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We previously selected and defined nine important post-operative morbidities linked to paediatric cardiac surgery, and prospectively measured their incidence following 3090 consecutive operations. Our aim was to study the impact of these morbidities on family functioning and parental quality of life over 6 months in a subset of cases. As part of a prospective case matched study in five of the ten children's cardiac centers in the UK, we compared outcomes for parents of children who had a 'single morbidity', 'multiple morbidities', 'extracorporeal life support (ECLS)' or 'no morbidity'. Outcomes were evaluated using the PedsQL Family impact module (FIM) at 6 weeks and 6 months post-surgery. Outcomes were modelled using mixed effects regression, with adjustment for case mix and clustering within centers. We recruited 340 patients with morbidity (60% of eligible patients) and 326 with no morbidity over 21 months. In comparison to the reference group of 'no morbidity', after adjustment for case mix, at 6 weeks parent health-related quality of life (HRQoL) and total FIM sores were lower (worse) only for ECLS (p < 0.005), although a higher proportion of parents in both the ECLS and multi-morbidity groups had low/very low scores (p < .05). At 6 months, parent outcomes had improved for all groups but parent HRQoL and total score for ECLS remained lower than the 'no morbidity' group (p < .05) and a higher proportion of families had low or very low scores in the ECLS (70%) group (p < .01). Post-operative morbidities impact parent HRQoL and aspects of family functioning early after surgery, with this impact lessening by 6 months. Families of children who experience post-operative morbidities should be offered timely psychological support.
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Procedimientos Quirúrgicos Cardíacos , Calidad de Vida , Niño , Humanos , Calidad de Vida/psicología , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Morbilidad , Padres/psicología , Incidencia , Encuestas y CuestionariosRESUMEN
OBJECTIVES: Children with CHD are at heightened risk of neurodevelopmental problems; however, the contribution of acute neurological events specifically linked to the perioperative period is unclear. AIMS: This secondary analysis aimed to quantify the incidence of acute neurological events in a UK paediatric cardiac surgery population, identify risk factors, and assess how acute neurological events impacted the early post-operative pathway. METHODS: Post-operative data were collected prospectively on 3090 consecutive cardiac surgeries between October 2015 and June 2017 in 5 centres. The primary outcome of analysis was acute neurological event, with secondary outcomes of 6-month survival and post-operative length of stay. Patient and procedure-related variables were described, and risk factors were statistically explored with logistic regression. RESULTS: Incidence of acute neurological events after paediatric cardiac surgery in our population occurred in 66 of 3090 (2.1%) consecutive cardiac operations. 52 events occurred with other morbidities including renal failure (21), re-operation (20), cardiac arrest (20), and extracorporeal life support (18). Independent risk factors for occurrence of acute neurological events were CHD complexity 1.9 (1.1-3.2), p = 0.025, longer operation times 2.7 (1.6-4.8), p < 0.0001, and urgent surgery 3.4 (1.8-6.3), p < 0.0001. Unadjusted comparison found that acute neurological event was linked to prolonged post-operative hospital stay (median 35 versus 9 days) and poorer 6-month survival (OR 13.0, 95% CI 7.2-23.8). CONCLUSION: Ascertainment of acute neurological events relates to local measurement policies and was rare in our population. The occurrence of acute neurological events remains a suitable post-operative metric to follow for quality assurance purposes.
