Safety and Risk in Airway Management During Bariatric Air Medical Retrieval.

OBJECTIVE: Bariatric anatomy and physiology present added clinical challenges to the provision of safe critical care and patient transport. LifeFlight Retrieval Medicine provides air medical retrieval services in Queensland, Australia, and performs over 6,000 retrieval missions annually using rotary wing, fixed wing, and ground ambulance platforms. METHODS: Bariatric patient retrievals were identified from the LifeFlight Retrieval Medicine electronic patient database. These cases were interrogated to quantify and describe adverse events during patient transport. RESULTS: Over the study period from July 2019 to December 2021 11,096 patient retrievals were completed. Of these patients, 816 (7.3%) had a body weight ≥ 120 kg (range, 120-246 kg; median = 146 kg). Bariatric patients were more likely to be male (70%) and to require critical care interventions than nonbariatric patients (25.9% vs. 19.9%). There was an absolute 1.5% increase of high-interest events during patient retrieval, corresponding to a 1.9-fold increased relative risk. Five hundred eleven of 11,096 patients were intubated by the retrieval team, and 61 of these weighed ≥ 120 kg. Bariatric patients undergoing intubation were of similar age and sex, weighed significantly more, had nonsignificant trends toward poorer airway visualization by Cormack-Lehane laryngoscopic grade, and tended toward reduced first-attempt success compared with nonbariatric patients. Rates of airway adverse events (AAEs) were significantly increased for the bariatric group (30/61, 49.2%) compared with the nonbariatric group (135/450, 30.0%) (χ2 likelihood ratio, P = .004). Postintubation desaturation was the most common AAE and was the only criterion significantly increased when comparing bariatric (26%) versus nonbariatric (12%) patients (χ2 likelihood ratio, P = .005). Using patient weight as a continuous variable, nominal logistic regression revealed a significant effect of increasing weight on AAEs (χ2 = 12.9, P = .0003) with a threshold of 105 kg providing an optimal 88% sensitivity for predicting AAEs. The odds of AAEs were increased significantly for those weighing 105 to 119 kg versus those weighing < 105 kg (odds ratio [OR] = 3.4; 95% confidence interval [CI], 1.6-7.5) and for those weighing ≥ 120 kg versus those weighing < 105 kg (OR = 2.5; 95% CI, 1.4-4.3). There was no difference between those weighing ≥ 120 kg versus those weighing 105 to 119 kg (OR = 0.73; 95% CI, 0.3-1.8). CONCLUSION: Air medical retrieval of bariatric patients is safe despite an increased risk of adverse events. Strategies to optimize emergency anesthesia should be used to maximize safe intubation in bariatric patients.

Influence of Chronic Electroconvulsive Seizures on Plasticity-Associated Gene Expression and Perineuronal Nets Within the Hippocampi of Young Adult and Middle-Aged Sprague-Dawley Rats.

BACKGROUND: Electroconvulsive seizure therapy is often used in both treatment-resistant and geriatric depression. However, preclinical studies identifying targets of chronic electroconvulsive seizure (ECS) are predominantly focused on animal models in young adulthood. Given that putative transcriptional, neurogenic, and neuroplastic mechanisms implicated in the behavioral effects of chronic ECS themselves exhibit age-dependent modulation, it remains unknown whether the molecular and cellular targets of chronic ECS vary with age. METHODS: We subjected young adult (2-3 months) and middle-aged (12-13 months), male Sprague Dawley rats to sham or chronic ECS and assessed for despair-like behavior, hippocampal gene expression, hippocampal neurogenesis, and neuroplastic changes in the extracellular matrix, reelin, and perineuronal net numbers. RESULTS: Chronic ECS reduced despair-like behavior at both ages, accompanied by overlapping and unique changes in activity-dependent and trophic factor gene expression. Although chronic ECS had a similar impact on quiescent neural progenitor numbers at both ages, the eventual increase in hippocampal progenitor proliferation was substantially higher in young adulthood. We noted a decline in reelin⁺ cell numbers following chronic ECS only in young adulthood. In contrast, an age-invariant, robust dissolution of perineuronal net numbers that encapsulate parvalbumin⁺ neurons in the hippocampus were observed following chronic ECS. CONCLUSION: Our findings indicate that age is a key variable in determining the nature of chronic ECS-evoked molecular and cellular changes in the hippocampus. This raises the intriguing possibility that chronic ECS may recruit distinct, as well as overlapping, mechanisms to drive antidepressant-like behavioral changes in an age-dependent manner.

