Molecular and functional alterations in the cerebral microvasculature in an optimized mouse model of sepsis-associated cognitive dysfunction.

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in systemic inflammation-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammatory response. In the acute phase, we identified novel molecular (e.g. upregulation of plasmalemma vesicle associated protein, a driver of endothelial permeability, and the pro-coagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small molecule BBB permeability, elevated levels of PAI-1, intra/perivascular fibrin/fibrinogen deposition and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor suggesting diffuse axonal injury, synapse degeneration and impaired neurotrophism. Our study serves as a standardized model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition. SIGNIFICANCE: The limited knowledge of how systemic inflammation contributes to cognitive decline is a major obstacle to the development of novel therapies for dementia and other neurodegenerative diseases. Clinical evidence supports a role for the cerebral microvasculature in sepsis-induced neurocognitive dysfunction, but the investigation of the underlying mechanisms has been limited by the lack of standardized experimental models. Herein, we optimized a mouse model that recapitulates important pathophysiological aspects of systemic inflammation-induced cognitive decline and identified key alterations in the cerebral microvasculature associated with cognitive dysfunction. Our study provides a reliable experimental model for mechanistic studies and therapeutic discovery of the impact of systemic inflammation on cerebral microvascular function and the development and progression of cognitive impairment.

Intermixed safety cues facilitate extinction retention in adult and adolescent mice.

Extinction learning is tremendously adaptive as it allows an animal to adjust their behavior in a changing environment. Yet, extinction is not without limitations and fear often reemerges over time (i.e. spontaneous recovery). Relative to adults, adolescent rodents and humans are particularly prone to spontaneous recovery following extinction. In this study, we aimed to address whether combining methods of fear regulation (extinction and conditioned inhibition) can facilitate extinction retention. Early adolescent (29 days old, n = 81) and adult (70 days old, n = 80) mice underwent extinction with or without a safety cue present. Safety cue presentations were systematically varied to overlap with or alternate with fear cue presentations. We found that initial safety learning was faster in adolescent mice. In addition, intermixing safety cues into extinction reduced spontaneous recovery during a test two weeks later. The decrease in spontaneous recovery relative to a standard extinction protocol was greater in adolescents than adults. Together, our findings provide initial evidence that safety learning may be inherently stronger during adolescence. These results inform the parameters by which conditioned safety and extinction learning may be merged to augment the inhibition of fear. While methods to enhance fear regulation are valuable for any age, the potential to do so during adolescence is particularly striking.

Translating Developmental Neuroscience to Understand Risk for Psychiatric Disorders.

The transition from childhood to adulthood represents the developmental time frame in which the majority of psychiatric disorders emerge. Recent efforts to identify risk factors mediating the susceptibility to psychopathology have led to a heightened focus on both typical and atypical trajectories of neural circuit maturation. Mounting evidence has highlighted the immense neural plasticity apparent in the developing brain. Although in many cases adaptive, the capacity for neural circuit alteration also induces a state of vulnerability to environmental perturbations, such that early-life experiences have long-lasting implications for cognitive and emotional functioning in adulthood. The authors outline preclinical and neuroimaging studies of normative human brain circuit development, as well as parallel efforts covered in this issue of the Journal, to identify brain circuit alterations in psychiatric disorders that frequently emerge in developing populations. Continued translational research into the interactive effects of neurobiological development and external factors will be crucial for identifying early-life risk factors that may contribute to the emergence of psychiatric illness and provide the key to optimizing treatments.

Developmental age and fatty acid amide hydrolase genetic variation converge to mediate fear regulation in female mice.

