Tolerancia aguda e hiperalgesia inducida por remifentanilo durante la anestesia con sevofluorano en el perro

Premio extraordinario de Trabajo Fin de Máster curso 2013-2014. Medicina, Sanidad y Mejora AnimalSe ha relacionado el remifentanilo con la hiperalgesia inducida por opioides (HIO) y tolerancia en ratas, lo cual produce una disminución en la reducción de sevofluorano. Esta disminución en la CAM de sevofluorano sugiere tolerancia aguda a opioides (TAO). El objetivo de este estudio es determinar si se puede desarrollar tolerancia aguda a opioides que limite la reducción de concentración alveolar mínima (CAM) de sevofluorano. La respuesta a estímulos nociceptivos mecánicos es evaluada y relacionada a HIO. Se evalúan mediante estímulos nociceptivos mecánicos (NMT) perros beagles, tras lo que se realiza anestesia con sevofluorano y 50% O2, se monitorizan y ventilan mecánicamente. Se determina la CAM de sevofluorano (CAMb1), tras lo que se administra remifentanilo (N=9) o salino (N=9) intravenoso. Veinte minutos después se determina de nuevo la CAM de sevofluorano (CAMpostfarm1) y treinta minutos después de la CAMpostfarm1 se determina la CAMpostfarm2. Una semana después, se determina la CAMb2. El NMT se determina a los 3 y 7 días de la primera anestesia para evaluar la HIO. Se considera TAO un aumento estadísticamente significativo de la CAMpostfarm2 respecto a la CAMpostfarm1 de sevofluorano. Hiperalgesia es considerada si hay una disminución del NMT a los días 3 y 7 y/o un aumento en la CAMb2 respecto a la CAMb1. La infusión continua de remifentanilo reduce la CAMpostfarm1 a 1.54±0.23% (43.7%). No se encuentran diferencias significativas entre la CAMpostfarm2 respecto a la CAMpostfarm1 ni en el grupo de salino (p 0.104) ni en el de remifentanilo (p 0.389). Tampoco se hallan entre la CAMb1 y CAMb2 (p 0.818) o entre RSb, RS3 y RS7 en ambos grupos. El remifentanilo induce tolerancia aguda en ratas; pero, en perros, la eficacia en reducir la CAM de sevofluorano no disminuye, sugiriendo que no se induce TAO. Ni produciéndose hiperalgesia en una semana.Remifentanil has been related to the development of opioid-induced hyperalgesia (OIH) and tolerance in rats, which, in turn, may produce a decrease in the sevoflurane-sparing effect. The decrease of the remifentanil efficacy in reducing the sevoflurane MAC in rats suggested acute opioid tolerance. The aim of this study was to determine if acute opioid tolerance could develop and limit the remifentanil-induced reduction in the sevoflurane minimum alveolar concentration (MAC). The response to mechanical nociceptive stimulus was evaluated and related to OIH. Beagle dogs were evaluated for nociceptive mechanical thresholds (NMT), then were anaesthetized with sevoflurane in 50% O2 and were monitored and mechanically ventilated. The sevoflurane MAC was determined (MACb1). Remifentanil (N=9) or saline (N=9) were administered IV and twenty minutes after, sevoflurane MAC was determined (MACpostfarm1) and again 30 minutes (MACpostfarm2) after MACpostfarm1 determination. One week after, sevoflurane MAC (MACb2) was determined. The NMT was also determined at 3 and 7 days after the first anesthesia to evaluate OIH. Acute opioid tolerance was considered to be a statistically significant increase in sevoflurane MACpostfarm2 respect to MACpostfarm1. Hyperalgesia was considered to be a decrease in NMT at 3 and 7 days and/or an increase in MACb2 respect to MACb1. The remifentanil CRI reduced the sevoflurane MACpostfarm1 to 1.54±0.23 (43.7%). The MACpostfarm2 was not different with respect to MACpostfarm1 either in saline (p 0.104) or remifentanil (p 0.389) groups. No significant differences were found between MACb1 and MACb2 (p 0.818) or between baseline, 3 and 7 days for NMT in S or R groups. Remifentanil induced acute tolerance in rats; but remifentanil efficacy in reducing the sevoflurane MAC did not diminished within a short term, suggesting that remifentanil did not induced acute tolerance in dogs. Remifentanil did not develop hyperalgesia one week after administration