Evaluation of real-world outcomes associated with use of a prescription digital therapeutic to treat substance use disorders.

BACKGROUND AND OBJECTIVES: Digital therapeutics can expand the reach and fidelity of behavioral treatment for substance use disorders (SUDs). This analysis evaluated real-world engagement and clinical outcomes in patients diagnosed with SUD who were prescribed reSET®, an FDA-authorized prescription digital therapeutic (PDT). METHODS: Patients were prescribed a 12-week PDT comprising 61 therapy lessons (31 "core" and 30 "keep learning" lessons) and contingency management rewards (positive reinforcement message or monetary gift cards) based on lesson completion and negative urine drug screens. Engagement (defined as any activity in the PDT), retention (any activity in Weeks 9-12), and substance use data were collected automatically by the PDT and analyzed descriptively. Associations between early lesson completion and end-of-treatment outcomes were assessed. RESULTS: Six hundred and fifty-eight patients filled their prescription. Evaluated were 602 patients who were exposed to therapeutic content by completing at least one lesson (median age 37 years, 33% female, 41% male, 26% unreported sex). Median lessons completed was 33 (out of 61 possible), and 52% of patients completed all core modules. Retention in treatment during the last 4 weeks of treatment was 74%, and 62% were abstinent (missing data considered positive). [Correction added on 13 December 2022, after first online publication: In the preceding sentence, the treatment percentage values were revised from 74.6% to 74%.] DISCUSSION AND CONCLUSIONS: Patients with SUD exhibited robust engagement with a PDT, high rates of retention through 12 weeks, and substantial rates of abstinence at end of treatment when the therapeutic was used in a real-world setting. PDT's hold promise as a new way to access effective SUD treatment. SCIENTIFIC SIGNIFICANCE: This study is the first to report real-world PDT engagement and clinical outcomes data from a large, geographically diverse population of patients with SUDs.

Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions.

Our understanding of depression and its treatment has advanced with the advent of ketamine as a rapid-acting antidepressant and the development and refinement of tools capable of selectively altering the activity of populations of neuronal subtypes. This work has resulted in a paradigm shift away from dysregulation of single neurotransmitter systems in depression towards circuit level abnormalities impacting function across multiple brain regions and neurotransmitter systems. Studies on the features of circuit level abnormalities demonstrate structural changes within the prefrontal cortex (PFC) and functional changes in its communication with distal brain structures. Treatments that impact the activity of brain regions, such as transcranial magnetic stimulation or rapid-acting antidepressants like ketamine, appear to reverse depression associated circuit abnormalities though the mechanisms underlying the reversal, as well as development of these abnormalities remains unclear. Recently developed optogenetic and chemogenetic tools that allow high-fidelity control of neuronal activity in preclinical models have begun to elucidate the contributions of the PFC and its circuitry to depression- and anxiety-like behavior. These tools offer unprecedented access to specific circuits and neuronal subpopulations that promise to offer a refined view of the circuit mechanisms surrounding depression and potential mechanistic targets for development and reversal of depression associated circuit abnormalities.

Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents.