Anxiety disorders are more prevalent in females than in males, yet a majority of basic neuroscience studies are performed in males. Furthermore, anxiety disorders peak in prevalence during adolescence, yet little is known about neurodevelopmental trajectories of fear expression, particularly in females. To examine these factors, we fear conditioned juvenile, adolescent, and adult female mice and exposed them to fear extinction and a long-term recall test. For this, we used knock-in mice containing a common human mutation in the gene for fatty acid amide hydrolase (FAAH), the primary catabolic enzyme for the endocannabinoid anandamide (FAAH-IN). This mutation has been shown to impart a low-anxiety phenotype in humans, and in rodents relative to their wild-type littermates. We find an impact of the FAAH polymorphism on developmental changes in fear behavior. Specifically, the FAAH polymorphism appears to induce a state of hypervigilance (increased fear) during adolescence. We also used markerless pose estimation software to classify alternative behaviors outside of freezing. These analyses revealed age differences in vigilance to indicators of threat and in the propensity of mice to explore an aversive environment, though genotypic differences were minimal. These findings address a gap in the literature regarding developmental patterns of fear learning and memory as well as the mechanistic contributions of the endocannabinoid system in females.

Low incidence of pulmonary hypertension in children with suspected obstructive sleep apnea: A prospective observational study.

OBJECTIVES: Pulmonary hypertension (PH) secondary to obstructive sleep apnea (OSA) is an uncommon but serious perioperative risk factor in children undergoing surgery for adenotonsillar hypertrophy. Routine pre-operative echocardiography is commonly requested if severe OSA is suspected. We investigated the incidence of PH in children with suspected OSA and explored the association between PH and OSA severity. METHODS: A prospective study of children aged 1-13 years with suspected OSA admitted for overnight oximetry (OO) and echocardiography at a pediatric referral hospital in Cape Town, South Africa from 2018 to 2019. OSA severity was defined by McGill Oximetry Score (MOS): MOS 1-2 (mild-moderate) and MOS 3-4 (severe). PH was defined as mean pulmonary arterial pressure (mPAP) ≥20 mmHg estimated on echocardiographic criteria. Children with congenital heart disease, underlying cardio-respiratory or genetic disorders, and severe obesity were excluded. RESULTS: One hundred and seventy children median age 3.8 years (IQR 2.7-6.4) were enrolled and 103 (60%) were female. Twenty-two (14%) had a BMIz >1.0 and 99 (59%) had tonsillar enlargement grade 3/4. One hundred and twenty-two (71%) and 48 (28%) children had mild-moderate and severe OSA, respectively. Echocardiographic assessment for PH was successful in 160 (94%) children of which eight (5%) had PH with mPAP 20.8 mmHg (SD 0.9): six with mild-moderate OSA and two with severe OSA. No significant difference in mPAP and other echocardiographic indices was observed in children with mild-moderate (16.1 mmHg; SD 2.4) and severe OSA (15.7 mmHg; SD 2.1). Similarly, no clinical and OSA severity differences were observed in children with and without PH. CONCLUSION: PH is uncommon in children with uncomplicated OSA and there is no association of PH with severity of OSA measured by OO. Routine echocardiographic screening for PH in children with clinical symptoms of OSA without co-morbidity is unwarranted.

The Added Value of Crosstalk Between Developmental Circuit Neuroscience and Clinical Practice to Inform the Treatment of Adolescent Anxiety.

Significant advances have been made in recent years regarding the developmental trajectories of brain circuits and networks, revealing links between brain structure and function. Emerging evidence highlights the importance of developmental trajectories in determining early psychiatric outcomes. However, efforts to encourage crosstalk between basic developmental neuroscience and clinical practice are limited. Here, we focus on the potential advantage of considering features of neural circuit development when optimizing treatments for adolescent patient populations. Drawing on characteristics of adolescent neurodevelopment, we highlight two examples, safety cues and incentives, that leverage insights from neural circuit development and may have great promise for augmenting existing behavioral treatments for anxiety disorders during adolescence. This commentary seeks to serve as a framework to maximize the translational potential of basic research in developmental populations for strengthening psychiatric treatments. In turn, input from clinical practice including the identification of age-specific clinically relevant phenotypes will continue to guide future basic research in the same neural circuits to better reflect clinical practices. Encouraging reciprocal communication to bridge the gap between basic developmental neuroscience research and clinical implementation is an important step toward advancing both research and practice in this domain.