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Procedimientos Quirúrgicos Cardíacos , Cardiopatías Congénitas , Complicaciones Posoperatorias , Humanos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Femenino , Masculino , Estudios Prospectivos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Lactante , Factores de Riesgo , Preescolar , Incidencia , Cardiopatías Congénitas/cirugía , Niño , Tiempo de Internación/estadística & datos numéricos , Reino Unido/epidemiología , Recién Nacido , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/epidemiologíaRESUMEN
OBJECTIVES: To explore whether postoperative morbidities after pediatric cardiac surgery affected children's health-related quality of life (HRQOL) at 6 months, through potentially modifiable parental psychological factors. DESIGN: We undertook a mediation analysis, to explore the causal pathway, based on data from a prospective, case-matched cohort study. PATIENTS: Six hundred sixty-six children undergoing cardiac surgery. SETTING: Five centers in the United Kingdom. INTERVENTIONS: No intervention. MEASUREMENTS AND MAIN RESULTS: Cases of morbidity were identified early after pediatric cardiac surgery, and matched controls with no morbidities were identified at discharge. Four mediators were assessed at 6 weeks after surgery, using the PedsQL Family Impact Module (Parent HRQOL and Family Function) and the PHQ-4 (Anxiety and Depression). The study outcome of child HRQOL was assessed at 6 months with the PedsQL. Of 666 children, 408 (65% of those surviving) contributed to the primary outcome. Children who had extracorporeal life support (ECLS) ( n = 11) ( p < 0.05) and multiple morbidities ( n = 62) ( p < 0.01) had worse 6-month HRQOL than those with a single morbidity ( n = 125) or no morbidity ( n = 209). After adjustment for case mix complexity and sociodemographic variables, there were significant indirect effects of parent HRQOL at 6 weeks, on the PedsQL Total Score (ECLS, -5.1 [-8.4 to -1.8]; p = 0.003; multiple morbidities, -2.1 [-3.7 to -0.5]; p = 0.01), PedsQL Physical Score (ECLS, -5.1 [-8.7 to -1.4]; p = 0.007; multiple morbidities, -2.1 [-3.8 to -0.4]; p = 0.016), and PedsQL Psychosocial Score (ECLS: -5.3 [-8.7 to -1.8); p = 0.003; multiple morbidities, -2.2 [-3.9 to -0.5]; p = 0.01). The proportion of the total effect of ECLS and multiple morbidity on the study outcomes mediated through parent HRQOL ranges between 18% and 61%. There was no evidence that the other three mediators had indirect effects on the study outcome. CONCLUSIONS: Parental HRQOL at 6 weeks after surgery contributes to child HRQOL at 6 months, among those with the severest types of morbidity, and as such should be a target for future interventions.
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Análisis de Mediación , Calidad de Vida , Niño , Humanos , Calidad de Vida/psicología , Estudios de Cohortes , Estudios Prospectivos , Padres/psicología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Encuestas y CuestionariosRESUMEN
OBJECTIVES: Renal replacement therapy (RRT) options are limited for small babies because of lack of available technology. We investigated the precision of ultrafiltration, biochemical clearances, clinical efficacy, outcomes, and safety profile for a novel non-Conformité Européenne-marked hemodialysis device for babies under 8 kg, the Newcastle Infant Dialysis Ultrafiltration System (NIDUS), compared with the current options of peritoneal dialysis (PD) or continuous venovenous hemofiltration (CVVH). DESIGN: Nonblinded cluster-randomized cross-sectional stepped-wedge design with four periods, three sequences, and two clusters per sequence. SETTING: Clusters were six U.K. PICUs. PATIENTS: Babies less than 8 kg requiring RRT for fluid overload or biochemical disturbance. INTERVENTIONS: In controls, RRT was delivered by PD or CVVH, and in interventions, NIDUS was used. The primary outcome was precision of ultrafiltration compared with prescription; secondary outcomes included biochemical clearances. MEASUREMENTS AND MAIN RESULTS: At closure, 97 participants were recruited from the six PICUs (62 control and 35 intervention). The primary outcome, obtained from 62 control and 21 intervention patients, showed that ultrafiltration with NIDUS was closer to that prescribed than with control: sd controls, 18.75, intervention, 2.95 (mL/hr); adjusted ratio, 0.13; 95% CI, 0.03-0.71; p = 0.018. Creatinine clearance was smallest and least variable for PD (mean, sd ) = (0.08, 0.03) mL/min/kg, larger for NIDUS (0.46, 0.30), and largest for CVVH (1.20, 0.72). Adverse events were reported in all groups. In this critically ill population with multiple organ failure, mortality was lowest for PD and highest for CVVH, with NIDUS in between. CONCLUSIONS: NIDUS delivers accurate, controllable fluid removal and adequate clearances, indicating that it has important potential alongside other modalities for infant RRT.