Intraoperative nociception assessment and determination of tolerance and hyperalgesia induced by remifentanil

El dolor aumenta las complicaciones tanto intraoperatorias como postoperatorias, pues es un fenómeno estresante que desencadena la liberación de catecolaminas dando lugar al predominio del Sistema Autónomo Simpático. La monitorización nociceptiva-antinociceptiva intraoperatoria se ha basado fundamentalmente en el control de la frecuencia cardiaca (FC) y la presión arterial, sin embargo, las variables hemodinámicas no solo se afectan por la nocicepción. El monitor Parasympathetic Tone Activity (PTA) ha sido desarrollado para las especies canina, felina y equina basado en el monitor Analgesia Nociception Index (ANI) (índice de nocicepción-analgesia) de aplicación en personas. El ANI está basado en la variabilidad de la FC, que refleja los cambios en el sistema nervioso autónomo (SNA), como respuesta a estímulos nociceptivos intraoperatorios y administración de fármacos. Los opioides son fármacos analgésicos que actúan sobre todas las fases de la nocicepción, que de manera simple se divide en: Transducción, Transmisión, Modulación y Percepción. No obstante, los opioides tienen efectos secundarios entre los que se encuentran en ratas, ratones y en humanos, el desarrollo de tolerancia e hiperalgesia debida a su uso, manifestadas como el aumento de la nocicepción intraoperatoria y de las necesidades de analgésicos postoperatorios. Tras realizar una revisión de los monitores con los que contamos en Medicina Veterinaria para la monitorización nociceptiva intraoperatoria, se plantearon dos estudios para evaluar el uso del monitor PTA, único monitor desarrollado hasta el momento para su uso en animales. En el primer estudio “Evaluation of the parasympathetic tone activity (PTA) index and its dynamic variation (ΔPTA) in dogs undergoing laparoscopic ovariectomy”, se emplearon 32 perras sometidas a ovariectomía laparoscópica para valorar si el índice PTA o su variación dinámica (ΔPTA) precede o coincide con cambios en la frecuencia cardiaca o en la presión arterial media (PAM) tras la aplicación de cuatro estímulos nociceptivos quirúrgicos: insuflación de neumoperitoneo, introducción de trócares, extirpación del ovario izquierdo y extirpación del ovario derecho. Para asegurar un plano anestésico estable se empleó el monitor de índice biespectral (BIS). Se registraron los parámetros de PTA, BIS, FC y PAM antes y 1 y 2 minutos tras la realización de cada uno de los estímulos quirúrgicos. Los datos se analizaron estadísticamente para detectar “eventos PTA” y “respuestas hemodinámicas” ocurridas durante el estudio, considerandose como evento PTA una disminución del índice PTA mayor o igual a un 20% y como respuesta hemodinámica un incremento de la FC o la PAM mayor o igual a un 20%. El índice PTA disminuyó significativamente (p = 0,007) 1 y 2 minutos después de la insuflación. Durante los eventos PTA, la PAM se incrementó significativamente (p = 0,001) tras 1 y 2 minutos, pero no la FC o el BIS. La ΔPTA fue significativamente diferente en los perros que presentaron respuesta hemodinámica durante la insuflación del pneumoperitoneo. Las curvas ROC mostraron un valor de corte de PTA basal (previo al estímulo quirúrgico) ≤ 51 para detectar una respuesta hemodinámica, con una sensibilidad y especificidad del 69 y 52% respectivamente. En el segundo estudio “Assessment of the autonomic nervous system activity by monitoring parasympathetic tone activity (PTA) in horses after a nociceptive stimulus and subsequent administration of morphine, ketamine and dobutamine”, se emplearon 20 caballos sometidos a cirugía electiva bajo anestesia general para valorar los cambios en el SNA, observados como cambios en los valores del índice PTA, tras un estímulo