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Background In patients with acute neurological injury, abrupt temperature change exacerbates increased intracranial pressures and negatively affects perfusion pressure and cerebral blood flow. Critical care nurses must provide coordinated and effective interventions to maintain normothermia without precipitating shivering immediately after acute neurological injury in pediatric patients. Objective To improve hyperthermia management in a 40-bed pediatric intensive care unit, an interdisciplinary pediatric critical care team developed, implemented, and evaluated a targeted temperature management protocol. Methods The project was guided by the organization’s plan-do-study-act quality improvement process. Quality improvement was assessed retrospectively using electronic medical records of patients meeting eligibility criteria. Samples of pediatric patients who received temperature interventions were compared before and after protocol implementation. The protocol included environmental, pharmacological, and body surface cooling device interventions, as well as use of a bedside shivering assessment scale and stepwise interventions to prevent and control shivering. Results Before implementation of the targeted temperature management protocol, 64% of patients had documented temperatures higher than 37.5 °C, and body surface cooling devices were used in 10% of patients. After protocol implementation, more than 80% of patients had documented temperatures higher than 37.5 °C, and body surface cooling devices were used in 62% of patients. Four patients (6%) before and 5 patients (31%) after protocol implementation were treated with body surface cooling without requiring use of neuromuscular blockade. Conclusions Creation and implementation of a targeted temperature management protocol increased nurses’ documented use of body surface cooling to manage hyperthermia in pediatric intensive care unit patients with acute neurological injury.

Pediatric neurocritical care survivorship is frequently accompanied by functional impairments. Lack of prognostic biomarkers is a barrier to early identification and management of impairment. We explored the association between blood biomarkers and functional impairment in children with acute acquired brain injury. This study is a secondary analysis of a randomized control trial evaluating early versus usual care rehabilitation in the pediatric intensive care unit (PICU). Forty-four children (17 [39%] female, median age 11 [interquartile range 6–13] years) with acute acquired brain injury admitted to the PICU were studied. A single center obtained serum samples on admission days 0, 1, 3, 5, and the day closest to hospital discharge. Biomarkers relevant to brain injury (neuron specific enolase [NSE], S100b), inflammation (interleukin [IL-6], C-reactive protein), and regeneration (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF]) were collected. Biomarkers were analyzed using a Luminex® bioassay. Functional status scale (FSS) scores were abstracted from the medical record. New functional impairment was defined as a (worse) FSS score at hospital discharge compared to pre-PICU (baseline). Individual biomarker fluorescence index (FI) values for each sample collection day were correlated with new functional impairment using Spearman rank correlation coefficient (ρ). Trends in repeated measures of biomarker FI over time were explored graphically, and the association between repeated measures of biomarker FI and new functional impairment was analyzed using covariate adjusted linear mixed-effect models. Functional impairment was inversely correlated with markers of regeneration and plasticity including BDNF at day 3 (ρ = − 0.404, p = .015), day 5 (ρ = − 0.549, p = 0.005) and hospital discharge (ρ = − 0.420, p = 0.026) and VEGF at day 1 (ρ = − 0.282, p = 0.008) and hospital discharge (ρ = − 0.378, p = 0.047), such that lower levels of both markers at each time point were associated with greater impairment. Similarly, repeated measures of BDNF and VEGF were inversely correlated with new functional impairment (B = − 0.001, p = 0.001 and B = − 0.001, p = 0.003, respectively). NSE, a biomarker of acute brain injury, showed a positive correlation between day 0 levels and new functional impairment (ρ = 0.320, p = 0.044). Blood-based biomarkers of regeneration and plasticity may hold prognostic utility for functional impairment among pediatric patients with neurocritical illness and warrant further investigation.

The cytokine-inducible SH2 domain containing protein (CISH) is the founding member of the suppressor of cytokine signaling (SOCS) family of negative feedback regulators and has been shown to be a physiological regulator of signaling in immune cells. This study sought to investigate novel functions for CISH outside of the immune system. Mice deficient in CISH were generated and analyzed using a range of metabolic and other parameters, including in response to a high fat diet and leptin administration. CISH knockout mice possessed decreased body fat and showed resistance to diet-induced obesity. This was associated with reduced food intake, but unaltered energy expenditure and microbiota composition. CISH ablation resulted in reduced basal expression of the orexigenic Agrp gene in the arcuate nucleus (ARC) region of the brain. Cish was basally expressed in the ARC, with evidence of co-expression with the leptin receptor (Lepr) gene in Agrp-positive neurons. CISH-deficient mice also showed enhanced leptin responsiveness, although Cish expression was not itself modulated by leptin. CISH-deficient mice additionally exhibited improved insulin sensitivity on a high-fat diet, but not glucose tolerance despite reduced body weight. These data identify CISH as an important regulator of homeostasis through impacts on appetite control, mediated at least in part by negative regulation of the anorexigenic effects of leptin, and impacts on glucose metabolism.

Accurate snowfall measurements are necessary for meteorology, hydrology, and climate research. Typical uses include creating and calibrating gridded precipitation products, the verification of model simulations, driving hydrologic models, input into aircraft deicing processes, and estimating streamflow runoff in the spring. These applications are significantly impacted by errors in solid precipitation measurements. The recent WMO Solid Precipitation Intercomparison Experiment (SPICE) attempted to characterize and reduce some of the measurement uncertainties through an international effort involving 15 countries utilizing over 20 types and models of precipitation gauges from various manufacturers. Key results from WMO-SPICE are presented herein. Recent work and future research opportunities that build on the results of WMO-SPICE are also highlighted.