Dysfunction of medial prefrontal cortex (mPFC) in association with imbalance of inhibitory and excitatory neurotransmission has been implicated in depression. However, the precise cellular mechanisms underlying this imbalance, particularly for GABAergic transmission in the mPFC, and the link with the rapid acting antidepressant ketamine remains poorly understood. Here we determined the influence of chronic unpredictable stress (CUS), an ethologically validated model of depression, on synaptic markers of GABA neurotransmission, and the influence of a single dose of ketamine on CUS-induced synaptic deficits in mPFC of male rodents. The results demonstrate that CUS decreases GABAergic proteins and the frequency of inhibitory post synaptic currents (IPSCs) of layer V mPFC pyramidal neurons, concomitant with depression-like behaviors. In contrast, a single dose of ketamine can reverse CUS-induced deficits of GABA markers, in conjunction with reversal of CUS-induced depressive-like behaviors. These findings provide further evidence of impairments of GABAergic synapses as key determinants of depressive behavior and highlight ketamine-induced synaptic responses that restore GABA inhibitory, as well as glutamate neurotransmission.

Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function.

Efforts to develop efficacious antidepressant agents with novel mechanisms have been largely unsuccessful since the 1950's until the discovery of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid and sustained antidepressant actions even in treatment-resistant patients. This finding has ushered in a new era for the development of novel rapid-acting antidepressants that act at the NMDA receptor complex, but without dissociative and psychotomimetic side effects of ketamine. Here, we review the current state of rapid-acting antidepressant drug development, including NMDA channel blockers, glycine site agents, and allosteric modulators, as well as ketamine stereoisomers and metabolites. In addition, we focus on the neurobiological mechanisms underlying the actions of these diverse agents and discuss evidence of convergent mechanisms including increased brain-derived neurotrophic factor signaling, increased synthesis of synaptic proteins, and most notably increased GluR1 and synaptic connectivity in the medial prefrontal cortex. These convergent mechanisms provide insight for potential additional novel targets for drug development (e.g., agents that increase synaptic protein synthesis and plasticity). Importantly, the convergent effects on synapse formation and plasticity also reverse the well-documented neuronal and synaptic deficits associated with stress and depression, and thereby target the underlying pathophysiology of major depressive disorder.

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD.

PURPOSE OF REVIEW: Posttraumatic stress disorder (PTSD) is characterized by hyperarousal and recurrent stressful memories after an emotionally traumatic event. Extensive research has been conducted to identify the neurobiological determinants that underlie the pathophysiology of PTSD. In this review, we examine evidence regarding the molecular and cellular pathophysiology of PTSD focusing on two primary brain regions: the vmPFC and the amygdala. RECENT FINDINGS: This discussion includes a review of the molecular alterations related to PTSD, focusing mainly on changes to glucocorticoid receptor signaling. We also examine postmortem gene expression studies that have been conducted to date and the molecular changes that have been observed in peripheral blood studies of PTSD patients. Causal, mechanistic evidence is difficult to obtain in human studies, so we also review preclinical models of PTSD. Integration of peripheral blood and postmortem studies with preclinical models of PTSD has begun to reveal the molecular changes occurring in patients with PTSD. These findings indicate that the pathophysiology of PTSD includes disruption of glucocorticoid signaling and inflammatory systems and occurs at the level of altered gene expression. We will assess the impact of these findings on the future of PTSD molecular research.

Suitability of the forearm for non-invasive blood pressure measurement in children.