Understanding emotional intelligence and its relationship to clinical reasoning in senior nursing students: A mixed methods study.

BACKGROUND: The complex healthcare environment requires nursing students to be prepared to effectively reason in emotionally charged situations. Clinical reasoning is a complex cognitive process that involves many elements, with little attention given to the role of emotions in this process. PURPOSE: The purpose of this pilot study was to explore the EI of senior Bachelor of Science in Nursing (BSN) students and its relationship to clinical reasoning to gain a better understanding of how emotions are used in clinical learning experiences. METHODS: This study utilized a convergent parallel mixed methods design. RESULTS: Quantitative findings indicated a positive relationship between Strategic EI and the clinical reasoning scale of inference (rs = 0.489, p = .044). A positive relationship was also found between the EI branch of Understanding Emotions and overall clinical reasoning (rs = 0.559, p = .024) and the clinical reasoning scale of induction (rs = 0.530, p = .035). The three categories that resulted from the qualitative findings: (1) Sadness for…, (2) Shifting Emotions, and (3) Presence converged with quantitative findings. CONCLUSION: EI is an important construct when it comes to reasoning and providing care during clinical experiences. Fostering the development of EI may be one way nurse educators can better prepare nurses for safe practice.

Leveraging WHO's Global Benchmarking Tool to strengthen capacity in clinical trials oversight for public health emergencies: the GHPP VaccTrain model.

BACKGROUND: A stable, well-functioning and integrated national medicines regulatory system is a core component of health systems resilient against infectious disease outbreaks. In many low- and middle-income countries, however, sizable gaps exist in the emergency preparedness framework of national regulatory authorities (NRAs). RegTrain-VaccTrain is a project of Germany Ministry of Health's Global Health Protection Programme that contributes to global efforts aimed at strengthening such regulatory systems by providing technical support and advice to partner NRAs. In this study, we probed the outputs of our capacity-strengthening activities for clinical trials oversight (CTO) to take stock of progress made and examine remaining priorities in order to provide specialized technical assistance in addressing them to improve operational readiness for emergencies. METHOD: Data validated from NRA self-benchmarking results in 2017 and worksheet records of November 2021 were utilized to assess the emergency preparedness capacity for CTO in three VaccTrain partner NRAs (Liberia, Sierra Leone, The Gambia) before and after interventional capacity-strengthening partnership, using specific public health emergency-related (sub-)indicators of the WHO Global Benchmarking Tool. RESULTS: A generally weak and vulnerable structural framework for CTO characterized the emergency preparedness capacity in all three partner NRAs at baseline, thus putting their operational readiness for public health emergencies at risk. VaccTrain's collaborative work was successful at supporting individual NRAs to develop the full spectrum of operational structures (including (draft) regulations, guidelines, and standard operating procedures) required to improve regulatory preparedness. A gap in the formal approval and implementation of developed legal documents in two of three NRAs still remains. Notwithstanding, a robust emergency framework now exists and the NRAs stand better prepared to respond to (future) locally-concerning health emergencies, during which time clinical trials activity was observed to heighten. CONCLUSIONS: These results exemplify a north-south capacity-strengthening partnership model that effectively contributes in developing structures to enhance regulatory oversight and support expeditious product development in response to crises. They further underscore the equally critical role local/national processes play in facilitating the full implementation of developed structures.

The Pivotal Role of Quality Technical Structures for Clinical Trials Oversight in the Achievement of Long-Term Capacity Strengthening Outcomes.