The central nucleus of the amygdala (CeA) is a key hub integrating sensory inputs and modulating behavioural outputs. The CeA is a complex structure with discrete subdivisions, high peptidergic heterogeneity and broad CNS afferent and efferent projections. While several neuropeptide systems within the CeA have been examined in detail, less is known about CeA preproenkephalin (ppENK) cells. Here, we used a recently developed transgenic Penk-Cre mouse line to advance our understanding of the efferent and afferent connectivity of ppENK in the CeA. First, to determine the fidelity of Cre expression in Penk-Cre transgenic mice, we conducted RNAscope in the CeA of Penk-Cre mice. Our analysis revealed that 96.6 % of CeA Cre+ neurons co-expressed pENK mRNA, and 99.7 % of CeA pENK+ neurons co-expressed Cre mRNA, indicating faithful recapitulation of Cre expression in CeA ppENK-expressing cells, supporting the fidelity of the Penk-Cre reporter mouse. Anterograde tracing of CeAsupPenk/supcells showed strong efferent projections to the extended amygdala, midbrain and hindbrain PBN and NTS. Retrograde tracing of Penk afferents to the CeA were more restricted, with primary innervation originating within the amygdala complex and bed nucleus of the stria terminalis, and minor innervation from the parabrachial nucleus and nucleus of the solitary tract. Together, our data provide a comprehensive map of ENKergic efferent and afferent connectivity of the CeA in Penk-Cre mice. Further, we highlight both the utility and limitations of the Penk-Cre mice to study the function of CeA, PBN and NTS ppENK cells.

Augmented reality (AR) is a relatively new technology that allows for digitally generated three-dimensional representations to be integrated with real environmental stimuli. AR can make use of smart phones, tablets, or other devices to achieve a highly stimulating learning environment and hands-on immersive experience. The use of AR in industry is becoming widespread with applications being developed for use not just for entertainment and gaming but also healthcare, retail and marketing, education, military, travel and tourism, automotive industry, manufacturing, architecture, and engineering. Due to the distinct learning advantages that AR offers, such as remote learning and interactive simulations, AR-based teaching programs are also increasingly being adopted within medical schools across the world. These advantages are further highlighted by the current COVID-19 pandemic, which has caused an even greater shift towards online learning. In this review, we investigate the use of AR in medical training/education and its effect on students’ experiences and learning outcomes. This includes the main goals of AR-based learning, such as to simplify the delivery and enhance the comprehension of complex information. We also describe how AR can enhance the experiences of medical students, by improving knowledge and understanding, practical skills and social skills. These concepts are discussed within the context of specific AR medical training programs, such as HoloHuman, OculAR SIM, and HoloPatient. Finally, we discuss the challenges of AR in learning and teaching and propose future directions for the use of this technology in medical education.

An emerging novel therapeutic agent for major depressive disorder, minocycline, has the potential to influence both gut microbiome and inflammatory status. The present study showed that chronic high fat diet feeding led to changes in both behaviour and the gut microbiome in male mice, without an overt inflammatory response. The diet-induced behavioural changes were characterised as increased immobility in the forced swim test and changes in locomotor activities in the open field test. Minocycline significantly altered the gut microbiome, rendering a community distinctly different to both untreated healthy and diet-affected states. In contrast, minocycline did not reverse high fat diet-induced changes in behaviour.

s: Few feasibility, safety, and efficacy data exist regarding ICU-based rehabilitative services for children. We hypothesized that early protocolized assessment and therapy would be feasible and safe versus usual care in pediatric neurocritical care patients.Randomized controlled trial.Three tertiary care PICUs in the United States.Fifty-eight children between the ages of 3-17 years with new traumatic or nontraumatic brain insult and expected ICU admission greater than 48 hours.Early protocolized (consultation of physical therapy, occupational therapy, and speech and language therapy within 72 hr ICU admission, n = 26) or usual care (consultation per treating team, n = 32).Primary outcomes were consultation timing, treatment type, and frequency of deferrals and safety events. Secondary outcomes included patient and family functional and quality of life outcomes at 6 months. Comparing early protocolized (n = 26) and usual care groups (n = 32), physical therapy was consulted during the hospital admission in 26 of 26 versus 28 of 32 subjects (p = 0.062) on day 2.4 ± 0.8 versus 7.7 ± 4.8 (p = 0.001); occupational therapy in 26 of 26 versus 23 of 32 (p = 0.003), on day 2.3 ± 0.6 versus 6.9 ± 4.8 (p = 0.001); and speech and language therapy in 26 of 26 versus 17 of 32 (p = 0.011) on day 2.3 ± 0.7 versus 13.0 ± 10.8 (p = 0.026). More children in the early protocolized group had consults and treatments occur in the ICU versus ward for all three services (all p0.001). Eleven sessions were discontinued early: nine during physical therapy and two during occupational therapy, none impacting patient outcome. There were no group differences in functional or quality of life outcomes.A protocol for early personalized rehabilitation by physical therapy, occupational therapy, and speech and language therapy in pediatric neurocritical care patients could be safely implemented and led to more ICU-based treatment sessions, accelerating the temporal profile and changing composition of interventions versus usual care, but not altering the total dose of rehabilitation.

