The microbiota regulate neuronal function and fear extinction learning.

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.

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.

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.

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.

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.

Ventral hippocampus interacts with prelimbic cortex during inhibition of threat response via learned safety in both mice and humans.

Heightened fear and inefficient safety learning are key features of fear and anxiety disorders. Evidence-based interventions for anxiety disorders, such as cognitive behavioral therapy, primarily rely on mechanisms of fear extinction. However, up to 50% of clinically anxious individuals do not respond to current evidence-based treatment, suggesting a critical need for new interventions based on alternative neurobiological pathways. Using parallel human and rodent conditioned inhibition paradigms alongside brain imaging methodologies, we investigated neural activity patterns in the ventral hippocampus in response to stimuli predictive of threat or safety and compound cues to test inhibition via safety in the presence of threat. Distinct hippocampal responses to threat, safety, and compound cues suggest that the ventral hippocampus is involved in conditioned inhibition in both mice and humans. Moreover, unique response patterns within target-differentiated subpopulations of ventral hippocampal neurons identify a circuit by which fear may be inhibited via safety. Specifically, ventral hippocampal neurons projecting to the prelimbic cortex, but not to the infralimbic cortex or basolateral amygdala, were more active to safety and compound cues than threat cues, and activity correlated with freezing behavior in rodents. A corresponding distinction was observed in humans: hippocampal-dorsal anterior cingulate cortex functional connectivity-but not hippocampal-anterior ventromedial prefrontal cortex or hippocampal-basolateral amygdala connectivity-differentiated between threat, safety, and compound conditions. These findings highlight the potential to enhance treatment for anxiety disorders by targeting an alternative neural mechanism through safety signal learning.

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.

The association between preoperative anemia and postoperative morbidity in pediatric surgical patients: A secondary analysis of a prospective observational cohort study.

BACKGROUND: The prevalence of anemia in the South African pediatric surgical population is unknown. Anemia may be associated with increased postoperative complications. We are unaware of studies documenting these findings in patients in low- and middle-income countries (LMICs). AIM: The primary aim of this study was to describe the association between preoperative anemia and 26 defined postoperative complications, in noncardiac pediatric surgical patients. Secondary aims included describing the prevalence of anemia and risk factors for intraoperative blood transfusion. METHOD: This was a secondary analysis of the South African Paediatric Surgical Outcomes Study, a prospective, observational surgical outcomes study. Inclusion criteria were all consecutive patients aged between 6 months and <16 years, presenting to participating centers during the study period who underwent elective and nonelective noncardiac surgery and had a preoperative hemoglobin recorded. Exclusion criteria were patients aged <6 months, undergoing cardiac surgery, or without a preoperative Hb recorded. To determine whether an independent association existed between preoperative anemia and postoperative complications, a hierarchical stepwise logistic regression was conducted. RESULTS: There were 1094 eligible patients. In children in whom a preoperative Hb was recorded 46.2% had preoperative anemia. Preoperative anemia was independently associated with an increased risk of any postoperative complication (odds ratio 2.0, 95% confidence interval: 1.3-3.1, P = .002). Preoperative anemia (odds ratio 3.6, 95% confidence interval: 1.8-7.1, P < .001) was an independent predictor of intraoperative blood transfusion. CONCLUSION: Preoperative anemia had a high prevalence in a LMIC and was associated with increased postoperative complications. The main limitation of our study is the ability to generalize the results to the wider pediatric surgical population, as these findings only relate to children in whom a preoperative Hb was recorded. Prospective studies are required to determine whether correction of preoperative anemia reduces morbidity and mortality in children undergoing noncardiac surgery.

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.

Neurocognitive Development of Motivated Behavior: Dynamic Changes across Childhood and Adolescence.

The ability to anticipate and respond appropriately to the challenges and opportunities present in our environments is critical for adaptive behavior. Recent methodological innovations have led to substantial advances in our understanding of the neurocircuitry supporting such motivated behavior in adulthood. However, the neural circuits and cognitive processes that enable threat- and reward-motivated behavior undergo substantive changes over the course of development, and these changes are less well understood. In this article, we highlight recent research in human and animal models demonstrating how developmental changes in prefrontal-subcortical neural circuits give rise to corresponding changes in the processing of threats and rewards from infancy to adulthood. We discuss how these developmental trajectories are altered by experiential factors, such as early-life stress, and highlight the relevance of this research for understanding the developmental onset and treatment of psychiatric disorders characterized by dysregulation of motivated behavior.