Background: Development of safe and efficacious medicines in many sub-Sahara African countries remains hampered due to fragmented health research infrastructure and ineffective regulatory oversight. To boost the latter in the area of Clinical Trials (CT) Oversight (CTO), many international programs and Regional Centers for Regulatory Excellence (RCORE) initiatives offer various trainings to help strengthen human resource capacity. Here, we aimed at evaluating the training outcomes (at home-institution level) of sponsored fellows for one of such capacity strengthening interventions; a measure that is less often reported and thus remains poorly understood. Method: The Global Health Protection Programme's VaccTrain project sponsored nine regulatory staff from eight National Medicines Regulatory Authorities (NMRAs) in sub-Saharan Africa for the RCORE CT Training Fellowship by FDA Ghana in a particular year. Using a systematized evaluation framework based on the theory of change, we assessed the individual- and NMRA-level achievement of pre-defined training outcomes. For this purpose, data was collected at pre-training and at short- and long-term evaluation time-points using a survey instrument. Results: At pre-training, our data revealed existence of differential expectations and orientations among the training participants, thus providing an early indication of potential distinctive patterns in achievement of desired training outcomes. In a short-term post-training follow-up evaluation, a two-group clustering of fellows based on the achievement of training outcomes where only one group (representing 44%) reported achievement of CTO-related outcomes was observed. At this time-point, achievement of training outcomes was associated with the vibrancy of CT activity and existence of a comprehensive technical structure for CTO. In a further long-term follow-up evaluation, our data revealed a successful achievement of CTO-related individual- and/or institutional-level outcomes in all but one fellow. Here again, availability of a robust technical structure for CTO (and perhaps fellow affiliation/selection)-but not CT vibrancy-showed a trend of temporal association with achievement of training outcomes. Conclusion: Given the pivotal role operational structures of international standards at home institutions play in translating training-acquired knowledge into measurable CTO-related outcomes, we encourage that capacity strengthening projects aimed at achieving health-related targets of Sustainable Development Goals adopt an approach built on this foundation.

Outcomes After Bidirectional Glenn Shunt in a Tertiary-Care Pediatric Hospital in South Africa.

OBJECTIVES: Large data sets have been published on short- and long-term outcomes following bidirectional Glenn surgery (BDG), or partial cavopulmonary connection, in high-income countries. Data from low-income and middle-income countries are few and often limited to the immediate postoperative period. The primary outcome was any in-hospital postoperative complication, assessed according to predefined criteria, in children who underwent BDG surgery at Red Cross War Memorial Children's Hospital. DESIGN: A retrospective cohort study. SETTING: A tertiary teaching hospital. PARTICIPANTS: The study authors identified 61 children (<18 years of age) who underwent BDG over 8 years. The median age of patients undergoing BDG was 2.5 years (interquartile range, 1.4-5.5 years). INTERVENTIONS: BDG surgery. MEASUREMENTS AND MAIN RESULTS: Thirty-five patients (57.4%) had a postoperative complication, with some patients (17 of 61, 27.9%) having more than 1 complication. The most frequent complications were infective (29.5%). Univariate analysis found that postoperative complications were associated with the use of nitric oxide (p = 0.004) and a longer duration of anesthesia (p = 0.045) and surgery (p = 0.004). Patients with complications spent longer in the pediatric intensive care unit (ICU) (p < 0.001) and in the hospital (p < 0.012). On multivariate analysis, a priori risk factors based on previous studies were not found to be statistically significant. A total of 37.3% of patients completed their single-ventricle palliation, and 30.5% of patients were lost to follow-up. CONCLUSIONS: Important findings were the older age at which the BDG was performed compared to high-income countries, an acceptable mortality rate of 3.3%, infection being the most common complication, the association of a complication with increased ICU and hospital lengths of stay, and the high rate of patients lost to follow-up.

WHO informal consultation on regulatory considerations for evaluation of the quality, safety and efficacy of RNA-based prophylactic vaccines for infectious diseases, 20-22 April 2021.