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Lesión Renal Aguda , Terapia de Reemplazo Renal Continuo , Hemofiltración , Diálisis Peritoneal , Humanos , Lactante , Diálisis Renal , Ultrafiltración , Estudios Transversales , RiñónRESUMEN
BACKGROUND: To determine in vitro whether infant hemofiltration and hemodialysis devices can reliably deliver precise ultrafiltration (UF) control. METHODS: We tested the Prismaflex, Aquarius and NIDUS devices which have different circuit types, by in vitro testing with a bag of saline set up as a dummy patient, and monitoring fluid shifts by precise weighing. We looked for differences between the UF rates set and achieved and between the UF result the device displays to the clinician and the true volumes removed, which may lead to clinical errors. We performed short studies at UF settings of zero and 40 ml/h, and with and without simulating poor withdrawal and return lines, and simulated a 4-h treatment session. RESULTS: The Prismaflex setting vs actual errors and display vs actual errors had wide variances, with SDs of 4.1 and 14.0 ml by 15 min, respectively, at both zero and 40 ml/h UF settings. The Aquarius values were wider at 17.3 and 30.3 ml, respectively. For the NIDUS, the mean UF errors were close to zero, and the variances were 0.17 ml. Stop-alarms induced by an obstructed line produced extra UF errors of up to 0.2 ml. A limitation was that we used crystalloid and not colloid for these tests. CONCLUSIONS: Hemotherapy devices with conventional circuits available in the UK do not regulate UF control sufficiently well to recommend for use in small infants, but the NIDUS volumetrically controlled circuit does. All hemotherapy devices intended for small infants should be tested for UF precision. We were unable to test the CARPEDIEM or Aquadex devices. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Hemofiltración , Humanos , Ultrafiltración , Diálisis Renal/efectos adversos , Soluciones CristaloidesRESUMEN
Social environment influences the trajectory of developing opioid use disorder (OUD). Thus, the present study tested the hypothesis that sociability levels will affect the responses to opioids. Mice were tested for their baseline sociability, anxiety levels, pain sensitivities, and their acute locomotor response to 5 mg/kg opioids. Then, they were administered repeatedly with saline, hydrocodone, or morphine (20 mg/kg for 5 days, and then 40 mg/kg for 5 days). Subsequently, they were examined for the expression of locomotor sensitization and retested for the effects of opioids on their sociability, anxiety levels, and pain sensitivity. On the basis of their baseline sociability level, mice were divided into socially avoiding and socially exploring. Socially avoiding and socially exploring mice did not differ in their baseline weight and anxiety sensitivities. Socially avoiding mice had slightly higher baseline heat sensitivity than those in socially exploring mice. Repeated administration of opioids had differential effects in socially avoiding and socially exploring mice. In both social groups, repeated morphine administration had overall stronger effects compared with hydrocodone. Morphine-treated socially exploring mice developed greater locomotor sensitization than those in morphine-treated socially avoiding mice. Morphine-treated socially avoiding mice, but not socially exploring mice, spent more time in the center zone of the open-field test and in the light zone of light/dark boxes, and developed heat hyperalgesia. This study suggests that socially exploring animals are more sensitive to the sensitizing effects of opioids. In contrast, opioids have greater effects on the stress and pain systems of socially avoiding animals. Thus, the underlying mechanisms for developing OUD might differ in individuals with various sociability levels.
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Analgésicos Opioides/farmacología , Trastornos Relacionados con Opioides/fisiopatología , Trastornos Relacionados con Opioides/psicología , Animales , Ansiedad/fisiopatología , Relación Dosis-Respuesta a Droga , Hidrocodona/farmacología , Hiperalgesia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/farmacología , Dolor/fisiopatología , Umbral del Dolor/efectos de los fármacos , Medio SocialRESUMEN
BACKGROUND: Fever improves pathogen control at a significant metabolic cost. No randomized clinical trials (RCT) have compared fever treatment thresholds in critically ill children. We performed a pilot RCT to determine whether a definitive trial of a permissive approach to fever in comparison to current restrictive practice is feasible in critically ill children with suspected infection. METHODS: An open, parallel-group pilot RCT with embedded mixed methods perspectives study in four UK paediatric intensive care units (PICUs) and associated retrieval services. Participants were emergency PICU admissions aged > 28 days to < 16 years receiving respiratory support and supplemental oxygen. Subjects were randomly assigned to permissive (antipyretic interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on respiratory support. Parents were invited to complete a questionnaire or take part in an interview. Focus groups were conducted with staff at each unit. Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between group separation of temperature and safety. RESULTS: One hundred thirty-eight children met eligibility criteria of whom 100 (72%) were randomized (11.1 patients per month per site) without prior consent (RWPC). Consent to continue in the trial was obtained in 87 cases (87%). The mean maximum temperature (95% confidence interval) over the first 48 h was 38.4 °C (38.2-38.6) in the restrictive group and 38.8 °C (38.6-39.1) in the permissive group, a mean difference of 0.5 °C (0.2-0.8). Protocol deviations were observed in 6.8% (99/1438) of 6-h time periods and largely related to patient comfort in the recovery phase. Length of stay, duration of organ support and mortality were similar between groups. No pre-specified serious adverse events occurred. Staff (n = 48) and parents (n = 60) were supportive of the trial, including RWPC. Suggestions were made to only include invasively ventilated children for the duration of intubation. CONCLUSION: Uncertainty around the optimal fever threshold for antipyretic intervention is relevant to many emergency PICU admissions. A more permissive approach was associated with a modest increase in mean maximum temperature. A definitive trial should focus on the most seriously ill cases in whom antipyretics are rarely used for their analgesic effects alone. TRIAL REGISTRATION: ISRCTN16022198 . Registered on 14 August 2017.