Using a Developmental Ecology Framework to Align Fear Neurobiology Across Species.

Children's development is largely dependent on caregiving; when caregiving is disrupted, children are at increased risk for numerous poor outcomes, in particular psychopathology. Therefore, determining how caregivers regulate children's affective neurobiology is essential for understanding psychopathology etiology and prevention. Much of the research on affective functioning uses fear learning to map maturation trajectories, with both rodent and human studies contributing knowledge. Nonetheless, as no standard framework exists through which to interpret developmental effects across species, research often remains siloed, thus contributing to the current therapeutic impasse. Here, we propose a developmental ecology framework that attempts to understand fear in the ecological context of the child: their relationship with their parent. By referring to developmental goals that are shared across species (to attach to, then, ultimately, separate from the parent), this framework provides a common grounding from which fear systems and their dysfunction can be understood, thus advancing research on psychopathologies and their treatment.

Mutual recognition in the European system: A blueprint for increasing access to medicines?

The European regulatory system for approval of medicinal products is globally recognised as a unique platform for regulatory work-sharing and mutual recognition. As such, it potentially serves as a role model for regulatory capacity building worldwide. While focusing on mutual recognition and decentralised procedures, this paper illustrates key success factors and structures allowing for the reliance-based authorisation of medicines in the European Economic Area from the perspective of a national regulatory authority (NRA). This paper presents major challenges in fulfilling the requirements for joining the European Medicines Regulatory Network (EMRN) and the strategies regarding how those challenges could be successfully addressed based on the example of the Agency for Medicinal Products and Medical Devices of Croatia, the most recent NRA in the EMRN. It also discusses the hallmarks of successful implementation of the European system of reliance as a blueprint for increasing access to safe and efficacious medicines from the perspective of a NRA.

Setting the occasion for adolescent inhibitory control.

During adolescence, individuals experience a broad range of dynamic environments as they strive to establish independence. Learning to respond appropriately in both new and previously encountered environments requires that an individual identify and learn the meaning of cues indicating that a behavior is appropriate, or alternatively, that it should be altered or inhibited. Although the ability to regulate goal-directed behavior continues to develop across adolescence, the specific circumstances under which adolescents experience difficulty with inhibitory control remain unclear. Here we review recent findings in our laboratory that address how adolescents learn to proactively inhibit a response. Much of our research has utilized a negative occasion setting paradigm, in which one cue (a feature) gates the meaning of a second cue (a target). The feature provides information that resolves the ambiguity of the target and indicates the appropriate behavioral response to the target. As such, we have been able to determine how adolescents learn about ambiguous stimuli, such as those whose meaning changes in accordance with other features of the surrounding environment. We consider why adolescents in particular exhibit difficulty in negative occasion setting compared to either pre-adolescents or adults. In addition, we review findings indicating that a balance in neural activity between orbitofrontal cortex and nucleus accumbens is necessary to support normal negative occasion setting. Finally, we consider aspects of associative learning that may contribute to adolescent inhibitory control, as well as provide insight into adolescent behavior as a whole.

Anesthesia-related and perioperative mortality: An audit of 8493 cases at a tertiary pediatric teaching hospital in South Africa.

AIM: This study aimed to quantify the incidence of anesthesia-related and perioperative mortality at a large tertiary pediatric hospital in South Africa. METHODS: This study included all children aged <18 years who died prior to discharge from hospital and within 30 days of their last anesthetic at the Red Cross War Memorial Children's Hospital between January 1, 2015 to December 31, 2015. A panel of three senior anesthetists reviewed each death to reach a consensus as to whether: (i) anesthesia caused the death; (ii) anesthesia may have contributed to or influenced the timing of death; or (iii) anesthesia was entirely unrelated to the death. RESULTS: There were 47 deaths within 30 days of anesthesia prior to discharge from hospital during this 12-month period. The in-hospital mortality within 24 h of administration of anesthesia was 16.5 per 10 000 cases (95% confidence intervals [CI]=7.8-25.1) and within 30 days of administration of anesthesia was 55.3 per 10 000 cases (95% CI=39.5-71.2). Age under 1 year (OR 4.5; 95% CI=2.5-8.0, P=.012) and cardiac surgery and interventional cardiology procedures (OR 2.5; 95% CI=1.2-5.2, P<.01) were both independent predictors of increased risk of perioperative mortality. CONCLUSION: The overall 24-h and 30-day anesthesia-related and in-hospital perioperative mortality rates in our study are comparable with other similar studies from tertiary pediatric centers.