This paper presents the key outcomes of the above WHO informal consultation with global stakeholders including regulatory authorities, vaccine developers and manufacturers, academia and other international health organizations and institutions involved in the development, evaluation and use of messenger RNA (mRNA) vaccines. The aim of the consultation was to further clarify the main principles to be presented in an upcoming WHO guidance document on the regulatory considerations in evaluating the quality, safety and efficacy of mRNA prophylactic vaccines for infectious diseases. This WHO guidance document is intended to facilitate global mRNA vaccine development and regulatory convergence in the assessment of such vaccines. The urgent need to develop such a document as a new WHO written standard is outlined in this report along with the key scientific and regulatory challenges. A number of key conclusions are provided at the end of this report along with an update on the steps taken following this meeting.

An Evaluation of Severe Anesthetic-Related Critical Incidents and Risks From the South African Paediatric Surgical Outcomes Study: A 14-Day Prospective, Observational Cohort Study of Pediatric Surgical Patients.

BACKGROUND: Severe anesthetic-related critical incident (SARCI) monitoring is an essential component of safe, quality anesthetic care. Predominantly retrospective data from low- and middle-income countries (LMICs) report higher incidence but similar types of SARCI compared to high-income countries (HIC). The aim of our study was to describe the baseline incidence of SARCI in a middle-income country (MIC) and to identify associated risk for SARCI. We hypothesized a higher incidence but similar types of SARCI and risks compared to HICs. METHODS: We performed a 14-day, prospective multicenter observational cohort study of pediatric patients (aged <16 years) undergoing surgery in government-funded hospitals in South Africa, a MIC, to determine perioperative outcomes. This analysis described the incidence and types of SARCI and associated perioperative cardiac arrests (POCAs). We used multivariable logistic regression analysis to identify risk factors independently associated with SARCI, including 7 a priori variables and additional candidate variables based on their univariable performance. RESULTS: Two thousand and twenty-four patients were recruited from May 22 to August 22, 2017, at 43 hospitals. The mean age was 5.9 years (±standard deviation 4.2). A majority of patients during this 14-day period were American Society of Anesthesiologists (ASA) physical status I (66.4%) or presenting for minor surgery (54.9%). A specialist anesthesiologist managed 59% of cases. These patients were found to be significantly younger (P < .001) and had higher ASA physical status (P < .001). A total of 426 SARCI was documented in 322 of 2024 patients, an overall incidence of 15.9% (95% confidence interval [CI], 14.4-17.6). The most common event was respiratory (214 of 426; 50.2%) with an incidence of 8.5% (95% CI, 7.4-9.8). Six children (0.3%; 95% CI, 0.1-0.6) had a POCA, of whom 4 died in hospital. Risks independently associated with a SARCI were age (adjusted odds ratio [aOR] = 0.95; CI, 0.92-0.98; P = .004), increasing ASA physical status (aOR = 1.85, 1,74, and 2.73 for ASA II, ASA III, and ASA IV-V physical status, respectively), urgent/emergent surgery (aOR = 1.35, 95% CI, 1.02-1.78; P = .036), preoperative respiratory infection (aOR = 2.47, 95% CI, 1.64-3.73; P < .001), chronic respiratory comorbidity (aOR = 1.75, 95% CI, 1.10-2.79; P = .018), severity of surgery (intermediate surgery aOR = 1.84, 95% CI, 1.39-2.45; P < .001), and level of hospital (first-level hospitals aOR = 2.81, 95% CI, 1.60-4.93; P < .001). CONCLUSIONS: The incidence of SARCI in South Africa was 3 times greater than in HICs, and an associated POCA was 10 times more common. The risk factors associated with SARCI may assist with targeted interventions to improve safety and to triage children to the optimal level of care.

Extinction trial spacing across days differentially impacts fear regulation in adult and adolescent male mice.