Background Antimicrobial impregnated catheters (AIC) are one strategy to prevent CLABSI with existing data for central lines required for short duration, however, the strength of evidence, particularly for children, is lacking. Recent 3-year CLABSI data at our institution show 60 (51%) infections occurred in central lines within 8 weeks of insertion, suggesting an opportunity for evaluation of an intervention targeting this time frame. We implemented AIC to evaluate their effectiveness in reducing CLABSI standardized infection ratio (SIR) in patients requiring central venous access for less than 8 weeks. We also monitored for complications (malfunction, line exchange, fungal infection). Methods A stepped wedge observational design was used to implement Minocycline + Rifampin impregnated catheters in a rolling fashion across the institution. Children > 3kg were eligible if admitted to a participating unit and required central venous access through a peripherally inserted central catheter (PICC), non-tunneled catheter, or tunneled non-cuffed femoral catheter for < 8 weeks. Units, prioritized based on CLABSI SIR, were added to the intervention monthly until AIC were used throughout the institution. A multidisciplinary team (infectious diseases and infection control experts, CLABSI leaders, unit-based physicians and nurses, proceduralists, supply chain) met weekly to facilitate implementation, assess for CLABSI and monitor for complications. Figure 1. Study design. This figure describes the stepped wedge study design where units were phased into the invention on a rolling monthly basis allowing for comparison between and within units. The shaded boxes represent time periods when units were using antimicrobial impregnated catheters and the white boxes represent time periods when units were using standard non-impregnated catheters. Results AIC were systematically implemented over a 7-month period. The institution’s CLABSI SIR decreased from 0.80 to 0.59 during this timeframe. There were no NHSH defined CLABSI in patients with an AIC during the intervention. Obstacles included shortage of catheters due to supply chain disruption, adjustment of technique for line insertion and cracked/broken lines. Infections and complications were reviewed by the multidisciplinary team and compared to historical rates with non-impregnated lines. This figure shows the institution’s rolling 12-month SIR during the intervention period. Conclusion CLABSI SIR decreased at our institution during the intervention period. While many efforts likely led to this reduction (optimizing maintenance bundle, unit based CLABSI initiatives), we believe the use of AIC contributed to this improvement. There were no pediatric-specific safety events identified during implementation. Disclosures Ravi Jhaveri, MD, AstraZeneca (Consultant)Dynavax (Consultant)Elsevier (Other Financial or Material Support, Editorial stipend as Co-EiC, Clinical Therapeutics)Hologic (Consultant)Seqirus (Consultant)

Blood culture overuse in the pediatric intensive care unit (PICU) can lead to unnecessary antibiotic use and contribute to antibiotic resistance. Optimizing blood culture practices through diagnostic stewardship may reduce unnecessary blood cultures and antibiotics.To evaluate the association of a 14-site multidisciplinary PICU blood culture collaborative with culture rates, antibiotic use, and patient outcomes.This prospective quality improvement (QI) collaborative involved 14 PICUs across the United States from 2017 to 2020 for the Bright STAR (Testing Stewardship for Antibiotic Reduction) collaborative. Data were collected from each participating PICU and from the Children's Hospital Association Pediatric Health Information System for prespecified primary and secondary outcomes.A local QI program focusing on blood culture practices in the PICU (facilitated by a larger QI collaborative).The primary outcome was blood culture rates (per 1000 patient-days/mo). Secondary outcomes included broad-spectrum antibiotic use (total days of therapy and new initiations of broad-spectrum antibiotics ≥3 days after PICU admission) and PICU rates of central line-associated bloodstream infection (CLABSI), Clostridioides difficile infection, mortality, readmission, length of stay, sepsis, and severe sepsis/septic shock.Across the 14 PICUs, the blood culture rate was 149.4 per 1000 patient-days/mo preimplementation and 100.5 per 1000 patient-days/mo postimplementation, for a 33% relative reduction (95% CI, 26%-39%). Comparing the periods before and after implementation, the rate of broad-spectrum antibiotic use decreased from 506 days to 440 days per 1000 patient-days/mo, respectively, a 13% relative reduction (95% CI, 7%-19%). The broad-spectrum antibiotic initiation rate decreased from 58.1 to 53.6 initiations/1000 patient-days/mo, an 8% relative reduction (95% CI, 4%-11%). Rates of CLABSI decreased from 1.8 to 1.1 per 1000 central venous line days/mo, a 36% relative reduction (95% CI, 20%-49%). Mortality, length of stay, readmission, sepsis, and severe sepsis/septic shock were similar before and after implementation.Multidisciplinary diagnostic stewardship interventions can reduce blood culture and antibiotic use in the PICU. Future work will determine optimal strategies for wider-scale dissemination of diagnostic stewardship in this setting while monitoring patient safety and balancing measures.

Objective Children at high risk for respiratory complication after adenotonsillectomy are often admitted to a pediatric intensive care unit (PICU) postoperatively. Although many patients receive care in such units, it is unknown how many utilize critical care resources. Methods A review was conducted to audit intensive care needs of postadenotonsillectomy patients admitted to the PICU at a tertiary, academic, pediatric hospital between July 2013, and March 2017. Demographic information, ICU indication, polysomnogram results, and comorbidities were collected. Patients were defined as needing ICU resources based on supplemental oxygen requirements greater than 2 L between 2 to 24 hours postoperatively, more than two desaturation events in a 2-hour period, or more than hourly nursing intervention. Factors associated with utilization of ICU resources were assessed. Results One hundred and ten patients were admitted to the PICU after adenotonsillectomy. Median age was 4.2 years, median body mass index was 90.8 percentile, and median apnea hypopnea index (AHI) was 34.3. Twenty patients (18.2%) utilized ICU resources by criteria defined. Of these patients, 14 were known to need such resources by 2 hours postoperatively (70%, negative predictive value 93.8%). Neither AHI nor obesity status was correlated with need for resources; however, resource need was associated with young age, gastrostomy tube status, and neuromuscular disorders (P = 0.048, P = 0.002 and 0.013, respectively). Conclusion Most high-risk adenotonsillectomy patients do not utilize critical care resources despite their increased perioperative risk. Patients with respiratory complications are frequently identifiable within the first 2 hours of surgery. Level of evidence 4 Laryngoscope, 129:1229-1234, 2019.