BACKGROUND: Measurement of forearm blood pressure (BP) in pediatric patients during general anesthesia is periodically employed despite a lack of evidence for this practice. Upper arm BP measurement may be impossible to perform for either patient or surgical reasons, and the forearm has theoretical benefits over the lower leg when an alternate site is required. We hypothesize that forearm BP measurement provides an accurate and reliable alternative to the upper arm. Published adult data do not support this hypothesis, and the little pediatric data published contain methodological shortcomings. METHODS: A dedicated, externally calibrated noninvasive oscillometer was used to compare BP measurements in the upper arm and ipsilateral forearm of pediatric patients undergoing general anesthesia prior to application of a surgical stimulus. Both upper arm BP and ipsilateral forearm BP were sequentially measured 20 seconds apart on 3 separate occasions with an appropriately sized cuff. The systolic, diastolic, and mean blood pressures were recorded under steady-state conditions. RESULTS: Thirty-five elective surgical patients aged 1 to 10 years were studied. The bias (±limits of agreement) for forearm minus upper arm blood pressures were as follows: mean BP -1.3 mm Hg (±7.2), diastolic BP -3.3 (±5.3), and systolic BP +3.2 mm Hg (±8.3). Differences greater than ±5 mm Hg occurred in 59% (systolic BP), 42% (diastolic BP), and 46% (mean BP) of all observations and greater than ±10 mm Hg in 17% (systolic BP), 8.6% (diastolic BP), and 15% (mean BP). CONCLUSION: The differences within mean ±1.96 standard deviations reside considerably outside the clinically accepted tolerance of ±5 mm Hg. Thus, the forearm may not be used interchangeably with upper limb BP readings in anesthetized healthy children. Future use of the forearm for BP measurement requires a validated anthropomorphically appropriate forearm cuff.

Pharmacodynamics and Pharmacokinetics of Morphine After Cardiac Surgery in Children With and Without Down Syndrome.

OBJECTIVE: To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome. DESIGN: Prospective, single-center observational trial. SETTING: PICU in a university-affiliated pediatric teaching hospital. PATIENTS: Twenty-one children with Down syndrome and 17 without, 3-36 months old, scheduled for cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: A loading dose of morphine (100 µg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 µg/kg/hr. During intensive care, nurses regularly assessed pain and discomfort with validated observational instruments (COMFORT-Behavior scale and Numeric Rating Scale-for pain). These scores guided analgesic and sedative treatment. Plasma samples were obtained for pharmacokinetic analysis. MEASUREMENTS AND MAIN RESULTS: Median COMFORT-Behavior and Numeric Rating Scale scores were not statistically significantly different between the two groups. The median morphine infusion rate during the first 24 hours after surgery was 31.3 µg/kg/hr (interquartile range, 23.4-36.4) in the Down syndrome group versus 31.7 µg/kg/hr (interquartile range, 25.1-36.1) in the control group (p = 1.00). Population pharmacokinetic analysis revealed no statistically significant differences in any of the pharmacokinetic variables of morphine between the children with and without Down syndrome. CONCLUSIONS: This prospective trial showed that there are no differences in pharmacokinetics or pharmacodynamics between children with and without Down syndrome if pain and distress management is titrated to effect based on outcomes of validated assessment instruments. We have no evidence to adjust morphine dosing after cardiac surgery in children with Down syndrome.

What other anomalies? Failure to wean post ventricular septal defect repair secondary to anomalous origin of the left coronary artery from the pulmonary artery.

A six week old infant underwent ventricular septal defect and atrial septal defect closure. Preoperative echocardiography showed evidence of pulmonary hypertension. The post operative course was complicated failure to wean from ventilatory and inotropic support. Echocardiography showed severe left ventricular (LV) dysfunction and suggested some fistulous drainage of the left coronary artery into the right pulmonary artery; this anomalous drainage of the left coronary artery into the right pulmonary artery (ALCAPA) was confirmed with coronary angiogram. Re-implantation of the left coronary artery into the aorta was performed. Extra-corporeal membrane oxygenation (ECMO) was required to allow time for ventricular recovery. Supports were weaned gradually, with concurrent evidence of LV recovery and the child was discharged on postoperative day 30. ALCAPA is rare and typically presents at 8 weeks of age with symptoms of heart failure, as pulmonary pressure falls leading to myocardial ischaemia due to myocardial hypoperfusion with relatively desaturated blood. In our case the pulmonary hypertension and left to right shunt preoperatively were protective, maintaining forward flow of relatively oxygenated blood. While protective to the myocardium this made the preoperative diagnosis of ALCAPA difficult, as there was no flow reversal on Doppler echocardiography. Closure of the septal defects meant this protective effect was lost, with subsequent severe myocardial ischaemia and heart failure. This case highlights the diagnostic challenges of ALCAPA, the 'protective' effects of pulmonary hypertension with ALCAPA, and the importance of early cardiac catheterization in the setting of unexplained failure to wean post cardiac surgery.