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Infecciones/complicaciones , Valores Limites del Umbral , Resultado del Tratamiento , Niño , Preescolar , Enfermedad Crítica/terapia , Femenino , Fiebre/etiología , Fiebre/fisiopatología , Grupos Focales/métodos , Humanos , Lactante , Infecciones/fisiopatología , Unidades de Cuidado Intensivo Pediátrico/organización & administración , Unidades de Cuidado Intensivo Pediátrico/estadística & datos numéricos , Masculino , Proyectos Piloto , Encuestas y Cuestionarios , Reino UnidoRESUMEN
Our previous studies showed that altering solely the drug experience of the cage mates with which rodents are housed affects the development of morphine dependence. In this study, we used designer receptors exclusively activated by designer drugs to artificially increase or decrease the activity of peripheral dorsal root ganglia sensory neurons expressing the G-protein-coupled receptor MRGPRB4. This is because sensory MRGPRB4-expressing neurons were shown to specifically detect the sensation of massage-like stroking resulting from social grooming, which is an important affiliative social behavior in the rodent. Blocking the sensation of social grooming in morphine-treated mice housed with drug-naive mice (i.e. morphine cage mates) significantly increased the display of jumping behavior in morphine-withdrawn animals. Activating the sensation of social grooming in morphine-treated animals housed solely with other morphine-treated animals (i.e. morphine only) did not significantly alter the display of jumping behavior in morphine-withdrawn animals. Repetitive jumping behaviors have been shown to correlate with morphine dependence. Thus, this study showed a role of social grooming in the protective effect of being housed with drug-naive mice on the development of morphine dependence. It further confirms a role of social support in the development of substance use problems.
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Aseo Animal , Dependencia de Morfina/psicología , Conducta Social , Percepción del Tacto , Animales , Drogas de Diseño/farmacología , Modelos Animales de Enfermedad , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Aseo Animal/efectos de los fármacos , Aseo Animal/fisiología , Ratones Transgénicos , Morfina/administración & dosificación , Dependencia de Morfina/fisiopatología , Actividad Motora/efectos de los fármacos , Narcóticos/administración & dosificación , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Medio Social , Síndrome de Abstinencia a Sustancias , Tacto/efectos de los fármacos , Tacto/fisiología , Percepción del Tacto/efectos de los fármacos , Percepción del Tacto/fisiologíaRESUMEN
Burn victim patients are frequently prescribed opioids at doses that are significantly higher than standard analgesic dosing guidelines, and, even despite an escalation in opioid dosing, many continue to experience pain. Thus, the aim of this study was to determine the effect of burn injury on opioid antinociception. Mice were examined for their baseline pain sensitivity thresholds using the von Frey filaments test. Then, they were subjected to burn or sham injury to the dorsal surface of the hindpaw and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 following the burn injury. The antinociceptive effects of the various drugs were analyzed by computing the daily difference between pain sensitivity threshold scores (in g) before and after treatment. This study showed that burn injury decreases opioid antinociception potency. A marked reduction was observed in the antinociceptive effectiveness of all opioids, and for both doses, in the burn-injured versus the sham animals. These results suggest that burn trauma limits the ability of opioids to be effective in reducing pain.
