cerebrospinal fluid concentrations were measured through validated chromatographic methods. RESULTS: We included 207 (providing 457 serum samples) and 41 patients (providing 41 cerebrospinal fluid samples). Participants were mostly male (68.2-72.8%) of median age of 50 years (50-53 years). Non-significant changes in dolutegravir maximum concentration and trough concentration were observed with age at Spearman's test (p values > 0.05); linear logistic regression showed a significant effect of age on dolutegravir trough concentration (p = 0.0013) (Fig. 1). Dolutegravir maximum concentration [3830 ng/mL (2311-5057) vs 4230 ng/mL (2919-5272), p = 0.311] and trough concentration [838 ng/mL (362-1587) vs 966 ng/mL (460-2085), p = 0.056] were non-significantly or borderline higher in patients aged > 50 years. Cerebrospinal dolutegravir concentrations were associated with plasma concentrations (ρ = 0.374, p = 0.016) and age (ρ = 0.537, p = 0.003); cerebrospinal fluid dolutegravir concentrations (13.8 vs 7.3 ng/mL, p = 0.015) and cerebrospinal fluid-to-plasma ratios (0.57 vs 0.32%, p = 0.017] were higher in participants aged > 50 years. CONCLUSIONS: We observed an increase in dolutegravir exposure in serum and in cerebrospinal fluid in older patients living with human immunodeficiency virus.

Pharmacokinetic/pharmacodynamic analysis of romidepsin used as an HIV latency reversing agent.

OBJECTIVES: To develop a population pharmacokinetic model for romidepsin given as an HIV latency reversing agent (LRA) and to explore the relationship between romidepsin exposure and its in vivo effects on viral gene expression and antiviral immunity. METHODS: A population pharmacokinetic analysis was performed in 15 HIV-1-infected patients who received three weekly infusions of romidepsin (5 mg/m2) within the BCN02 clinical trial. A full pharmacokinetic profile was obtained for each participant at the first dose, and additional samples thereafter. A population pharmacokinetic model was developed. Bayesian estimates of the individual pharmacokinetic parameters of romidepsin were used to simulate individual time-concentration curves on each occasion. The relationship between romidepsin AUC0-∞ and its in vivo effects was assessed. RESULTS: Romidepsin pharmacokinetics were best described by a three-compartment model with linear kinetics. Body weight influenced romidepsin disposition. A significant relationship was observed between romidepsin AUC0-∞ and increases in expression of exhaustion markers by CD4+ and CD8+ T cells and apoptosis markers in CD4+, but not with histone acetylation levels or HIV-1 cell-associated RNA in CD4+ T cells. For each increase of 100 ng·h/mL in romidepsin AUC0-∞, CD4+ counts decreased by a mean (95% CI) of 74 (42-94) cells/mm3 after dosing. CONCLUSIONS: A population model describing the pharmacokinetics of romidepsin as an HIV LRA was developed. Higher exposure to romidepsin resulted in higher expression of apoptosis markers and declines in CD4+ count but did not increase viral reactivation levels. These observations have important implications for the optimization of effective kick-and-kill strategies for an HIV-1 cure.

Morbimortalidad asociada a la disfagia en pacientes ingresados en un hospital general universitario

RESUMEN Introducción: La disfagia tiene una morbimortalidad importante en pacientes hospitalizados. Objetivos: principal; describir las características de los pacientes con disfagia hospitalizados y, secundarios; cuantificar y analizar la prevalencia de mortalidad y de reingresos. Metodología: Estudio transversal descriptivo de las hospitalizaciones por disfagia durante el año 2015 en un Hospital General Universitario. Resultados: Se evaluaron 431 historias clínicas. La edad de los pacientes fue de 83,21 (DE 11,4) años, el 52,5% fueron mujeres y el 47,2% varones; la estancia media fue de 11,1 (DE 7,99) días. En el 71,2 % de los casos la disfagia fue por afectación de la fase orofaríngea. En el 80,51% de los casos se diagnosticaron complicaciones respiratorias: 48,12% neumonía aspirativa por líquidos, 40,05 % neumonitis química por aspiración y 11,81% neumonía aspirativa por sólidos. La mortalidad general asociada a las complicaciones respiratorias respecto del total de los casos de disfagia fue del 24,49%. El 50,48% de los pacientes con neumonía aspirativa fallecieron. La principal causa de la disfagia fue las enfermedades neurológicas (un 77,25%). La mortalidad fue significativamente mayor en las mujeres - 42,3% frente al 7,8% - (p < 0,01) y esta diferencia se mantuvo tras ajustar el resultado por edad: OR 9,937, IC95%: 5,446; 18,131. El 13,10% de los pacientes reingresaron al menos en una ocasión. Los pacientes de geriatría presentaron un mayor número de reingresos por número de ingresos. Discusión: las enfermedades neurológicas fueron la principal causa de disfagia. La mortalidad fue significativamente mayor en las mujeres.