Exercise reduces the anxiogenic effects of meta-chlorophenylpiperazine: The role of 5-HT2C receptors in the bed nucleus of the stria terminalis.

Introduction: Two weeks of voluntary exercise in group-housed mice produces a reduction in anxiety-like behaviors across a number of different measures, including a reduction in the anxiety levels typically produced by the anxiogenic serotonergic drug m-chlorophenylpiperazine (mCPP), an agonist at 5-HT2C/2b receptors. We have previously demonstrated that 2-weeks of voluntary exercise blunted the anxiogenic effects of systemic mCPP, and we have also shown that mCPP infused into the bed nucleus of the stria terminalis (BNST) is anxiogenic. Here we follow up on these reports. Methods: In Experiment 1 we infused several doses of mCPP into the BNST with or without the 5-HT2C antagonist SB242084. In Experiment 2, we administered mCPP into amygdala subregions and the dorsal hippocampus to investigate site specificity. In Experiment 4 we lesioned the BNST and subsequently infused mCPP systemically, and in Experiment 4 we used RNAscope® to assess BNST 5-HT2C transcripts following wheel running. Results: BNST mCPP infusion increased acoustic startle responding, which was by 5-HT2C antagonism, while neither mCPP infused into the amygdala nor hippocampus was anxiogenic. Lesions of the BNST prevented the anxiogenic effect of systemically administered mCPP. Lastly, exercise reduced 5-HT2C transcripts in the BNST. Discussion: These results suggest that the BNST is a critical site of action for the effects of exercise on mCPP. Together these data suggest that exercise may reduce 5-HT2C receptor function in the BNST, which may, in part, explain some of the anxiolytic effects associated with wheel running.

A prospective crossover comparison of neurally adjusted ventilatory assist and pressure-support ventilation in a pediatric and neonatal intensive care unit population.

OBJECTIVE: To compare neurally adjusted ventilatory assist ventilation with pressure-support ventilation. DESIGN: Prospective, crossover comparison study. SETTING: Tertiary care pediatric and neonatal intensive care unit. PATIENTS: Sixteen ventilated infants and children: mean age = 9.7 months (range = 2 days-4 yrs) and mean weight = 6.2 kg (range = 2.4-13.7kg). INTERVENTIONS: A modified nasogastric tube was inserted and correct positioning was confirmed. Patients were ventilated in pressure-support mode with a pneumatic trigger for a 30-min period and then in neurally adjusted ventilatory assist mode for up to 4 hrs. MEASUREMENTS AND MAIN RESULTS: Data collected for comparison included activating trigger (neural vs. pneumatic), peak and mean airway pressures, expired minute and tidal volumes, heart rate, respiratory rate, pulse oximetry, end-tidal CO2 and arterial blood gases. Synchrony was improved in neurally adjusted ventilatory assist mode with 65% (+/-21%) of breaths triggered neurally vs. 35% pneumatically (p < .001) and 85% (+/-8%) of breaths cycled-off neurally vs. 15% pneumatically (p = .0001). The peak airway pressure in neurally adjusted ventilatory assist mode was significantly lower than in pressure-support mode with a 28% decrease in pressure after 30 mins (p = .003) and 32% decrease after 3 hrs (p < .001). Mean airway pressure was reduced by 11% at 30 mins (p = .13) and 9% at 3 hrs (p = .31) in neurally adjusted ventilatory assist mode although this did not reach statistical significance. Patient hemodynamics and gas exchange remained stable for the study period. No adverse patient events or device effects were noted. CONCLUSIONS: In a neonatal and pediatric intensive care unit population, ventilation in neurally adjusted ventilatory assist mode was associated with improved patient-ventilator synchrony and lower peak airway pressure when compared with pressure-support ventilation with a pneumatic trigger. Ventilating patients in this new mode seem to be safe and well tolerated.