RXFP3 (relaxin-family peptide 3 receptor) is the cognate G-protein-coupled receptor for the neuropeptide, relaxin-3. RXFP3 is expressed widely throughout the brain, including the hypothalamus, where it has been shown to modulate feeding behavior and neuroendocrine activity in rodents. In order to better characterize its potential mechanisms of action, this study determined whether RXFP3 is expressed by dopaminergic neurons within the arcuate nucleus (ARC) and dorsomedial hypothalamus (DMH), in addition to the ventral tegmental area (VTA). Neurons that express RXFP3 were visualized in coronal brain sections from RXFP3-Cre/tdTomato mice, which express the tdTomato fluorophore within RXFP3-positive cells, and dopaminergic neurons in these areas were visualized by simultaneous immunohistochemical detection of tyrosine hydroxylase-immunoreactivity (TH-IR). Approximately 20% of ARC neurons containing TH-IR coexpressed tdTomato fluorescence, suggesting that RXFP3 can influence the dopamine pathway from the ARC to the pituitary gland that controls prolactin release. The ability of prolactin to reduce leptin sensitivity and increase food consumption therefore represents a potential mechanism by which RXFP3 activation influences feeding. A similar proportion of DMH neurons containing TH-IR expressed RXFP3-related tdTomato fluorescence, consistent with a possible RXFP3-mediated regulation of stress and neuroendocrine circuits. In contrast, RXFP3 was barely detected within the VTA. TdTomato signal was absent from the ARC and DMH in sections from Rosa26-tdTomato mice, suggesting that the cells identified in RXFP3-Cre/tdTomato mice expressed authentic RXFP3-related tdTomato fluorescence. Together, these findings identify potential hypothalamic mechanisms through which RXFP3 influences neuroendocrine control of metabolism, and further highlight the therapeutic potential of targeting RXFP3 in feeding-related disorders.

BACKGROUND: Pediatric Asthma Assessment tools used to guide the weaning of inhaled therapies during inpatient hospitalization require further evaluation and validation. This study aimed to compare 2 asthma assessment tools: an asthma scale versus an asthma score. METHODS: A prospective, physician-blinded, comparison study was conducted in 2 separate 6-week phases of patients > 2 y old admitted to a tertiary care children's hospital with status asthmaticus between July and November 2014. The asthma scale categorized 5 components (oxygen, auscultation, dyspnea, breathing frequency, and pulse oximetry) into 1 of 3 respiratory assessments: mild, moderate, or severe. The asthma score used a sum of the components, resulting in a score of 1–15. Study tool predictability was measured using a metric based on hours on continuous albuterol, with area under the curve ≥ 0.8 indicating good predictability. Agreement between clinicians was measured using the Cohen kappa statistic. Study tool clinical correlation was measured using Spearman coefficient. Usability was evaluated using web-based surveys. RESULTS: Phase 1 included 1,971 assessments (97 unique subjects), whereas phase 2 included 607 assessments (69 unique subjects). Using the continuous albuterol metric, predictability of the asthma scale had an area under the curve of 0.62 versus the asthma score area under the curve of 0.80. Agreement early in hospitalization for the asthma scale was kappa = 0.34 (95% CI 0.18–0.5; n = 84) versus kappa = 0.55 (95% CI 0.35–0.76; n = 44) for the asthma score. Agreement late in hospitalization for the asthma scale was kappa = 0.38 (95% CI 0.17–0.59; n = 66) versus kappa = 0.41 (95% CI 0.13–0.69; n = 33) for the asthma score. Clinical correlation for the asthma scale (no. = 1,908) was r = 0.57 (P < .001) versus r = 0.80 (P < .001) for the asthma score (no. = 558). Mean asthma scale usability was 3.38 versus 3.68 for the asthma score. CONCLUSIONS: The asthma score showed better clinical predictability and clinical correlation compared to the asthma scale. Numerical scores provided more objective assessments compared to categorical scores. Validated scoring tools such as the asthma score are crucial to the success of management of inpatient asthma care.

The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that aim to stimulate mitochondrial biogenesis to boost ATP generation above a critical disease threshold. Here, we examine the effects of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), on mitochondrial biogenesis in cybrid cells containing >90% of the m.3243A>G mutation associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PioG + dNs combination treatment increased mtDNA copy number and mitochondrial mass in both control (CON) and m.3243A>G (MUT) cybrids, with no adverse effects on cell proliferation. PioG + dNs also increased mtDNA-encoded transcripts in CON cybrids, but had the opposite effect in MUT cybrids, reducing the already elevated transcript levels. Steady-state levels of mature oxidative phosphorylation (OXPHOS) protein complexes were increased by PioG + dNs treatment in CON cybrids, but were unchanged in MUT cybrids. However, treatment was able to significantly increase maximal mitochondrial oxygen consumption rates and cell respiratory control ratios in both CON and MUT cybrids. Overall, these findings highlight the ability of PioG + dNs to improve mitochondrial respiratory function in cybrid cells containing the m.3243A>G MELAS mutation, as well as their potential for development into novel therapies to treat mitochondrial disease.