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Analgésicos Opioides/farmacología , Quemaduras/complicaciones , Umbral del Dolor/efectos de los fármacos , Dolor/tratamiento farmacológico , Administración Oral , Analgésicos Opioides/administración & dosificación , Animales , Quemaduras/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hidrocodona/administración & dosificación , Hidrocodona/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/administración & dosificación , Morfina/farmacología , Oxicodona/administración & dosificación , Oxicodona/farmacología , Factores de TiempoRESUMEN
BACKGROUND: Pain is the most frequent complaint of burn-injured patients. Opioids are commonly used in the course of treatment. However, there is a lack of rodent studies that examine the differential effects of various opioids on burn pain. OBJECTIVE: This study compared the ability of morphine, oxycodone, and hydrocodone to suppress the development of burn-induced mechanical allodynia and reduce pain sensitivity. METHODS: Mice were examined for their baseline pain sensitivity thresholds using the von Frey Filaments test. Then, they were subjected to burn or sham injury and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 postburn. RESULTS: In the sham animals, morphine produced significant opioid-induced hyperalgesia (OIH). Development of OIH was minimal for hydrocodone and was not observed for oxycodone. Secondary mechanical allodynia was observed beginning four days after the burn injury and intensified with time. All opioids produced comparable antinociceptive effects. Hydrocodone was effective in suppressing the development of burn-induced mechanical allodynia and fully treated the burn-induced increase in pain sensitivity. In contrast, morphine and oxycodone had only minimal effects on the development of burn-induced mechanical allodynia and only partially treated the burn-induced increase in pain sensitivity. CONCLUSIONS: This study demonstrated that hydrocodone is effective in suppressing the development of burn-induced mechanical allodynia, while both morphine and oxycodone had minimal effects. These findings underscore the need for additional studies on the differences among various opioids using clinically relevant pain models.
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Quemaduras/tratamiento farmacológico , Hidrocodona/uso terapéutico , Morfina/uso terapéutico , Oxicodona/uso terapéutico , Analgésicos Opioides/uso terapéutico , Animales , Quemaduras/complicaciones , Relación Dosis-Respuesta a Droga , Hidrocodona/administración & dosificación , Hiperalgesia/tratamiento farmacológico , Masculino , Ratones Endogámicos C57BL , Morfina/administración & dosificación , Oxicodona/administración & dosificación , Dolor/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacosRESUMEN
BACKGROUND: Opioids alter the responses of D2-like dopamine receptors (D2DRs), known to be involved in the pathology of addiction and other mental illnesses. Importantly, our recent results demonstrated that various opioids differentially modulate the behavioral responses of D2DRs. OBJECTIVE: To examine the effect of various opioids on striatal activation levels of Akt and ERK1/2, as well as the signaling responses of D2DRs following opioid exposure. METHODS: Mice were pre-treated with 20 mg/kg morphine, hydrocodone, oxycodone, or saline for 6 days. Twenty-four hours later, mice were injected with vehicle or a D2/D3 receptor agonist, quinpirole. Thirty minutes later, dorsal striatum was collected and analyzed using Western blot. RESULTS: In morphine-pretreated animals, baseline Akt activation level was unchanged, but was reduced in response to quinpirole. In contrast, baseline Akt activation levels were reduced in mice pretreated with hydrocodone and oxycodone, but were unchanged in response to quinpirole. In mice pretreated with all opioids, baseline ERK2 activation levels were unchanged and increased in response to quinpirole. However, quinpirole-induced ERK2 activation was significantly higher than drug naïve animals only in the morphine-pretreated mice. CONCLUSIONS: Various opioids differentially modulate the baseline activation levels of signaling molecules, which in turn results in ligand-selective effects on the responses to a D2/D3 dopamine receptor agonist. This demonstrates a complex interplay between opioid receptors and D2DRs, and supports the notion that various opioids carry differential risks to the dopamine reward system. This information should be considered when prescribing opioid pain medication, to balance effectiveness with minimal risk.