Rapastinel, an NMDAR positive modulator, produces distinct behavioral, sleep, and EEG profiles compared with ketamine.

Rapastinel, a positive NMDAR modulator, produces rapid-acting and long-lasting antidepressant-like effects; however, unlike ketamine, the abuse potential for rapastinel is minimal. Ketamine has also been shown to induce psychotomimetic/dissociative side effects, aberrant gamma oscillations, and effects similar to sleep deprivation, which may potentially limit its clinical use. In this study, we compared the side effect profile and potential sleep-altering properties of rapastinel (3, 10, and 30 mg/kg) to ketamine (30 mg/kg) in rodents. In addition, we investigated corresponding changes in transcriptomics and proteomics. Rapastinel exhibited no effect on locomotor activity and prepulse inhibition in mice, while ketamine induced a significant increase in locomotor activity and a significant decrease in prepulse inhibition, which are indications of a psychosis-like state. The effects of rapastinel on sleep architecture were minimal, and rapastinel did not alter gamma frequency oscillations. In contrast, ketamine administration resulted in a greater latency to slow wave and REM sleep, disrupted duration of sleep, and affected duration of wakefulness during sleep. Further, ketamine increased cortical oscillations in the gamma frequency range, which is a property associated with psychosis. Rapastinel induced similar plasticity-related changes in transcriptomics to ketamine in rats but differed in several gene ontology classes, some of which may be involved in the regulation of sleep. In conclusion, rapastinel demonstrated a lower propensity than ketamine to induce CNS-related adverse side effects and sleep disturbances.

Ketamine increases vmPFC activity: Effects of (R)- and (S)-stereoisomers and (2R,6R)-hydroxynorketamine metabolite.

Ketamine, an NMDA receptor antagonist and fast acting antidepressant, produces a rapid burst of glutamate in the ventral medial prefrontal cortex (mPFC). Preclinical studies have demonstrated that pyramidal cell activity in the vmPFC is necessary for the rapid antidepressant response to ketamine in rodents. We sought to characterize the effects of ketamine and its stereoisomers (R and S), as well as a metabolite, (2R,6R)-hydroxynorketamine (HNK), on vmPFC activity using a genetically encoded calcium indicator (GCaMP6f). Ratiometric fiber photometry was utilized to monitor GCaMP6f fluorescence in pyramidal cells of mouse vmPFC prior to and immediately following administration of compounds. GCaMP6f signal was assessed to determine correspondance of activity between compounds. We observed dose dependent effects with (R,S)-ketamine (3-100 mg/kg), with the greatest effects on GCaMP6f activity at 30 mg/kg and lasting up to 20 min. (S)-ketamine (15 mg/kg), which has high affinity for the NMDA receptor channel produced similar effects to (R,S)-ketamine, but compounds with low NMDA receptor affinity, including (R)-ketamine (15 mg/kg) and (2R,6R)-HNK (30 mg/kg) had little or no effect on GCaMP6f activity. The initial response to administration of (R,S)-ketamine as well as (S)-ketamine is characterized by a brief period of robust GCaMP6f activation, consistent with increased activity of vmPFC pyramidal neurons. Because (2R,6R)-HNK and (R)-ketamine are reported to have antidepressant activity in rodent models the current results indicate that different initiating mechanisms lead to similar brain adaptive consequences that underlie the rapid antidepressant responses.

The impact of introducing nurse-led analgesia and sedation guidelines in ventilated infants following cardiac surgery.