nocieptivo o la administración de morfina, ketamina o dobutamina. Para ello, se valoraron los parámetros de índice PTA, FC y PAM antes y 1, 3 y 5 minutos tras la incisión quirúrgica. Dichos parámetros también se registraron antes y después de la administración de fármacos: antes y a los 10 minutos de la administración de morfina, antes y a los 5 minutos del inicio de una infusión continua de dobutamina, y antes y a los 3 y 5 minutos de la administración de un bolo de ketamina. La morfina se administró siempre una vez registrados los parámetros estudiados tras la incisión quirúrgica. La dobutamina se administró cuando la PAM fue inferior a 62 mmHg y la ketamina si el animal presentó aumento del reflejo palpebral, nistagmo o ventilación espontánea. Se consideró evento PTA si el índice PTA disminuyó un 20% o más, evento FC si la FC se incrementó un 10% o más y evento PAM si la PAM se incrementó un 20% o más, momento en el que se registraron los parámetros de índice PTA, FC y PAM antes (retorspectivo) y 1, 3 y 5 minutos después de que se observara el evento. El índice PTA disminuyó significativamente a los 3 minutos de la administración de ketamina (p = 0,042) y 1 minuto después de la identificación de un evento PTA (p = 0,016). La PAM disminuyó significativamente a los 10 minutos de la administración de morfina (p = 0,009) y 5 minutos tras la administración de ketamina (p = 0,010). En el tercer estudio “Determination of acute tolerance and hyperalgesia to remifentanil constant rate infusion in dogs undergoing sevoflurane anaesthesia”, se emplearon 9 perros de raza beagle para determinar si la infusión continua de remifentanilo produce tolerancia aguda o hiperalgesia en el perro. Se observó si la infusión continua de remifentanilo disminuyó la reducción de la concentración alveolar mínima (CAM) de sevoflurano en el perro (tolerancia aguda), así como si disminuyó el umbral nociceptivo al aplicar un estímulo mecánico a los 3 o 7 días o si aumentó la CAM basal una semana después de la administración de remifentanilo (hiperalgesia). Para ello se realizó la inducción y mantenimiento de la anestesia con sevoflurano. Se determinó la CAM basal 1 (MACb1) y se inició la administración de remifentanilo 0,3 μg kg-1 minuto-1 o suero salino. Veinte minutos tras el inicio de la administración de remifentanilo o suero salino se determinó la CAM post fármaco 1 (MACpostdrug1) y 30 minutos después de la determinación de MACpostdrug1, se determinó la CAM post fármaco 2 (MACpostdrug2). Una semana más tarde, los perros se anestesiaron de nuevo con sevoflurano para la determinación de la CAM basal 2 (MACb2). Antes de la primera anestesia, a los 3 y a los 7 días se determinó la respuesta al estímulo mecánico. La infusión continua de remifentanilo redujo la MACb1 en un 43,7%. No hubo diferencias significativas entre MACpostdrug1 y MACpostdrug2, MACb1 y MACb2, ni entre los estímulos mecánicos en el grupo del remifentanilo ni del salino. La monitorización nociceptiva intraoperatoria es una tarea compleja, que se complica por el posible desarrollo de tolerancia e hiperalgesia a los opioides. En estos tres estudios, se encontró que el índice PTA no fue efectivo para determinación de nocicepción intraoperatoria en relación a cambios en la FC y la PAM en perros anestesiados. Además, la ΔPTA no predijo las respuestas hemodinámicas tras estímulos nociceptivos en el perro. En el caballo, no se observaron cambios en la actividad del SNA tras el estímulo quirúrgico o la administración de morfina o dobutamina empleando el índice PTA. Solo la ketamina produjo una disminución del mismo, que se interpreta como un aumento de la actividad del sistema nervioso simpático. Bajo las circunstancias del estudio III, no se hallaron indicios de tolerancia e hiperalgesia tras el uso de remifentanilo, ya que no se alteró la reducción de la CAM de sevoflurano ni se disminuyó el umbral nociceptivo para la respuesta al estímulo