Increased sign-tracking behavior in adolescent rats.

An autoshaping procedure was used to test the notion that conditioned stimuli (CSs) gain greater incentive salience during adolescence than young adulthood under conditions of social isolation rearing and food restriction. Rats were single-housed and placed on food restriction during 10 daily training sessions in which a lever (CS+ ) was presented then followed immediately by a food unconditioned stimulus (US). A second lever (CS- ) was presented on intermixed trials and was not reinforced. Despite the fact that food delivery was not contingent on the rats' behavior, all rats exhibited behaviors directed towards the lever (i.e., sign-tracking). In the adolescent group, the rate of lever pressing and the percentage of trials with a lever press were higher than in young adults. Initially, group differences were observed when rats were retrained when the adolescents had reached young adulthood. These findings support the hypothesis that cues that come to predict reward become imbued with excessive motivational value in adolescents, perhaps contributing to the hyper-responsiveness to reward-related stimuli typically observed during this period of development.

Neural and behavioral mechanisms of proactive and reactive inhibition.

Response inhibition is an important component of adaptive behavior. Substantial prior research has focused on reactive inhibition, which refers to the cessation of a motor response that is already in progress. More recently, a growing number of studies have begun to examine mechanisms underlying proactive inhibition, whereby preparatory processes result in a response being withheld before it is initiated. It has become apparent that proactive inhibition is an essential component of the overall ability to regulate behavior and has implications for the success of reactive inhibition. Moreover, successful inhibition relies on learning the meaning of specific environmental cues that signal when a behavioral response should be withheld. Proactive inhibitory control is mediated by stopping goals, which reflect the desired outcome of inhibition and include information about how and when inhibition should be implemented. However, little is known about the circuits and cellular processes that encode and represent features in the environment that indicate the necessity for proactive inhibition or how these representations are implemented in response inhibition. In this article, we will review the brain circuits and systems involved in implementing inhibitory control through both reactive and proactive mechanisms. We also comment on possible cellular mechanisms that may contribute to inhibitory control processes, noting that substantial further research is necessary in this regard. Furthermore, we will outline a number of ways in which the temporal dynamics underlying the generation of the proactive inhibitory signal may be particularly important for parsing out the neurobiological correlates that contribute to the learning processes underlying various aspects of inhibitory control.

Contribution of the retrosplenial cortex to temporal discrimination learning.

The retrosplenial cortex (RSC) has an important role in contextual learning and memory. While the majority of experiments have focused on the physical context, the present study asked whether the RSC is involved in processing the temporal context. Rats were trained in a temporal discrimination procedure where the duration of the intertrial interval (ITI) signaled whether or not the next tone conditioned stimulus would be paired with food pellet reinforcement. When the tone was presented after a 16-min ITI it was reinforced, but when it was presented after a 4-min ITI it was not. Rats demonstrated successful discrimination in this procedure by responding more to the tone on reinforced trials than on non-reinforced trials. Pre-training electrolytic lesions of the RSC attenuated acquisition of the temporal discrimination. The results are the first to demonstrate a role for the RSC in processing temporal information and in turn extend the role of the RSC beyond the physical context to now include the temporal context.

Enhancing Clinical Reasoning Through Simulation Debriefing: A Multisite Study.

AIM: The aim of this research was to replicate Dreifuerst's 2012 findings of enhanced clinical reasoning scores using a structured debriefing: Debriefing for Meaningful Learning (DML). BACKGROUND: The direct effect of debriefing on clinical reasoning is not well studied. The nursing education literature supports debriefing as a reflective dialogue necessary to enhance clinical reasoning. METHOD: A quasi-experimental, pretest-posttest, repeated measure research design was used to evaluate nursing students' clinical reasoning using the Health Sciences Reasoning Test (HSRT). RESULTS: The change in HSRT mean scores was determined to be significant for the intervention group at the .05 level and insignificant for the control group. The change in HSRT mean scores between the intervention and control groups was determined to be significant at the .10 level. CONCLUSION: Nursing students who had the DML debriefing scored significantly higher in their clinical reasoning than nursing students who had usual and customary debriefing.