INTRODUCTION: Enhanced clinical outcomes in the Paediatric Intensive Care Unit following standardisation of analgesia and sedation practice are reported. Little is known about the impact of standardisation of analgesia and sedation practice including incorporation of a validated distress assessment instrument on infants post cardiac surgery, a subset of whom have Trisomy 21. This study investigated whether the parallel introduction of nurse-led analgesia and sedation guidelines including regular distress assessment would impact on morphine administered to infants post cardiac surgery, and whether any differences observed would be amplified within the Trisomy 21 population. METHODOLOGY: A retrospective single centre before/after study design was used. Patients aged between 44 weeks postconceptual age and one year old who had open cardiothoracic surgery were included. RESULTS: 61 patients before and 64 patients after the intervention were included. After the intervention, a reduction in the amount of morphine administered was not evident, while greater use of adjuvant sedatives and analgesics was observed. Patients with Trisomy 21 had a shorter duration of mechanical ventilation after the change in practice. CONCLUSION: The findings from this study affirm the importance of the nurses' role in managing prescribed analgesia and sedation supported by best available evidence. A continued education and awareness focus on analgesia and sedation management in the pursuit of best patient care is imperative.

Health-related quality of life after prolonged pediatric intensive care unit stay.

OBJECTIVE: To investigate the long-term health-related quality of life (HRQOL) outcomes for patients requiring at least 28 days of pediatric intensive care. DESIGN: Retrospective cohort and prospective follow-up study. SETTING: A 21-bed pediatric intensive care unit (PICU) in a university-affiliated, tertiary referral pediatric hospital. PATIENTS: One hundred ninety-three patients who spent 28 days or longer in the PICU between January 1, 1997 and December 31, 2004. INTERVENTIONS: Quality of life was measured using the Pediatric Quality of Life Inventory (Peds QL 4.0) parent-proxy version at 2 to 10 yrs after discharge. The PedsQL 4.0 is a modular measure of HRQOL, which is reliable in children aged 2 to 18 yrs. It generates a total score and physical, emotional, social, school, and psychosocial subscores. MEASUREMENTS AND MAIN RESULTS: Of the 193 patients, 41 died during their PICU admission and 27 died between PICU discharge and follow-up. Quality of life questionnaires were posted to parents of 108 of the 125 survivors and 70 were returned completed. Forty children (57.1%) had scores indicating a normal quality of life, whereas 30 (42.9%) had scores indicating impaired HRQOL. Of these, 14 (20%) had scores indicating poor quality of life with ongoing disabling health problems requiring hospitalization or the equivalent. CONCLUSIONS: Our results indicate that, while long PICU stay is associated with significant mortality, the long-term HRQOL is normal for the majority of surviving children.

Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects.

Impaired function in the medial prefrontal cortex (mPFC) contributes to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by mPFC activity. The mPFC contains multiple types of pyramidal cells, but it is unclear whether a particular subtype mediates the rapid antidepressant actions of ketamine. Here we tested two major subtypes, Drd1 and Drd2 dopamine receptor expressing pyramidal neurons and found that activating Drd1 expressing pyramidal cells in the mPFC produces rapid and long-lasting antidepressant and anxiolytic responses. In contrast, photostimulation of Drd2 expressing pyramidal cells was ineffective across anxiety-like and depression-like measures. Disruption of Drd1 activity also blocked the rapid antidepressant effects of ketamine. Finally, we demonstrate that stimulation of mPFC Drd1 terminals in the BLA recapitulates the antidepressant effects of somatic stimulation. These findings aid in understanding the cellular target neurons in the mPFC and the downstream circuitry involved in rapid antidepressant responses.

Two Weeks of Variable Stress Increases Gamma-H2AX Levels in the Mouse Bed Nucleus of the Stria Terminalis.