Sundowners are downslope windstorms that occur over the southern slopes of the east–west-trending Santa Ynez range in Santa Barbara County, California. In the past, many extreme fires in the area, including the Painted Cave, Montecito Tea, Jesusita, and Sherpa fires, have occurred during sundowner events. A high-resolution 11-yr dynamically downscaled climatology was produced using a numerical weather prediction model in order to elucidate the general dynamical characteristics of sundowners. The downscaled climatology is validated with observations during the 2016 Sherpa fire. A sundowner index (SI) is computed from the climatology that quantifies the magnitude of adiabatic warming and northerly (downslope) wind component during sundowner events. The SI allows for the classification of historical events into categories of various strengths. The primary characteristics of strong sundowners from this classification include 1) internal gravity wave breaking over the Santa Ynez range, 2) initiation in the western Santa Ynez range with eastward progression over the course of a day, 3) a maximum likelihood of occurrence in April and May near 2000 Pacific standard time, and 4) a limited downstream extent for most events, such that the long-term historical weather station, Santa Barbara airport, often does not experience moderate events. Analysis of an operational forecast rubric composed of the surface pressure difference from Bakersfield to Santa Barbara indicates that this rubric is not skillful. However, offshore pressure gradients are skillful and are related to the strong northwesterly alongshore jet. The findings presented herein can be used to provide guidance for fire weather forecasts and support resource allocation during fire suppression efforts.

Downslope Sundowner winds in southern California's Santa Ynez Mountains favor wildfire growth. To explore differences between Sundowners and Santa Ana winds (SAWs), we use surface observations from 1979 to 2014 to develop a climatology of extreme Sundowner days. The climatology was compared to an existing SAW index from 1979 to 2012. Sundowner (SAW) occurrence peaks in late spring (winter). SAWs demonstrate amplified 500 hPa geopotential heights over western North America and anomalous positive inland mean sea-level pressures. Sundowner-only conditions display zonal 500 hPa flow and negative inland sea-level pressure anomalies. A low-level northerly coastal jet is present during Sundowners but not SAWs.

Opioids are widely used as therapeutic agents against moderate to severe acute and chronic pain. Still, these classes of analgesic drugs have many potential limitations as they induce analgesic tolerance, addiction and numerous behavioural adverse effects that often result in patient non-compliance. As opium and opioids have been traditionally used as painkillers, the exact mechanisms of their adverse reactions over repeated use are multifactorial and not fully understood. Older adults suffer from cancer and non-cancer chronic pain more than younger adults, due to the physiological changes related to ageing and their reduced metabolic capabilities and thus show an increased number of adverse reactions to opioid drugs. All clinically used opioids are μ-opioid receptor agonists, and the major adverse effects are directly or potentially connected to this receptor. Multifunctional opioid ligands or peripherally restricted opioids may elicit fewer adverse effects, as shown in preclinical studies, but these results need reproducibility from further extensive clinical trials. The current review aims to overview various mechanisms involved in the adverse effects induced by opioids, to provide a better understanding of the underlying pathophysiology and, ultimately, to help develop an effective therapeutic strategy to better manage pain.

Purpose of review Cardiac arrest in childhood is associated with a high risk for mortality and poor long-term functional outcome. This review discusses the current evidence for neuroprotective therapies and goals for postarrest care in the context of the pathophysiology of hypoxic-ischemic injury, modalities for neurologic prognostication in these children and potential future monitoring paradigms for maximizing cerebral perfusion in the postarrest period. Recent findings The recent publication of the in-hospital and out-of-hospital Therapeutic Hypothermia After Cardiac Arrest trials demonstrated a lack of statistically significant benefit for the use of postarrest therapeutic hypothermia. As a result, targeted normothermic temperature management has become standard of care. Continuous electroencephalographic monitoring during the acute postarrest period provides useful additional data for neurologic prognostication, in addition to its value for detection of seizures. Ongoing research into noninvasive monitoring of cerebrovascular autoregulation has the potential to individualize blood pressure goals in the postarrest period, maximizing cerebral perfusion in these patients. Summary Therapeutic strategies after cardiac arrest seek to maximize cerebral perfusion while mitigating the effects of secondary brain injury and loss of autoregulation. Future research into new monitoring strategies and better long-term outcome measures may allow more precise targeting of therapies to these goals.

Relaxin-3/RXFP3 signalling is proposed to be involved in the neuromodulatory control of arousal- and stress-related neural circuits. Furthermore, previous studies in rats have led to the proposal that relaxin-3/RXFP3 signalling is associated with activation of the hypothalamic-pituitary-adrenal axis, but direct evidence for RXFP3-related actions on the activity of hypothalamic corticotropin-releasing hormone (CRH) neurons is lacking. In this study, we investigated characteristics of the relaxin-3/RXFP3 system in mouse hypothalamus. Administration of an RXFP3 agonist (RXFP3-A2) intra-cerebroventricularly or directly into the paraventricular nucleus of hypothalamus (PVN) of C57BL/6J mice did not alter corticosterone levels. Similarly, there were no differences between serum corticosterone levels in Rxfp3 knockout (C57BL/6JRXFP3TM1) and wild-type mice at baseline and after stress, despite detection of the predicted stress-induced increases in serum corticosterone. We examined the nature of the relaxin-3 innervation of PVN in wild-type mice and in Crh-IRES-Cre;Ai14 mice that co-express the tdTomato fluorophore in CRH neurons, identifying abundant relaxin-3 fibres in the peri-PVN region, but only sparse fibres associated with densely packed CRH neurons. In whole-cell voltage-clamp recordings of tdTomato-positive CRH neurons in these mice, we observed a reduction in sEPSC frequency following local application of RXFP3-A2, consistent with an activation of RXFP3 on presynaptic glutamatergic afferents in the PVN region. These studies clarify the relationship between relaxin-3/RXFP3 inputs and CRH neurons in mouse PVN, with implications for the interpretation of current and previous in vivo studies and future investigations of this stress-related signalling network in normal and transgenic mice, under normal and pathological conditions.