Fear regulation changes as a function of age and adolescence is a key developmental period for the continued maturation of fear neural circuitry. A consistent finding in the literature is diminished extinction retention in adolescents. However, these studies often directly compare adolescents to adults using a single protocol and therefore provide little insight into learning parameters that improve adolescent fear regulation. Studies in adults highlight the benefits of spaced learning over massed learning. These findings have been extended to fear regulation, with adult rodents exhibiting improved extinction learning and retention when cues are distributed over days versus a single session. However, similar studies have not been performed in adolescents. Here, we systematically examine the impact of trial spacing across days on fear regulation. Adolescent or adult male mice were exposed to one of three extinction paradigms that presented the same number of trials but differed in the temporal distribution of trials across days (one day, two days, or four days). We found that introducing consolidation events into the protocol improves adult extinction learning and short-term extinction retention but these effects disappear after two weeks. For adolescents, all three protocols were comparably effective in reducing freezing across extinction training and improved retention at both short-term and long-term fear recall time points relative to extinction-naive mice. These findings suggest that extinction protocols that incorporate consolidation events are optimal for adults but additional booster training may be required for enduring efficacy. In contrast, protocols incorporating either massed or spaced presentations show immediate and enduring benefits for adolescents.

Environmental certainty influences the neural systems regulating responses to threat and stress.

Flexible calibration of threat responding in accordance with the environment is an adaptive process that allows an animal to avoid harm while also maintaining engagement of other goal-directed actions. This calibration process, referred to as threat response regulation, requires an animal to calculate the probability that a given encounter will result in a threat so they can respond accordingly. Here we review the neural correlates of two highly studied forms of threat response suppression: extinction and safety conditioning. We focus on how relative levels of certainty or uncertainty in the surrounding environment alter the acquisition and application of these processes. We also discuss evidence indicating altered threat response regulation following stress exposure, including enhanced fear conditioning, and disrupted extinction and safety conditioning. To conclude, we discuss research using an animal model of coping that examines the impact of stressor controllability on threat responding, highlighting the potential for previous experiences with control, or other forms of coping, to protect against the effects of future adversity.

Accelerated Development of COVID-19 Vaccines: Technology Platforms, Benefits, and Associated Risks.

Multiple preventive COVID-19 vaccines have been developed during the ongoing SARS coronavirus (CoV) 2 pandemic, utilizing a variety of technology platforms, which have different properties, advantages, and disadvantages. The acceleration in vaccine development required to combat the current pandemic is not at the expense of the necessary regulatory requirements, including robust and comprehensive data collection along with clinical product safety and efficacy evaluation. Due to the previous development of vaccine candidates against the related highly pathogenic coronaviruses SARS-CoV and MERS-CoV, the antigen that elicits immune protection is known: the surface spike protein of SARS-CoV-2 or specific domains encoded in that protein, e.g., the receptor binding domain. From a scientific point of view and in accordance with legal frameworks and regulatory practices, for the approval of a clinic trial, the Paul-Ehrlich-Institut requires preclinical testing of vaccine candidates, including general pharmacology and toxicology as well as immunogenicity. For COVID-19 vaccine candidates, based on existing platform technologies with a sufficiently broad data base, pharmacological-toxicological testing in the case of repeated administration, quantifying systemic distribution, and proof of vaccination protection in animal models can be carried out in parallel to phase 1 or 1/2 clinical trials. To reduce the theoretical risk of an increased respiratory illness through infection-enhancing antibodies or as a result of Th2 polarization and altered cytokine profiles of the immune response following vaccination, which are of specific concern for COVID-19 vaccines, appropriate investigative testing is imperative. In general, phase 1 (vaccine safety) and 2 (dose finding, vaccination schedule) clinical trials can be combined, and combined phase 2/3 trials are recommended to determine safety and efficacy. By applying these fundamental requirements not only for the approval and analysis of clinical trials but also for the regulatory evaluation during the assessment of marketing authorization applications, several efficacious and safe COVID-19 vaccines have been licensed in the EU by unprecedentedly fast and flexible procedures. Procedural and regulatory-scientific aspects of the COVID-19 licensing processes are described in this review.

An Adolescent Sensitive Period for Threat Responding: Impacts of Stress and Sex.