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OBJECTIVES: Prolonged pleural effusion/chylothorax (PPE/C) is a less investigated complication following paediatric cardiac surgery, and its true incidence, risk factors and impact on postoperative outcomes are not well described. We aim to address these gaps in knowledge using data from a prospective, multicentre study. METHODS: Data on 9 post-operative morbidities (unplanned reinterventions, extracorporeal life support, necrotising enterocolitis, PPE/C, renal replacement therapy, major adverse events, acute neurological events, feeding issues and postsurgical infection) were prospectively collected at 5 UK centres between 2015 and 2017, following paediatric cardiac surgery. Incidence of PPE/C, associations with procedure types, and risk factors were described. Mortality (30-day and 6-month) and hospital length of stay (HLoS) were compared between those with isolated PPE/C, single non-PPE/C morbidity, no morbidity, multimorbidity PPE/C and non-PPE/C multimorbidity. RESULTS: A total of 3090 procedures (2861 patients) were included (median age, 228 days). There were 202 PPE/C (incidence of 6.5%), occurring at a median of 6 days postoperatively (IQR: 3-10). PPE/C was associated with excess early mortality only when complicating scenarios where at least two other post-operative morbidities occurred. On average PPE/C is associated with 8 more HLoS days, but the relative impact is greatest when comparing isolated PPE/C with no morbidity (p < 0.001), whereas in multimorbidity scenarios, PPE/C does not significantly contribute to an increase of HLoS. CONCLUSIONS: Addition of PPE/C increases mortality but not HLoS in multimorbidity and HLoS only in single morbidity scenarios. This reinforces the important role of prevention, early detection and management of PPE/C in complex situations.
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Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.
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COVID-19 , Neutrófilos , Síndrome de Respuesta Inflamatoria Sistémica , Humanos , Niño , Neutrófilos/inmunología , COVID-19/inmunología , COVID-19/virología , COVID-19/complicaciones , Masculino , Femenino , Preescolar , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Fiebre/inmunología , SARS-CoV-2/inmunología , Lactante , Interferones/metabolismo , Infecciones Bacterianas/inmunología , Linfocitos T/inmunología , Síndrome Mucocutáneo Linfonodular/inmunología , Adolescente , Apoptosis , Activación NeutrófilaRESUMEN
Social/peer influences are among the strongest predictors of adolescent drug use. However, this important subject does not get much attention in pre-clinical studies. We recently observed that exposure to different social partners modulates morphine locomotor sensitization. Sensitivity to the hyper-locomotor response of drugs of abuse is a predictor of sensitivity to other drug-induced behaviors. Thus, this study examined how exposure to different social partners affected the rewarding properties of morphine. All animals were group-housed four per cage in one of two conditions referred to as 'only' and 'cage-mates'. In the mixed treatment condition, morphine- and saline-treated mice were housed together. These groups are referred to as 'morphine cage-mates' and 'saline cage-mates', respectively. In the separated treatment conditions, all mice in the cage received morphine (i.e. 'morphine only') or saline (i.e. 'saline only'), and cages were visually separated from each other. All animals were subsequently individually tested for the acquisition of morphine conditioned place preference (CPP) following one conditioning session with 10, 20 or 40 mg/kg morphine or saline. As expected, one conditioning session established morphine CPP in the morphine only animals, but not in the saline only animals. Notably, morphine CPP was not acquired by the morphine cage-mate animals. Additionally, 40 mg/kg morphine was sufficient to establish morphine CPP in the saline cage-mate animals. These results indicate that social environment has an effect on the rewarding properties of morphine. It suggests that exposure to different peers can alter the abuse potential of opioids and potentially other illicit drugs.
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Analgésicos Opioides/farmacología , Conducta de Elección/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Morfina/farmacología , Medio Social , Trastornos Relacionados con Sustancias/psicología , Adolescente , Analgésicos Opioides/administración & dosificación , Análisis de Varianza , Animales , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Vivienda para Animales , Humanos , Masculino , Ratones , Modelos Animales , Morfina/administración & dosificación , Grupo Paritario , Distribución Aleatoria , Recompensa , Cloruro de Sodio/administración & dosificación , Estrés Psicológico/sangre , Factores de Tiempo , Adulto JovenRESUMEN
Given that social influences are among the strongest predictors of adolescents' drug use, this study examines the effects of social interactions on morphine sensitization in both adolescent and adult rats. Rats treated with morphine (twice daily, 6 days, 2.5-10 mg/kg, subcutaneously, s.c.) or saline were group-housed in two different conditions. Thus, four experimental groups were examined for each age group: (1) morphine-treated rats housed physically and visually separate from saline-injected rats ('morphine only'); (2) morphine-treated rats housed together with saline-injected rats ('morphine cage-mates'); (3) saline-injected rats housed together with morphine-treated rats ('saline cage-mates'); and (4) saline-injected rats housed physically and visually separate from morphine-treated rats ('saline only'). Starting 9 days following the last morphine injection, rats were individually examined once daily for 5 consecutive days for their locomotor response to 2.5 mg/kg of morphine. For both age groups, there were no significant differences in morphine-induced hyper-locomotion between saline cage-mates and saline only rats. Morphine only rats exhibited morphine locomotor sensitization as compared to both the saline only and saline cage-mates rats. Notably, a significant difference was observed between the adolescent morphine cage-mates and morphine only rats. The adolescent morphine cage-mates did not exhibit the enhanced locomotor response as compared to the saline only and saline cage-mate rats. A trend of reduced morphine locomotor sensitization was observed in the adult morphine cage-mates as compared to morphine only but it did not reach statistical significance. Thus, this study demonstrates social influences on morphine sensitization which are more prevalent in adolescents as compared to adults.