ABSTRACT Introduction: Dysphagia is an important associated morbidity and mortality in hospitalized patient. Objectives: Main; to describe the characteristics of patients admitted for dysphagia and secondary; quantify and analyze the prevalence of mortality and readmissions. Methodology: Cross-sectional study descriptive revenues by dysphagia during the year 2015 in a University General Hospital. Results: 431 records were evaluated. The age of the patients was 83,21 (11.4), 52.5% women and 47.2% male; the average stay was 11.1 (7.99) days. In 71,2% of cases the dysphagia was involvement of the oropharyngeal phase. 80.51% of cases were diagnosed respiratory complications. The percentage distribution of these complications were: in 48.12% aspiration pneumonia due to fluids, in 40.05% chemical aspiration pneumonitis and in 11.81% aspiration pneumonia due to solids. The overall mortality associated with respiratory complications compared to the total of cases of dysphagia was 24.49%. 50.48% of patients diagnosed with aspiration pneumonia died. The main cause of dysphagia was neurological diseases (77.25%). Mortality was significantly higher in women - 42.3% of women compared with 7.8% of males - (p < 0.01) and this difference remained after adjusting the result by age: OR 9,937, 95% CI: 5,446; 18,131. 13.10% of patients re-entered at least on one occasion. Patients of geriatric unit that presented in greater number of readmissions by admissions. Discussion: neurological diseases were the main cause of dysphagia. Mortality was significantly higher in women

Association of C677T and A1298C MTHFR Polymorphisms and Fluoropyrimidine-induced Toxicity in Mestizo Patients With Metastatic Colorectal Cancer.

BACKGROUND/AIM: Enzymatic variants involved in fluoropyrimidine metabolism have been associated with adverse events (AEs). We assessed the association between C677T (rs1801133) and A1298 (rs1801131) methylenetetrahydrofolate reductase (MTHFR) polymorphisms and AEs in patients with first-line fluoropyrimidine-based chemotherapy. PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were prospectively followed-up during the first 4 cycles of fluoropyrimidine-based treatment to assess AEs. Germline DNA was analyzed to determine the C677T and A1298C MTHFR polymorphisms. The associations between MTHFR polymorphisms and toxicity were examined. RESULTS: Individuals carrying at least one mutant allele of the MTHFR C677T polymorphism had increased risk to experience anemia (OR=1.69, 95% CI=1.13-2.53, p=0.005), neutropenia (OR=2.27, 95% CI=1.47-3.42, p<0.001) thrombocytopenia (OR=1.91, 95% CI=1.30-2.70, p<0.001), neuropathy (OR=1.77, 95% CI=1.16-2.70, p=0.02), diarrhea (OR=1.69, 95% CI=1.13-2.53, p=0.005), and hand-foot syndrome (OR=1.56, 95% CI=1.08-2.27, p=0.013), compared to patients carrying the wild type alleles. The presence of the mutant allele C of the MTHFR A1298C polymorphism was associated with increased risk of anemia (OR=2.75, 95% CI=1.01-7.48, p=0.02) and thrombocytopenia (OR=3.14, 95% CI=1.01-9.78, p=0.03); however, the prevalence of this allele in the sample was quite low (20%). CONCLUSION: MTHFR C677T and A1298C polymorphisms predicted toxicity in a subset of Mestizo patients with colorectal adenocarcinoma.

HIVconsv Vaccines and Romidepsin in Early-Treated HIV-1-Infected Individuals: Safety, Immunogenicity and Effect on the Viral Reservoir (Study BCN02).

Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control.

Skin picking disorder in 97 Italian and Spanish Cri du chat patients.

Skin picking (SP) disorder is characterized by recurrent SP resulting in skin lesions. Several studies estimated its prevalence as approximately 2-4 % of the general population. It is also present in a high percentage of patients with intellectual and developmental disabilities, such as Cri du chat (CdC) syndrome, a rare genetic disorder caused by variable size deletions of the short arm of chromosome 5. The aim of this study was to evaluate, in 97 patients with CdC syndrome, the following data: frequency of SP, patient's age at onset, type, and topographic-anatomic distribution of the lesions presented. The results show that 85% of patients confirm a SP disorder, usually concentrated on the hands, fingers, and the face, with onset between 6 and 10 years of age, regardless of patient's sex. Evidence for early appearance of SP behavior, high prevalence in stressful circumstances, and efficacy of distracting actions immediately suggest the possibility that proper parental information about SP behavior and parental education concerning the methods to deal with this problem may result in its efficient reduction already in childhood.

Dopamine modulates the reward experiences elicited by music.

Understanding how the brain translates a structured sequence of sounds, such as music, into a pleasant and rewarding experience is a fascinating question which may be crucial to better understand the processing of abstract rewards in humans. Previous neuroimaging findings point to a challenging role of the dopaminergic system in music-evoked pleasure. However, there is a lack of direct evidence showing that dopamine function is causally related to the pleasure we experience from music. We addressed this problem through a double blind within-subject pharmacological design in which we directly manipulated dopaminergic synaptic availability while healthy participants (n = 27) were engaged in music listening. We orally administrated to each participant a dopamine precursor (levodopa), a dopamine antagonist (risperidone), and a placebo (lactose) in three different sessions. We demonstrate that levodopa and risperidone led to opposite effects in measures of musical pleasure and motivation: while the dopamine precursor levodopa, compared with placebo, increased the hedonic experience and music-related motivational responses, risperidone led to a reduction of both. This study shows a causal role of dopamine in musical pleasure and indicates that dopaminergic transmission might play different or additive roles than the ones postulated in affective processing so far, particularly in abstract cognitive activities.