mecánico.Pain increases intraoperative and postoperative risks. Since, it is a stressful process that triggers catecholamines release that increases predominance of the sympathetic nervous system. Intraoperative nociception monitor is based mainly in heart rate (HR) and blood pressure changes. However, there are more players involved in haemodynamic changes. The Parasympathetic Tone Activity (PTA) index has been developed for dogs, cats and horses. It is the homologous of the Analgesia Nociception Index (ANI) monitor for humans. It is based on the HR variability that reflects the changes on the autonomous nervous system (ANS) as consequence of intraoperative nociceptive stimuli and drugs administration. Opioids are analgesic drugs that acts at the different phases of the nociception: transduction, transmission, modulation and perception. Nevertheless, opioids show side effects as development of tolerance and hyperalgesia. These phenomena can be observed as an intraoperative nociception increase and higher needs of postoperative analgesic drugs. These phenomenons have been demonstrated in rats, mice and humans. After reviewing the intraoperative nociception monitors, two studies were planned using the PTA monitor, the only one developed for veterinary medicine. The objective of the first study “Evaluation of the parasympathetic tone activity (PTA) index and its dynamic variation (ΔPTA) in dogs undergoing laparoscopic ovariectomy”, was to assess if the PTA index or its dynamic variation (ΔPTA) coincide or precede with changes on heart rate or mean arterial pressure (MAP) after nociceptive surgical stimuli: insufflation, introduction of the trocars, removal of the left and right ovaries. A total of 32 bitches undergoing laparoscopic ovariectomy were included in this study. The bispectral index (BIS) was used to ensure that a stable depth of anaesthesia was maintained. Data for PTA, BIS, HR and MAP were registered before and after 1 and 2 minutes from the nociceptive surgical stimulus. For the statistical analysis, A PTA event was considered if the PTA index decreased by 20% or more than 20% and a haemodynamic response was considered if HR and/or MAP increased 20% or more than 20% regarding baseline values. The PTA index decreased significantly (p = 0.007) 1 and 2 minutes after insufflation. During PTA events, the MAP increased significantly 1 minute (p = 0.001) and 2 minutes (p = 0.001) later but HR (p = 0.192) and BIS (p = 0.245) did not change. The ΔPTA was significantly different between dogs that presented a haemodynamic response and dogs that did not present it at pneumoperitoneum insufflation (p = 0.005). ROC curves showed a threshold value of PTAbaseline ≤ 51 to detect a haemodynamic response (sensitivity 69%, specificity 52%). The second study “Assessment of the autonomic nervous system activity by monitoring parasympathetic tone activity (PTA) in horses after a nociceptive stimulus and subsequent administration of morphine, ketamine and dobutamine”, determined if ANS activity changes in response to a surgical nociceptive stimulus or during the administration of morphine, ketamine and dobutamine observed as changes on PTA index. A total of 20 horses undergoing general anaesthesia for elective surgeries were included in this study. HR, MAP and PTA index were monitored before and 1, 3 and 5 minutes after the surgical incision, and before and 10 minutes after morphine administration. If an increase of the palpebral reflex was noted or nystagmus or spontaneous ventilation was observed, a ketamine bolus was given and the three variables were registered before, 3 and 5 minutes after the administration. If the MAP fell below 62 mmHg, a dobutamine infusion was administered and the three variables were registered before and 5 minutes after the infusion was started or increased. If the PTA index decreased ≥ 20% (PTA event), HR increased ≥ 10% (HR event) or MAP increased ≥ 20% (MAP event), the three variables were registered before and 1, 3 and 5 minutes after each event. The PTA index decreased significantly 3 minutes after the ketamine bolus (p = 0.042) and 1 minute after a PTA event was identified (p = 0.016). The MAP decreased significantly 10 minutes after morphine administration (p = 0.009) and 5 minutes after ketamine administration (p = 0.010). The third study of this Thesis “Determination of acute tolerance and hyperalgesia to remifentanil constant rate infusion in dogs undergoing sevoflurane anaesthesia”, determined if acute opioid tolerance (AOT) or opioidinduced hyperalgesia (OIH) could develop and limit the remifentanil-induced reduction in the sevoflurane minimum alveolar concentration (MAC). The response to mechanical nociceptive threshold (MNT) was evaluated and related to OIH. A total of nine beagle dogs were included in this study. The dogs were anaesthetized with sevoflurane. Baseline sevoflurane MAC was measured (MACb1). Remifentanil (0.3 μg kg-1 minute-1) or 0.9% saline constant rate infusion (CRI) was administered intravenously (IV). Sevoflurane MAC was determined 20 minutes after CRI was initiated (MACpostdrug1), 30 minutes after MACpostdrug1 determination (MACpostdrug2) and after 1 week (MACb2). The MNT was determined at baseline (before anaesthesia), 3 and 7 days after anaesthesia. Remifentanil CRI reduced sevoflurane MACpostdrug1 by 43.7% with respect to MACb1. MACpostdrug2 was no different with respect to MACpostdrug1 in the saline (p = 0.62) or remifentanil (p = 0.78) treatments. No significant differences were observed in the saline (p = 0.99) or remifentanil (p = 0.99) treatments between MACb1 and MACb2, or for MNT values between baseline, 3 and 7 days. The intraoperative nociception monitor is a complex duty that is complicated with the possible development of tolerance and hyperalgesia to opioids. Among these studies, it was found that the PTA index did not effectively assess intraoperative nociception regarding haemodynamic changes, neither ΔPTA predicted a haemodynamic response in anaesthetised dogs. Furthermore, no changes in ANS activity, using the PTA index, were registered in anaesthetised horses after a surgical nociceptive stimulus or dobutamine and morphine administration. The PTA index demonstrated an increase in sympathetic nervous system activity after ketamine administration. In dogs, under the third study conditions, remifentanil efficacy in reducing sevoflurane MAC did not diminish in the short term, suggesting remifentanil did not induce AOT. Hyperalgesia was not detected 3 or 7 days after the administration of remifentanil. Contrary to data from humans and rodents, development of AOT or OIH in dogs is not supported by the findings of this study

Parasympathetic Tone Changes in Anesthetized Horses after Surgical Stimulation, and Morphine, Ketamine, and Dobutamine Administration

Autonomic nervous system (ANS) activity can modify cardiovascular parameters in response to nociceptive stimuli or drugs in anesthetized animals. The aim of this study was to determine if a surgical nociceptive stimulus and morphine, ketamine, and dobutamine administration would modify ANS activity observed as a change in the mean parasympathetic tone activity (PTAm) in anesthetized horses. In 20 anesthetized horses, heart rate (HR), mean arterial pressure (MAP), and PTAm were monitored before and 1, 3, and 5 min after surgical incision, and before and 10 min after the administration of morphine (0.2 mg/kg IV). If nystagmus or spontaneous ventilation was observed, ketamine (0.5 mg/kg IV) was given, and the three variables were registered before and 3 and 5 min afterward. If MAP reached ≤ 62 mmHg, a dobutamine infusion was administered, and the three variables were recorded before and 5 min after starting/increasing the infusion (0.25 μg/kg/min IV every 5 min). The three variables were registered before and 1, 3, and 5 min after a PTAm decrease of ≥ 20%, HR increase of ≥ 10%, or MAP increase of ≥ 20%. The PTAm decreased 3 min after the administration of ketamine and 1 min after a PTA event. The surgical incision, dobutamine, and morphine did not modify PTAm. The absence of changes in ANS activity after the nociceptive stimulus and lack of correlation between PTAm and HR or MAP suggest that PTAm is a poor indicator of sympathetic activation under the study conditions. Ketamine seems to affect ANS activity by decreasing PTAm