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Morfina/farmacología , Narcóticos/farmacología , Trastornos Relacionados con Opioides/psicología , Conducta Social , Envejecimiento/fisiología , Análisis de Varianza , Animales , Locomoción/efectos de los fármacos , Morfina/administración & dosificación , Actividad Motora/efectos de los fármacos , Narcóticos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Medio SocialRESUMEN
Systemic infusions of the orexigenic peptide ghrelin (GHR) increase dopamine levels within the nucleus accumbens and augment cocaine-stimulated locomotion and conditioned place preference in rats; observations that suggest an important role for GHR and GHR receptors (GHR-Rs) in drug reinforcement. In the present studies, we examined the development of cocaine locomotor sensitization in rats, sustaining either pharmacologic antagonism or genetic ablation of GHR-Rs. In a pharmacologic study, adult male rats were injected (i.p.) with either 0, 3 or 6 mg/kg JMV 2959 (a GHR-R1 receptor antagonist), and 20 minutes later, with either vehicle or 10 mg/kg cocaine HCl on each of 7 consecutive days. Rats pretreated with JMV 2959 showed significantly attenuated cocaine-induced hyperlocomotion. In a second study, adult wild-type (WT) or mutant rats sustaining ENU-induced knockout of GHR-R [GHR-R ((-/-) )] received daily injections (i.p.) of vehicle (0.9% saline) or 10.0 mg/kg cocaine HCl for 14 successive days. GHR-R null rats treated repeatedly with cocaine showed diminished development of cocaine locomotor sensitization relative to WT rats treated with cocaine. To verify the lack of GHR-R function in the GHR-R ((-/-) ) rats, a separate feeding experiment was conducted in which WT rats, but not GHR-R ((-/-) ) rats, were noted to eat more after a systemic injection of 15 nmol GHR than after vehicle. These results suggest that GHR-R activity is required for the induction of locomotor sensitization to cocaine and complement an emerging literature implicating central GHR systems in drug reward. GHR is an orexigenic gut peptide that is transported across the blood-brain barrier and interacts with GHR-Rs located on ventral tegmental dopamine neurons.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Locomoción/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Receptores de Ghrelina , Animales , Conducta Animal/efectos de los fármacos , Técnicas de Inactivación de Genes , Glicina/análogos & derivados , Glicina/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/antagonistas & inhibidores , Receptores de Ghrelina/genética , Receptores de Ghrelina/fisiología , Triazoles/farmacologíaRESUMEN
Ghrelin (GHR) is an orexigenic gut peptide that interacts with brain ghrelin receptors (GHR-Rs) to promote food intake. Recent research suggests that GHR acts as a modulator of motivated behavior, suggesting a direct influence of GHR on brain reinforcement circuits. In the present studies, we investigated the role of GHR and GHR-Rs in brain reinforcement function. Pharmacological magnetic resonance imaging was used to spatially resolve the functional activation produced by systemic administration of an orexigenic GHR dose. The imaging data revealed a focal activation of a network of subcortical structures that comprise brain reinforcement circuits-ventral tegmental area, lateral hypothalamus and nucleus accumbens. We next analyzed whether brain reinforcement circuits require functional GHR-Rs. To this purpose, wild-type (WT) or mutant rats sustaining N-ethyl-N-nitrosourea-induced knockout of GHR-Rs (GHR-R null rats) were implanted with stimulating electrodes aimed at the lateral hypothalamus, shaped to respond for intracranial self-stimulation (ICSS) and then tested using a rate-frequency procedure to examine ICSS response patterns. WT rats were readily shaped using stimulation intensities of 75 µA, whereas GHR-R null rats required 300 µA for ICSS shaping. No differences in rate-frequency curves were noted for WT rats at 75 µA and GHR-R null rats at 300 µA. When current intensity was lowered to 100 µA, GHR-R null rats did not respond for ICSS. Taken collectively, these data suggest that systemic GHR can activate mesolimbic dopaminergic areas, and highlight a facilitative role of GHR-Rs on the activity of brain reinforcement systems.