Recent reports demonstrate that DNA damage is induced, and rapidly repaired, in circuits activated by experience. Moreover, stress hormones are known to slow DNA repair, suggesting that prolonged stress may result in persistent DNA damage. Prolonged stress is known to negatively impact physical and mental health; however, DNA damage as a factor in stress pathology has only begun to be explored. Histone H2A-X phosphorylated at serine 139 (γH2AX) is a marker of DNA double-strand breaks (DSB), a type of damage that may lead to cell death if unrepaired. We hypothesized that a 14-day period of variable stress exposure sufficient to alter anxiety-like behavior in male C57BL/6J mice would produce an increase in γH2AX levels in the bed nucleus of the stria terminalis (BNST), a region implicated in anxiety and stress regulation. We observed that 14 days of variable stress, but not a single stress exposure, was associated with increased levels of γH2AX 24 h after termination of the stress paradigm. Further investigation found that phosphorylation levels of a pair of kinases associated with the DNA damage response, glycogen synthase kinase 3 ß (GSK3ß) and p38 mitogen-activated protein kinase (MAPK) were also elevated following variable stress. Our results suggest that unrepaired DNA DSBs and/or repetitive attempted repair may represent an important component of the allostatic load that stress places on the brain.

Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior.

BACKGROUND: Chronic stress-induced inflammatory responses occur in part via danger-associated molecular pattern (DAMP) molecules, such as high mobility group box 1 protein (HMGB1), but the receptor(s) underlying DAMP signaling have not been identified. METHODS: Microglia morphology and DAMP signaling in enriched rat hippocampal microglia were examined during the development and expression of chronic unpredictable stress (CUS)-induced behavioral deficits, including long-term, persistent changes after CUS. RESULTS: The results show that CUS promotes significant morphological changes and causes robust upregulation of HMGB1 messenger RNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent upregulation of receptor for advanced glycation end products (RAGE) messenger RNA, but not toll-like receptor 4 in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia as determined by flow cytometry and returned to basal levels 5 weeks after CUS. Importantly, exposure to short-term stress was sufficient to increase RAGE surface expression as well as anhedonic behavior, reflecting a primed state that results from a persistent increase in RAGE messenger RNA expression. Further evidence for DAMP signaling in behavioral responses is provided by evidence that HMGB1 infusion into the hippocampus was sufficient to cause anhedonic behavior and by evidence that RAGE knockout mice were resilient to stress-induced anhedonia. CONCLUSIONS: Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure.

Activity-Dependent Brain-Derived Neurotrophic Factor Release Is Required for the Rapid Antidepressant Actions of Scopolamine.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology and treatment of depression. Recent clinical studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in patients with depression. Rodent studies demonstrate that scopolamine increases glutamate transmission and synaptogenesis in the medial prefrontal cortex (mPFC). Here we tested the hypothesis that activity-dependent BDNF release within the mPFC is necessary for the antidepressant actions of scopolamine. METHODS: Behavioral effects of scopolamine were assessed in BDNF Val/Met knock-in mice, in which BDNF processing and release are impaired. In addition, intra-mPFC infusion of a BDNF-neutralizing antibody was performed to test the necessity of BDNF release in driving scopolamine-induced behavioral responses. Further in vivo and in vitro experiments were performed to delineate BDNF-dependent mechanisms underlying the effects of scopolamine. RESULTS: We found that BDNF Met/Met mice have attenuated responses to scopolamine and that anti-BDNF antibody infusions into the mPFC prevented the antidepressant-like behavioral effects of scopolamine. In vitro experiments show that scopolamine rapidly stimulates BDNF release and tropomyosin receptor kinase B-extracellular signal-regulated kinase signaling. Moreover, these effects require alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor activation and are blocked by neuronal silencing. Importantly, pretreatment with verapamil prevented scopolamine-induced behavioral responses and BDNF-tropomyosin receptor kinase B signaling, suggesting that these effects are dependent on activation of voltage-dependent calcium channels. CONCLUSIONS: The results identify an essential role for activity-dependent BDNF release in the rapid antidepressant effects of scopolamine. Attenuation of responses in BDNF Met mice indicates that patients with the Met allele may be less responsive to scopolamine.