Hippocampus is innervated by γ-aminobutyric acid (GABA) ‘projection' neurons of the nucleus incertus (NI), including a population expressing the neuropeptide, relaxin-3 (RLN3). In studies aimed at gaining an understanding of the role of RLN3 signaling in hippocampus via its Gi/o-protein-coupled receptor, RXFP3, we examined the distribution of RLN3-immunoreactive nerve fibres and RXFP3 mRNA-positive neurons in relation to hippocampal GABA neuron populations. RLN3-positive elements were detected in close-apposition with a substantial population of somatostatin (SST)- and GABA-immunoreactive neurons, and a smaller population of parvalbumin- and calretinin-immunoreactive neurons in different hippocampal areas, consistent with the relative distribution patterns of RXFP3 mRNA and these marker transcripts. In light of the functional importance of the dentate gyrus (DG) hilus in learning and memory, and our anatomical data, we examined the possible influence of RLN3/RXFP3 signaling in this region on spatial memory. Using viral-based Cre/LoxP recombination methods and adult mice with a ‘floxed' Rxfp3 gene, we deleted Rxfp3 from DG hilar neurons and assessed spatial memory performance and affective behaviors. Following infusions of an AAV(1/2)-Cre-IRES-eGFP vector, Cre expression was observed in DG hilar neurons, including SST-positive cells, and in situ hybridization histochemistry for RXFP3 mRNA confirmed receptor deletion relative to levels in floxed-RXFP3 mice infused with an AAV(1/2)-eGFP (control) vector. RXFP3 depletion within the DG hilus impaired spatial reference memory in an appetitive T-maze task reflected by a reduced percentage of correct choices and increased time to meet criteria, relative to control. In a continuous spontaneous alternation Y-maze task, RXFP3-depleted mice made fewer alternations in the first minute, suggesting impairment of spatial working memory. However, RXFP3-depleted and control mice displayed similar locomotor activity, anxiety-like behavior in light/dark box and elevated-plus maze tests, and learning and long-term memory retention in the Morris water maze. These data indicate endogenous RLN3/RXFP3 signaling can modulate hippocampal-dependent spatial reference and working memory via effects on SST interneurons, and further our knowledge of hippocampal cognitive processing. This article is protected by copyright. All rights reserved.

Objectives Characterize current practices for PICU-based rehabilitation, and physician perceptions and attitudes, barriers, resources, and outcome assessment in contemporary PICU settings. Design International, self-administered, quantitative, cross-sectional survey. Setting Online survey distributed from March 2017 to April 2017. Patients or subjects Pediatric critical care physicians who subscribed to email distribution lists of the Pediatric Acute Lung Injury and Sepsis Investigators, the Pediatric Neurocritical Care Research Group, or the Prevalence of Acute Critical Neurological Disease in Children: A Global Epidemiological Assessment study group, and visitors to the World Federation of Pediatric Intensive and Critical Care Societies website. Interventions None. Measurements and main results Of the 170 subjects who began the survey, 148 completed it. Of those who completed the optional respondent information, most reported working in an academic medical setting and were located in the United States. The main findings were 1) a large majority of PICU physicians reported working in institutions with no guidelines for PICU-based rehabilitation, but expressed interest in developing and implementing such guidelines; 2) despite this lack of guidelines, an overwhelming majority of respondents reported that their current practices would involve consultation of multiple rehabilitation services for each case example provided; 3) PICU physicians believed that additional research evidence is needed to determine efficacy and optimal implementation of PICU-based rehabilitation; 4) PICU physicians reported significant barriers to implementation of PICU-based rehabilitation across centers; and 5) low routine assessment of long-term functional outcomes of PICU patients, although some centers have developed multidisciplinary follow-up programs. Conclusions Physicians lack PICU-based rehabilitation guidelines despite great interest and current practices involving a high degree of PICU-based rehabilitation consultation. Data are needed to identify best practices and necessary resources in the delivery of ICU-based multidisciplinary rehabilitation and long-term functional outcomes assessment to optimize recovery of children and families affected by critical illness.

Salt overconsumption contributes to hypertension, which is a major risk factor for stroke, heart and kidney disease. Characterising neuronal pathways that may control salt consumption is therefore important for developing novel approaches for reducing salt overconsumption. Here, we identify neurons within the mouse central amygdala (CeA), lateral parabrachial nucleus (LPBN), intermediate nucleus of the solitary tract (iNTS), and caudal NTS (cNTS) that are activated and display Fos immunoreactivity in mice that have consumed salt in order to restore a salt debt, relative to salt replete and salt depleted controls. Double-label immunohistochemical studies revealed that salt restoring mice had significantly greater densities of activated enkephalin neurons within the CeA and iNTS, while statistically significant changes within the LPBN and cNTS were not observed. Furthermore, within the CeA, restoration of salt debt conferred a significant increase in the density of activated calretinin neurons, while there was no change relative to control groups in the density of activated neurons that co-expressed protein kinase C delta (PKC-δ). Taken together, these studies highlight the importance of opioid systems within the CeA and iNTS in neuronal processes associated with salt restoration, and may aid the development of future pharmacological and other strategies for reducing salt overconsumption.

The world’s ever-growing population presents a major challenge in providing sustainable food options and in reducing pressures on the Earth’s agricultural land and freshwater resources. Current estimates suggest that agriculture contributes ~30% of global greenhouse gas (GHG) emissions. Additionally, there is an increased demand for animal protein, the production of which is particularly polluting. Therefore, the climate-disrupting potential of feeding the planet is likely to substantially worsen in the future. Due to the nutritional value of animal-based protein, it is not a simple solution to recommend a wholesale reduction in production/consumption of animal proteins. Rather, employing strategies which result in the production of low carbon animal protein may be part of the solution to reduce the GHGs associated with our diets without compromising diet quality. We suggest that farmed mussels may present a partial solution to this dilemma. Mussel production has a relatively low GHG production and does not put undue pressure on land or fresh water supplies. By drawing comparisons to other protein sources using the Australian Food and Nutrient Database and other published data, we demonstrate that they are a sustainable source of high-quality protein, long-chain omega-3 fatty acids, phytosterols, and other key micronutrients such as B-12 and iron. The aim of this review is to summarise the current knowledge on the health benefits and potential risks of increasing the consumption of farmed mussels.

Due to the importance of dietary sodium and its paucity within many inland environments, terrestrial animals have evolved an instinctive sodium appetite that is commensurate with sodium deficiency. Despite a well-established role for central opioid signaling in sodium appetite, the endogenous influence of specific opioid receptor subtypes within distinct brain regions remains to be elucidated. Using selective pharmacological antagonists of opioid receptor subtypes, we reveal that endogenous mu-opioid receptor (MOR) signaling strongly drives sodium appetite in sodium-depleted mice, whereas a role for kappa (KOR) and delta (DOR) opioid receptor signaling was not detected, at least in sodium-depleted mice. Fos immunohistochemistry revealed discrete regions of the mouse brain displaying an increased number of activated neurons during sodium gratification: the rostral portion of the nucleus of the solitary tract (rNTS), the lateral parabrachial nucleus (LPB), and the central amygdala (CeA). The CeA was subsequently targeted with bilateral infusions of the MOR antagonist naloxonazine, which significantly reduced sodium appetite in mice. The CeA is therefore identified as a key node in the circuit that contributes to sodium appetite. Moreover, endogenous opioids, acting via MOR, within the CeA promote this form of appetitive behavior.

Alcoholism is a chronic relapsing disorder, and stress is a key precipitant of relapse. The nucleus incertus (NI) is highly responsive to corticotrophin-releasing factor (CRF) and psychological stressors, receives a CRF innervation and expresses CRF1 and CRF2 receptor mRNA. Furthermore, the ascending NI relaxin-3 system is implicated in alcohol seeking in rats. Therefore, in alcohol-preferring rats, we examined the effect of bilateral injections into the NI of the CRF1 receptor antagonist, CP376395 or the CRF2 receptor antagonist, astressin-2B on yohimbine-induced reinstatement of alcohol seeking. Using quantitative PCR analysis of NI micropunches, we assessed the effects of chronic alcohol consumption on gene expression profiles for components of the relaxin-3 and CRF systems. Bilateral intra-NI injections of CP376395 (500 ng/0.25 µl) attenuated yohimbine-induced reinstatement of alcohol seeking. In contrast, intra-NI injections of astressin-2B (200 ng/0.25 µl) had no significant effect. In line with these data, CRF1 , but not CRF2 , receptor mRNA was upregulated in the NI following chronic ethanol intake. Relaxin family peptide 3 receptor mRNA was also increased in the NI following chronic ethanol. Our quantitative PCR analysis also identified CRF mRNA within the rat NI, and the existence of a newly identified population of CRF-containing neurons was subsequently confirmed by detection of CRF immunoreactivity in rat and mouse NI. These data suggest that NI neurons contribute to reinstatement of alcohol seeking, via an involvement of CRF1 signalling. Furthermore, chronic ethanol intake leads to neuroadaptive changes in CRF and relaxin-3 systems within rat NI.

Recent extreme fire seasons in California have prompted utilities such as Pacific Gas and Electric to pre-emptively de-energize portions of the electrical grid during periods of extreme fire weather to reduce the risk of powerline-related fire ignitions. The policy was deployed in 2019, resulting in 12 million person-days of power outages and widespread societal disruption. Retrospective weather and vegetation moisture data highlight hotspots of historical risk across northern California. We estimate an average of 1.6 million person-days of de-energization per year, based on recent historical climate conditions and assuming publicly stated utility de-energization thresholds. We further estimate an additional 70% increase in the population affected by de-energization when vegetation remains abnormally dry later into autumn—suggesting that climate change will likely increase population vulnerable to de-energization. Adaptation efforts to curtail fire risk can be beneficial, but efforts to prepare affected populations, modernize the grid, and refine decision-making surrounding such policies have high potential to reduce the magnitude of negative externalities experienced during the 2019 de-energization events.

Background The consumption of dietary salt (NaCl) is controlled by neuronal pathways that are modulated by endogenous opioid signalling. The latter is disrupted by chronic use of exogenous opioid receptor agonists, such as morphine. Therefore, opioid dependence may influence salt consumption, which we investigated in two complimentary studies in humans and mice. Methods Human study: three groups were recruited: i. Individuals who are currently opioid dependent and receiving opioid substitution treatment (OST); ii. Previously opioid dependent individuals, who are currently abstinent, and; iii. Healthy controls with no history of opioid dependence. Participants tasted solutions containing different salt concentrations and indicated levels of salt ‘desire’, salt ‘liking’, and perceptions of ‘saltiness’. Mouse study: preference for 0.1 M versus 0.2 M NaCl and overall levels of salt consumption were recorded during and after chronic escalating morphine treatment. Results Human study: Abstinent participants’ ‘desire’ for and ‘liking’ of salt was shifted towards more highly concentrated salt solutions relative to control and OST individuals. Mouse study: Mice increased their total salt consumption during morphine treatment relative to vehicle controls, which persisted for 3 days after cessation of treatment. Preference for ‘low’ versus ‘high’ concentrations of salt were unchanged. Conclusion These findings suggest a possible common mechanistic cross-sensitization to salt that is present in both mice and humans and builds our understanding of how opioid dependence can influence dietary salt consumption. This research may help inform better strategies to improve the diet and overall wellbeing of the growing number of individuals who develop opioid dependence.