Asunto(s)
Estimulantes del Apetito/farmacología , Encéfalo/efectos de los fármacos , Ghrelina/farmacología , Receptores de Ghrelina/fisiología , Refuerzo en Psicología , Animales , Circulación Cerebrovascular/efectos de los fármacos , Ingestión de Alimentos , Hormona del Crecimiento/metabolismo , Imagen por Resonancia Magnética , Masculino , Ratas , Ratas Endogámicas , Ratas Sprague-Dawley , AutoestimulaciónRESUMEN
OBJECTIVE: To evaluate the relationship between morbidities after infant cardiac surgery and neurodevelopment and behaviour at age 2-3 years. DESIGN/SETTING: A prospective cohort follow-up study, in four paediatric cardiac centres. We excluded children with known syndromes. Home-based neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) were undertaken in 81 children and secondary outcome measures of development and behaviour were completed by parents. A further 41 families completed the secondary outcome measures remotely. RESULTS: Children were grouped as multiple morbidities/extracorporeal life support (ECLS) (n=19), single morbidities (n=36) and no morbidities (n=59). Group comparisons found that children with multiple morbidities/ECLS, compared with no morbidities, had: (a) lower adjusted mean scores for core Bayley-III composites (none reached the level of statistical significance), with mean differences of cognitive -6.1 (95% CI -12.4 to 0.1) p=0.06, language -9.1 (95% CI -18.6 to 0.3) p=0.06 and motor -4.4 (95% CI -12.0 to 3.1) p=25; (b) greater adjusted odds of at least one low or borderline Bayley-III composite result 4.0 (95% CI 1.0 to 16.0) (p=0.05); (c) greater adjusted risk of an abnormal Ages and Stages Questionnaire (ASQ) result 5.3 (95% CI 1.3 to 21.1) (p=0.03) and a borderline ASQ result 4.9 (95% CI 1.0 to 25.0) (p=0.05); and no difference in the risk of an abnormal Strengths and Difficulties Questionnaire result 1.7 (95% CI 0.3 to 10.4) p=0.58. These outcomes were not statistically different between the single morbidity and no morbidity groups. CONCLUSIONS: Children who experience multiple morbidities/ECLS after infant heart surgery are at a greater risk of neurodevelopmental difficulties than their peers who had no complications and should be prioritised for neurodevelopmental follow-up.
RESUMEN
The ability to control the bandwidth, amplitude and duration of echolocation pulses is a crucial aspect of echolocation performance but few details are known about the neural mechanisms underlying the control of these voice parameters in any mammal. The basal ganglia (BG) are a suite of forebrain nuclei centrally involved in sensory-motor control and are characterized by their dependence on dopamine. We hypothesized that pharmacological manipulation of brain dopamine levels could reveal how BG circuits might influence the acoustic structure of bat echolocation pulses. A single intraperitoneal injection of a low dose (5 mg kg(-1)) of the neurotoxin 1-methyl-4-phenylpyridine (MPTP), which selectively targets dopamine-producing cells of the substantia nigra, produced a rapid degradation in pulse acoustic structure and eliminated the bat's ability to make compensatory changes in pulse amplitude in response to background noise, i.e. the Lombard response. However, high-performance liquid chromatography (HPLC) measurements of striatal dopamine concentrations revealed that the main effect of MPTP was a fourfold increase rather than the predicted decrease in striatal dopamine levels. After first using autoradiographic methods to confirm the presence and location of D(1)- and D(2)-type dopamine receptors in the bat striatum, systemic injections of receptor subtype-specific agonists showed that MPTP's effects on pulse acoustics were mimicked by a D(2)-type dopamine receptor agonist (Quinpirole) but not by a D(1)-type dopamine receptor agonist (SKF82958). The results suggest that BG circuits have the capacity to influence echolocation pulse acoustics, particularly via D(2)-type dopamine receptor-mediated pathways, and may therefore represent an important mechanism for vocal control in bats.