Anxiety and fear-related disorders peak in prevalence during adolescence, a window of rapid behavioral development and neural remodeling. However, understanding of the development of threat responding and the underlying neural circuits remains limited. Preclinical models of threat conditioning and extinction have provided an unparalleled glimpse into the developing brain. In this review we discuss mouse and rat studies on the development of threat response regulation, with a focus on the adolescent period. Evidence of nonlinear patterns of threat responding during adolescence and the continued development of the underlying circuitry is highly indicative of an adolescent sensitive period for threat response regulation. While we highlight literature in support of this unique developmental window, we also emphasize the need for causal studies to clarify the parameters defining such a sensitive period. In doing so, we explore how stress and biological sex affect the development and expression of threat response regulation during adolescence and beyond. Ultimately, a deeper understanding of how these factors interact with and affect developmental trajectories of learning and memory will inform treatment and prevention strategies for pediatric anxiety disorders.

Pre-adolescent stress disrupts adult, but not adolescent, safety learning.

Anxiety disorders are highly prevalent across the lifespan, although diagnoses peak early in adolescence. As a method for inhibiting fear, safety signals have the potential to augment conventional treatments for anxiety. However, the ability to acquire and use safety signals during adolescence remains unclear. Moreover, the impact of stress on safety learning has received surprisingly little attention given that stress is a major factor preceding anxiety onset. In this study, mice were trained in a discriminative conditioning protocol to facilitate safety learning and were tested for fear inhibition using a conditioned safety signal. Next, independent groups of mice were exposed to chronic unpredictable stress (CUS) conditions between postnatal day 22 and 28, followed by tests for anxiety-like phenotypes or fear inhibition using a safety signal, performed either 24 h or five weeks following CUS. Pre-adolescent CUS reduced weight in adolescence and this effect endured into adulthood. CUS also increased specific anxiety-like behaviors in adolescence that were unique from the increase in anxiety observed in adulthood. Despite increased anxiety-like behaviors, adolescents were able to learn about and effectively use safety signals to inhibit fear. In contrast, adults that experienced CUS showed a subtle increase in anxiety but had impaired safety signal learning and usage. Together, these findings indicate that pre-adolescent stress has immediate and enduring effects on anxiety-like behaviors but impairs the capacity for conditioned inhibition only following incubation.

A systematic review of outcomes reported inpediatric perioperative research: A report from the Pediatric Perioperative Outcomes Group.

The Pediatric Perioperative Outcomes Group (PPOG) is an international collaborative of clinical investigators and clinicians within the subspecialty of pediatric anesthesiology and perioperative care which aims to use COMET (Core Outcomes Measures in Effectiveness Trials) methodology to develop core outcome setsfor infants, children and young people that are tailored to the priorities of the pediatric surgical population.Focusing on four age-dependent patient subpopulations determined a priori for core outcome set development: i) neonates and former preterm infants (up to 60 weeks postmenstrual age); ii) infants (>60 weeks postmenstrual age - <1 year); iii) toddlers and school age children (>1-<13 years); and iv) adolescents (>13-<18 years), we conducted a systematic review of outcomes reported in perioperative studies that include participants within age-dependent pediatric subpopulations. Our review of pediatric perioperative controlled trials published from 2008 to 2018 identified 724 articles reporting 3192 outcome measures. The proportion of published trials and the most frequently reported outcomes varied across pre-determined age groups. Outcomes related to patient comfort, particularly pain and analgesic requirement, were the most frequent domain for infants, children and adolescents. Clinical indicators, particularly cardiorespiratory or medication-related adverse events, were the most common outcomes for neonates and infants < 60 weeks and were the second most frequent domain at all other ages. Neonates and infants <60 weeks of age were significantly under-represented in perioperative trials. Patient-centered outcomes, heath care utilization, and bleeding/transfusion related outcomes were less often reported. In most studies, outcomes were measured in the immediate perioperative period, with the duration often restricted to the post-anesthesia care unit or the first 24 postoperative hours. The outcomes identified with this systematic review will be combined with patient centered outcomes identified through a subsequent stakeholder engagement study to arrive at a core outcome set for each age-specific group.