The bed nucleus of the stria terminalis (BNST) is a critical node involved in stress and reward-related behaviors. Relaxin family peptide receptor 3 (RXFP3) signaling in the BNST has been implicated in stress-induced alcohol seeking behavior. However, the neurochemical phenotype and connectivity of BNST RXFP3-expressing (RXFP3+) cells have yet to be elucidated. We interrogated the molecular signature and electrophysiological properties of BNST RXFP3+ neurons using a RXFP3-Cre reporter mouse line. BNST RXFP3+ cells are circumscribed to the dorsal BNST (dBNST) and are neurochemically heterogeneous, comprising a mix of inhibitory and excitatory neurons. Immunohistochemistry revealed that ~48% of BNST RXFP3+ neurons are GABAergic, and a quarter of these co-express the calcium-binding protein, calbindin. A subset of BNST RXFP3+ cells (~41%) co-express CaMKIIα, suggesting this subpopulation of BNST RXFP3+ neurons are excitatory. Corroborating this, RNAscope® revealed that ~35% of BNST RXFP3+ cells express vVGluT2 mRNA, indicating a subpopulation of RXFP3+ neurons are glutamatergic. RXFP3+ neurons show direct hyperpolarization to bath application of a selective RXFP3 agonist, RXFP3-A2, while around 50% of cells were depolarised by exogenous corticotrophin releasing factor. In behaviorally naive mice the majority of RXFP3+ neurons were Type II cells exhibiting Ih and T type calcium mediated currents. However, chronic swim stress caused persistent plasticity, decreasing the proportion of neurons that express these channels. These studies are the first to characterize the BNST RXFP3 system in mouse and lay the foundation for future functional studies appraising the role of the murine BNST RXFP3 system in more complex behaviors.

The pervasive use of refined sugars in highly accessible, palatable foods and persistent exposure to reinforcing food-associated cues has contributed to overconsumption of sugar-rich diets and the current obesity epidemic in Western society. We have shown previously that brain relaxin-3 mRNA levels positively correlate with sucrose and alcohol intake, and that central antagonism of relaxin-3 receptors (RXFP3) attenuates alcohol self-administration and alcohol-seeking in rats, but food-seeking behaviour and palatable food consumption in mice. To further examine the relationship between motivated appetitive behaviours and relaxin-3/RXFP3 signalling, we investigated the effect of Rxfp3 gene deletion in C57BL/6J mice on sucrose and alcohol self-administration and cue-induced reinstatement (RNST) of sucrose- and alcohol-seeking. Acquisition and maintenance of sucrose and alcohol self-administration was assessed in male wild-type (WT) and Rxfp3 knockout (KO) (C57BL/6J(RXFP3TM1) (/) (DGen) ) littermate mice using fixed ratio (FR) schedules of reinforcement. Mice were subsequently challenged with a progressive ratio (PR) test to measure motivation and, following extinction training, re-exposed to reward-associated cues to evaluate RNST of active lever-responding. Wild-type and Rxfp3 KO mice displayed similar acquisition of FR1 sucrose self-administration, but Rxfp3 KO mice responded less when the instrumental requirement was increased to FR3. These mice also showed a lower breakpoint for sucrose and attenuated cue-induced RNST of sucrose-seeking. Notably, no marked genotype differences in alcohol-responding were observed. In mice, endogenous relaxin-3/RXFP3 signalling promotes self-administration of sucrose under high response requirements and cue-induced RNST of sucrose-seeking, but does not apparently regulate motivation to consume alcohol or alcohol-seeking behaviour.

Anxiety disorders are among the most prevalent neuropsychiatric conditions, but their precise aetiology and underlying pathophysiological processes remain poorly understood. In light of putative anatomical and functional interactions of the relaxin-3/RXFP3 system with anxiety-related neural circuits, we assessed the ability of central administration of the RXFP3 agonist, RXFP3-A2, to alter anxiety-like behaviours in adult C57BL/6J mice. We assessed how RXFP3-A2 altered performance in tests measuring rodent anxiety-like behaviour (large open field (LOF), elevated plus maze (EPM), light/dark (L/D) box, social interaction). We examined effects of RXFP3-A2 on low 'basal' anxiety, and on elevated anxiety induced by the anxiogenic benzodiazepine, FG-7142; and explored endogenous relaxin-3/RXFP3 signalling modulation by testing effects of an RXFP3 antagonist, R3(B1-22)R, on these behaviours. Intracerebroventricular (icv) injection of RXFP3-A2 (1 nmol, 15 min pre-test) did not alter anxiety-like behaviour under 'basal' conditions in the LOF, EPM or L/D box, but reduced elevated indices of FG-7142-induced (30 mg/kg, ip) anxiety-like behaviour in the L/D box and a single-chamber social interaction test. Furthermore, R3(B1-22)R (4 nmol, icv, 15 min pre-test) increased anxiety-like behaviour in the EPM (reflected by reduced entries into the open arms), but not consistently in the LOF, L/D box or social interaction tests, suggesting endogenous signaling only weakly participates in regulating 'basal' anxiety-like behaviour, in line with previous studies of relaxin-3 and RXFP3 gene knockout mice. Overall, these data suggest exogenous RXFP3 agonists can reduce elevated (FG-7142-induced) levels of anxiety in mice; data important for gauging how conserved such effects are, with a view to modelling human pathophysiology and the likely therapeutic potential of RXFP3-targeted drugs.