Impact of COVID-19 pandemic on the PREDIMED-Plus randomized clinical trial: Effects on the interventions, participants follow-up, and adiposity

Background: The COVID-19 pandemic has affected the implementation of most ongoing clinical trials worldwide including the PREDIMED-Plus study. The PREDIMED-Plus is an ongoing, multicenter, controlled intervention trial, aimed at weight-loss and cardiovascular disease prevention, in which participants were randomized (1:1 ratio) to an intervention group (energy-reduced Mediterranean diet, promotion of physical activity, and behavioral support) or to a control group (Mediterranean diet with usual care advice). When the pandemic began, the trial was in the midst of the planned intervention. The objective of this report was to examine the effects of the pandemic on the delivery of the intervention and to describe the strategies established to mitigate the possible adverse effects of the pandemic lockdown on data collection and adiposity. Methods: We assessed the integrity of the PREDIMED-Plus trial during 5 identified periods of the COVID-19 pandemic determined according to restrictions dictated by the Spanish government authorities. A standardized questionnaire was delivered to each of the 23 PREDIMED-Plus recruiting centers to collected data regarding the trial integrity. The effect of the restrictions on intervention components (diet, physical activity) was evaluated with data obtained in the three identified lockdown phases: pre lockdown, lockdown proper, and post lockdown. Results: During the lockdown (March/2020-June/2021), 4,612 participants (48% women, mean age 65y) attended pre-specified yearly follow-up visits to receive lifestyle recommendations and obtain adiposity measures. The overall mean (SD) of the proportions reported by each center showed that 40.4% (25.4) participants had in-person visits, 39.8% (18.2) participants were contacted by telephone and 35% (26.3) by electronic means. Participants' follow-up and data collection rates increased across lockdown periods (from ≈10% at onset to ≈80% at the end). Compared to pre-lockdown, waist circumference increased during (0.75 cm [95% CI: 0.60-0.91]) and after (0.72 cm [95% CI: 0.56-0.89]) lockdown. Body weight did not change during lockdown (0.01 kg [95% CI: -0.10 to 0.13) and decreased after lockdown (-0.17 kg [95% CI: -0.30 to -0.04]). Conclusion: Mitigating strategies to enforce the intervention and patient's follow-up during lockdown have been successful in preserving the integrity of the trial and ensuring its continuation, with minor effects on adiposity. Clinical trial registration: https://doi.org/10.1186/ISRCTN89898870, identifier ISRCTN89898870. Keywords: COVID-19; Mediterraean diet; PREDIMED-Plus; clinical trial; lockdown; weight-loss. Copyright © 2023 Paz-Graniel, Fitó, Ros, Buil-Cosiales, Corella, Babio, Martínez, Alonso-Gómez, Wärnberg, Vioque, Romaguera, López-Miranda, Estruch, Tinahones, Lapetra, Serra-Majem, Bueno-Cavanillas, Tur, Martín-Sánchez, Pintó, Gaforio, Matía-Martín, Vidal, Vázquez, Daimiel, García-Gavilán, Toledo, Nishi, Sorlí, Castañer, García-Ríos, García de la Hera, Barón-López, Ruiz-Canela, Morey, Casas, Garrido-Garrido, Tojal-Sierra, Fernández-García, Vázquez-Ruiz, Fernández-Carrión, Goday, Peña-Orihuela, Compañ-Gabucio, Schröder, Martínez-Gonzalez and Salas-Salvadó. Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics