Optimal Dose of Intranasal Dexmedetomidine for Laceration Repair in Children: A Phase II Dose-Ranging Study.

STUDY OBJECTIVE: To determine the optimal sedative dose of intranasal dexmedetomidine for children undergoing laceration repair. METHODS: This dose-ranging study employing the Bayesian Continual Reassessment Method enrolled children aged 0 to 10 years with a single laceration (<5 cm), requiring single-layer closure, who received topical anesthetic. Children were administered 1, 2, 3, or 4 mcg/kg intranasal dexmedetomidine. The primary outcome was the proportion with adequate sedation (Pediatric Sedation State Scale score of 2 or 3 for ≥90% of the time from sterile preparation to tying of the last suture). Secondary outcomes included the Observational Scale of Behavior Distress-Revised (range: 0 [no distress] to 23.5 [maximal distress]), postprocedure length of stay, and adverse events. RESULTS: We enrolled 55 children (35/55 [64%] males; median [interquartile range {IQR}] age 4 [2, 6] years). At 1, 2, 3, and 4 mcg/kg intranasal dexmedetomidine, respectively, the proportion of participants "adequately" sedated was 1/3 (33%), 2/9 (22%), 13/21 (62%), and 12/21 (57%); the posterior mean (95% equitailed credible intervals) for the probability of adequate sedation was 0.38 (0.04, 0.82), 0.25 (0.05, 0.54), 0.61 (0.41, 0.80), and 0.57 (0.36, 0.76); the median (IQR) Observational Scale of Behavior Distress-Revised scores during suturing was 2.7 (0.3, 3), 0 (0, 3.8), 0.6 (0, 5), and 0 (0, 3.7); the median (IQR) postprocedure length of stay was 67 (60, 78), 76 (60, 100), 89 (76, 109), and 113 (76, 150) minutes. There was 1 adverse event, a decrease in oxygen saturation at 4 mcg/kg, which resolved with head repositioning. CONCLUSION: Despite limitations, such as our limited sample size and subjectivity in Pediatric Sedation State Scale scoring, sedation efficacy for 3 and 4 mcg/kg were similarly based on equitailed credible intervals suggesting either could be considered optimal.

Cathelicidin is a "fire alarm", generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa.

Pulmonary infections are a major global cause of morbidity, exacerbated by an increasing threat from antibiotic-resistant pathogens. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against infection, take on ever greater significance. Pseudomonas aeruginosa is an important multidrug-resistant, opportunistic respiratory pathogen, the clearance of which can be enhanced in vivo by the innate immune modulatory properties of antimicrobial host defence peptides from the cathelicidin family, including human LL-37. Initially described primarily as bactericidal agents, cathelicidins are now recognised as multifunctional antimicrobial immunomodulators, modifying host responses to pathogens, but the key mechanisms involved in these protective functions are not yet defined. We demonstrate that P. aeruginosa infection of airway epithelial cells promotes extensive infected cell internalisation of LL-37, in a manner that is dependent upon epithelial cell interaction with live bacteria, but does not require bacterial Type 3 Secretion System (T3SS). Internalised LL-37 acts as a second signal to induce inflammasome activation in airway epithelial cells, which, in contrast to myeloid cells, are relatively unresponsive to P. aeruginosa. We demonstrate that this is mechanistically dependent upon cathepsin B release, and NLRP3-dependent activation of caspase 1. These result in LL-37-mediated release of IL-1ß and IL-18 in a manner that is synergistic with P. aeruginosa infection, and can induce caspase 1-dependent death of infected epithelial cells, and promote neutrophil chemotaxis. We propose that cathelicidin can therefore act as a second signal, required by P. aeruginosa infected epithelial cells to promote an inflammasome-mediated altruistic cell death of infection-compromised epithelial cells and act as a "fire alarm" to enhance rapid escalation of protective inflammatory responses to an uncontrolled infection. Understanding this novel modulatory role for cathelicidins, has the potential to inform development of novel therapeutic strategies to antibiotic-resistant pathogens, harnessing innate immunity as a complementation or alternative to current interventions.

Hyoscine butylbromide versus acetaminophen for nonspecific colicky abdominal pain in children: a randomized controlled trial.

BACKGROUND: Less than two-thirds of children with abdominal pain in the emergency department receive analgesia. We sought to determine whether hyoscine butylbromide was superior to acetaminophen for children with nonspecific colicky abdominal pain. METHODS: We randomly allocated children aged 8-17 years with nonspecific colicky abdominal pain who presented to the pediatric emergency department of London Health Sciences Centre, London, Ontario to receive hyoscine butylbromide, 10 mg given orally, or acetaminophen, 15 mg/kg given orally (maximum 975 mg). We considered the minimal clinically important difference for the primary outcome (self-reported pain at 80 min) to be 13 mm on a 100 mm visual analogue scale. Secondary outcomes included administration of rescue analgesia, adverse effects and pain score less than 30 mm at 80 minutes. RESULTS: A total of 236 participants (120 in the hyoscine butylbromide group and 116 in the acetaminophen group) were included in the trial. The mean visual analogue scale scores at 80 minutes were 29 mm (standard deviation [SD] 26 mm) and 30 mm (SD 29 mm) with hyoscine butylbromide and acetaminophen, respectively (adjusted difference 1, 95% confidence interval -7 to 7). Rescue analgesia was administered to 4 participants (3.3%) in the hyoscine butylbromide group and 1 participant (0.9%) in the acetaminophen groups (p = 0.2). We found no significant differences in rates of adverse effects between hyoscine butylbromide (32/116 [27.6%]) and acetaminophen (28/115 [24.3]) (p = 0.5); no serious adverse effects were observed. The proportion with a pain score less than 30 mm at 80 minutes was 66 (55.0%) with hyoscine butylbromide and 63 (54.3%) with acetaminophen (p = 0.9). INTERPRETATION: Hyoscine butylbromide was not superior to acetaminophen in this setting. Both agents were associated with clinically important pain reduction, and either can be considered for children presenting to the emergency department with nonspecific colicky abdominal pain. Trial registration: Clinicaltrials.gov, no. NCT02582307.

Mindfulness-Based Stress Reduction for Health Care Staff: Expanding Holistic Nursing Paradigms to the Whole System.

Mindfulness-based stress reduction (MBSR) is a well-known mindfulness meditation program for patients that also may benefit health care providers and clinic staff themselves. An abbreviated MBSR program adapted into 6 weekly 75-minute sessions held during staff lunch breaks provided a feasible and acceptable staff training approach within the workplace setting.

Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy with Older Adults: A Qualitative Review of Randomized Controlled Outcome Research.

Objective: Many older adults cope with various chronic physical health conditions, and in some cases, with mental health and/or cognitive difficulties. Mindfulness-based interventions offer an evidence-based, mind-body complementary treatment approach for a wide range of comorbidities, yet most investigations were conducted with young or middle-aged adults. The purpose of this review was to identify randomized controlled trials (RCTs) of two leading mindfulness-based interventions conducted with older adults. Methods: Our search of five databases identified seven RCT investigations of either Mindfulness-Based Stress Reduction (MBSR) or Mindfulness-Based Cognitive Therapy (MBCT) conducted exclusively with older adults. Results: Results generally supported the use of MBSR for chronic low back pain, chronic insomnia, improved sleep quality, enhanced positive affect, reduced symptoms of anxiety and depression, and improved memory and executive functioning. In a sample of older adults exhibiting elevated anxiety in the absence of elevated depression, MBCT effectively reduced symptoms of anxiety. Conclusions: This review highlights the feasibility and possible benefits of MBSR and MBCT for older adults. Additional large scale RCTs conducted with older adults coping with the range of physical, behavioral, and cognitive challenges older adults commonly face still are needed. Clinical Implications: MBSR may be a promising intervention for older adults experiencing a variety of health concerns and possibly even cognitive decline. MBCT may reduce geriatric anxiety, although its effects on geriatric depression were not measured.

Effectiveness of Mindfulness-Based Stress Reduction Bibliotherapy: A Preliminary Randomized Controlled Trial.

OBJECTIVE: This randomized controlled investigation examined the effectiveness of a self-help bibliotherapy format of the evidence-based mindfulness-based stress reduction (MBSR) intervention. METHOD: College students seeking stress reduction were randomly assigned to a 10-week MBSR bibliotherapy intervention group (n = 47) or a no-treatment control group (n = 45). Self-report measures were collected at baseline and postintervention. RESULTS: A total of 25 bibliotherapy and 43 control group participants provided final data following the intervention period. Compared to the control group, bibliotherapy participants reported increased mindfulness following the intervention. Significant decreases on measures of depression, anxiety, stress, perceived stress, and anxiety sensitivity also were reported postintervention as well as increased quality of life in physical health, psychological, and environmental domains. No statistically significant group effects were found for social relationships quality of life domain, worry, and experiential avoidance measures. CONCLUSION: This MBSR workbook may provide an acceptable and effective alternative for motivated individuals seeking to reduce stress, at least for a select group of individuals who are willing and able to sustain participation in the intervention.

Acceptability of a Self-Led Mindfulness-Based Intervention for Teens with Type 1 Diabetes: Pilot Randomized Controlled Trial.

BACKGROUND: Diabetes distress among adolescents with type 1 diabetes has been associated with suboptimal diabetes outcomes, including lower quality of life, increased diabetes self-management challenges, and suboptimal glycemic outcomes. OBJECTIVE: This study examined the feasibility and acceptability of a scalable self-led mindfulness-based intervention to reduce diabetes distress in adolescents with type 1 diabetes. METHODS: Adolescents (N=25) aged between 14 and 18 years diagnosed with type 1 diabetes completed a baseline assessment. Participants were randomized to receive a 10-week self-guided mindfulness-based stress reduction workbook program (e-book or paper option) immediately (n=15) or after a 10-week wait (n=10). During the intervention period, participants completed weekly assignments and feedback surveys. At 10 weeks and 20 weeks, follow-up assessments were completed. RESULTS: Findings indicated that participants did not find the original intervention feasible or acceptable. Adolescents reported barriers to completing the weekly material, such as that they forgot or that the material was not sufficiently related to their diabetes management. Adolescents also reported that a digital format rather than a workbook or e-book may be more acceptable. Results from weekly surveys provided the foundation for recommendations for future iterations of the mindfulness-based intervention for adolescents with type 1 diabetes. CONCLUSIONS: Participant feedback informed recommendations for self-led mindfulness programs for youth with type 1 diabetes. Adolescents indicated that a shorter, digital mindfulness-based intervention focused on diabetes-specific behaviors may be more helpful. TRIAL REGISTRATION: ClinicalTrials.gov NCT05115175; https://clinicaltrials.gov/study/NCT05115175.

Relationships Between Burnout, Secondary Traumatic Stress, Mindfulness, and Self-Compassion in Victim Advocates.

Victim advocates experience burnout and secondary traumatic stress (STS) in response to their exposure to trauma at work. Mindful awareness may serve as a protective factor against these negative outcomes. The current study examined a sample of 133 victim advocates from across the country to better understand and predict STS and burnout. Higher mindful awareness was found to be associated with lower STS and burnout, even when controlling for other best-known predictors. Self-compassion partially mediated these relationships. These findings support further research exploring the effects of mindful awareness training for victim advocates to reduce STS and burnout.

Mindfulness-based stress reduction for comorbid anxiety and depression: case report and clinical considerations.

Growing research literature has documented the effectiveness of mindfulness-based interventions for anxiety and depressive disorders. Mindfulness-based stress reduction (MBSR) teaches a series of mindfulness meditation and yoga practices, delivered in a group format during eight weekly sessions plus one full-day session. This case report demonstrates how MBSR was associated with dramatic clinical improvement of an individual with symptoms of panic, generalized anxiety, and depression. Scores on clinical assessment measures suggested clinically severe levels of anxious arousal, generalized anxiety, worry, fear of negative evaluation, and depression at the beginning of the intervention. The scores on all these measures fell well within normal limits 7 weeks later at the end of the intervention, and no remaining symptoms were reported afterward. Increased life satisfaction and quality of life were documented as well. This case illustrates the potential benefit of MBSR as an alternative or adjunctive treatment for comorbid anxiety and depressive disorder symptoms.

Does mindfulness-based intervention improve cognitive function?: A meta-analysis of controlled studies.

Theoretical accounts and preliminary evidence suggest that Mindfulness-Based Interventions (MBIs) improve cognitive function, but reviews of empirical studies have provided mixed results. To clarify empirical evidence, we conducted a meta-analysis of 25 studies (n = 1439) and examined the effects of MBIs on four cognitive domains: attention, working memory, long-term memory, and executive function. The summary effect sizes indicate that MBIs produce non-significant effects on attention (SMD = 0.07), working memory (SMD = 0.16), and long-term memory (SMD = -0.12), while a small effect was observed for executive function (SMD = 0.29). Given significant heterogeneity across studies, we conducted meta-regression analyses with sample characteristics, age, number of treatment sessions, treatment duration, intervention type, control group type, and study design. We found moderating effects of intervention type on attention and executive function. Although the current study highlights preliminary evidence for improvements in executive function, overall results suggest non-significant findings for attention, working memory, and long-term memory. To draw a firm conclusion, further research is needed to address methodological challenges in meta-analysis and the limitations of existing studies.

Grid cells are modulated by local head direction.

Grid and head direction codes represent cognitive spaces for navigation and memory. Pure grid cells generate grid codes that have been assumed to be independent of head direction, whereas conjunctive cells generate grid representations that are tuned to a single head direction. Here, we demonstrate that pure grid cells also encode head direction, but through distinct mechanisms. We show that individual firing fields of pure grid cells are tuned to multiple head directions, with the preferred sets of directions differing between fields. This local directional modulation is not predicted by previous continuous attractor or oscillatory interference models of grid firing but is accounted for by models in which pure grid cells integrate inputs from co-aligned conjunctive cells with firing rates that differ between their fields. We suggest that local directional signals from grid cells may contribute to downstream computations by decorrelating different points of view from the same location.

Exposure to the antimicrobial peptide LL-37 produces dendritic cells optimized for immunotherapy.

Immunization of patients with autologous, ex vivo matured dendritic cell (DC) preparations, in order to prime antitumor T-cell responses, is the focus of intense research. Despite progress and approval of clinical approaches, significant enhancement of these personalized immunotherapies is urgently needed to improve efficacy. We show that immunotherapeutic murine and human DC, generated in the presence of the antimicrobial host defense peptide LL-37, have dramatically enhanced expansion and differentiation of cells with key features of the critical CD103+/CD141+ DC subsets, including enhanced cross-presentation and co-stimulatory capacity, and upregulation of CCR7 with improved migratory capacity. These LL-37-DC enhanced proliferation, activation and cytokine production by CD8+ (but not CD4+) T cells in vitro and in vivo. Critically, tumor antigen-presenting LL-37-DC increased migration of primed, activated CD8+ T cells into established squamous cell carcinomas in mice, and resulted in tumor regression. This advance therefore has the potential to dramatically enhance DC immunotherapy protocols.

CBT intensity and outcome for panic disorder in a primary care setting.

A hybrid efficacy-effectiveness design in which participants (n = 91/93) were retained in the study regardless of whether or not they received treatment enabled evaluation of CBT intensity in relation to panic disorder in the primary care setting. CBT intensity was operationalized as number of cognitive-behavioral therapy sessions, number of follow-up booster phone calls, and secondarily, as number of cognitive behavioral coping and exposure strategies. Baseline psychosocial and demographic predictors of CBT intensity were analyzed first. Severity of anxiety sensitivity predicted number of cognitive behavioral sessions, but no baseline variables predicted number of follow-up booster phone calls or number of coping and exposure strategies. Multivariate logistic and linear regressions were used to evaluate the degree to which treatment intensity predicted 3-month and 12-month outcomes (anxiety sensitivity, phobic avoidance, depressive symptoms, disability, and medical and mental health functioning) after controlling for potential confounding baseline variables. Number of cognitive behavioral therapy sessions predicted lower anxiety sensitivity at 3 and 12 months, and number of follow-up booster phone calls predicted lower anxiety sensitivity, less phobic avoidance, and less depression at 12 months. These findings indicate that "dose" of psychotherapy was an important predictor of outcome. The significance of follow-up booster phone contact is discussed as an index of continued self-management of panic and anxiety following acute treatment.

Cell-Type Specific Responses to DNA Replication Stress in Early C. elegans Embryos.

To better understand how the cellular response to DNA replication stress is regulated during embryonic development, we and others have established the early C. elegans embryo as a model system to study this important problem. As is the case in most eukaryotic cell types, the replication stress response is controlled by the ATR kinase in early worm embryos. In this report we use RNAi to systematically characterize ATR pathway components for roles in promoting cell cycle delay during a replication stress response, and we find that these genetic requirements vary, depending on the source of stress. We also examine how individual cell types within the embryo respond to replication stress, and we find that the strength of the response, as defined by duration of cell cycle delay, varies dramatically within blastomeres of the early embryo. Our studies shed light on how the replication stress response is managed in the context of embryonic development and show that this pathway is subject to developmental regulation.

Predictors of willingness to consider medication and psychosocial treatment for panic disorder in primary care patients.

The purpose of this investigation was to identify demographic and clinical patient characteristics related to willingness to consider panic disorder treatments in the primary care setting. Given the prevalence of anxiety disorders and the increased provision of mental health treatments in general medical settings, patients were selected from primary care settings. An unselected sample of 4,198 patients completed a brief questionnaire containing questions about demographic characteristics, physical health status, and symptoms of panic disorder, social phobia and PTSD. The 1,043 patients indicating a recent panic attack episode answered additional questions about their willingness to consider both medication and psychosocial forms of intervention for panic. Of these panic patients, 64% reported willingness to consider medication and 67% reported willingness to consider a psychosocial intervention for their panic. Logistic regression analyses for these panic patients revealed that willingness to consider medication treatment for panic was associated with older age, lower education, poorer health status and the presence of social phobia and/or PTSD symptoms. In addition, Asian and African American patients were less likely than Caucasian patients to indicate willingness to consider medication treatment for their panic. However, only the presence of comorbid social phobia and PTSD symptoms predicted willingness to consider a psychosocial intervention. Results suggest that acceptability of psychosocial treatment is unrelated to demographic and physical health factors, while primary care patients with certain demographic characteristics, good physical health, or who suffer from fewer comorbid mental health conditions may need additional encouragement to begin medication treatment for panic.

Prevalence of irritable bowel syndrome among university students: the roles of worry, neuroticism, anxiety sensitivity and visceral anxiety.

OBJECTIVE: Relationships between presence of irritable bowel syndrome (IBS) and generalized anxiety disorder (GAD), chronic worry, neuroticism, anxiety sensitivity and anxiety about visceral sensations were examined among university students. METHODS: College student participants were administered self-report diagnostic measures of IBS and GAD, the Penn State Worry Questionnaire (PSWQ), the Neuroticism subscale of the Eysenck Personality Questionnaire, the Anxiety Sensitivity Index (ASI) and five additional items designed to measure visceral anxiety. RESULTS: The prevalence of IBS and its associated characteristics among students were similar to previous community survey studies, with the exception of lower symptom severity in the university sample. IBS was associated with a higher frequency of GAD and greater worry, neuroticism, anxiety sensitivity and visceral anxiety. Logistic regression analyses further showed that the measure of anxiety specific to visceral sensations was the strongest predictor of IBS diagnostic status. CONCLUSIONS: While various aspects of anxiety appear related to IBS, specific anxiety about visceral sensations appears to be the most significant factor. Implications of the associations between anxiety-related variables, particularly anxiety about visceral sensations, are discussed.

Interpretive cues and ambiguity in generalized anxiety disorder.

The current study investigated whether generalized anxiety disorder (GAD) individuals rely on antecedent information to interpret ambiguity and whether reliance on such preceding cues persists in the absence of potential threat. Twenty-six GAD and 23 nonanxious control college students performed a lexical decision task, using homographs (i.e. words with multiple meanings) as ambiguous primes. In half the trials, a homograph prime that possessed both threat-related, as well as neutral meanings was followed by a target word related to one of these two meanings. In addition, each ambiguous prime was immediately preceded by a series of four antecedent words that were either: (a) associated with the threatening meaning of the prime; (b) associated with the neutral meaning of the prime; or (c) unrelated to either meaning of the homograph, as well as the target. Homographs for which both meanings were neutral in valence comprised the other half of the trials. Effect size statistics suggest that GAD participants utilized the antecedent words to interpret the homograph primes with threat-related meanings, unlike their nonanxious counterparts (p<0.06). When both meanings of the homograph prime were neutral in valence, the GAD group appeared deficient in the use of preceding information to interpret the ambiguous prime.

The relationship of thought-action fusion to pathologicial worry and generalized anxiety disorder.

Meta-cognitive beliefs associated with pathological worry and generalized anxiety disorder (GAD) may encompass the likelihood subtype of thought-action fusion (TAF), the belief that one's thoughts can influence outside events. In the current study of 494 undergraduate college students, positive correlations between scores on the Penn State Worry Questionnaire (PSWQ) and the two Likelihood subscales of the TAF Scale were found, and participants endorsing at least some DSM-IV diagnostic criteria for GAD scored significantly higher on both TAF-Likelihood subscales than participants reporting no GAD symptoms. However, these TAF scales did not predict GAD diagnostic status with PSWQ included as a predictor. In contrast to previous research, the TAF-Moral scale did not correlate with worry. Relationships between TAF, pathological worry, and meta-cognition are discussed in relation to GAD.