Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aß axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.

Successful treatment of severe passenger lymphocyte syndrome with efgartigimod synergy.

INTRODUCTION: This case describes passenger lymphocyte syndrome (PLS) generating human platelet antigen 1a (HPA-1a) alloantibodies against the recipient's platelets after liver transplant. Given the rarity of PLS, especially in liver transplant with HPA-1a alloantibodies, disease course and management options are poorly described. METHODS: The patient had cirrhosis secondary to nonalcoholic steatohepatitis complicated by hepatocellular carcinoma, encephalopathy, and severe ascites. The model for end-stage liver disease (MELD) score was 15 at presentation. The patient developed hepatic artery thrombosis after an orthotopic liver transplant and was relisted for transplant with a MELD score of 40. The patient received a hepatitis C virus antibody positive, hepatitis C virus nucleic amplification test positive donor liver on postoperative day (POD) 7 after first transplant. On POD 7 after the second transplant, the patient developed profound thrombocytopenia refractory to platelet infusion. They were found to have serum antibody to HPA-1a based upon serum platelet alloantibody testing. The donor was later found to be negative for HPA-1a by genetic testing. However, the patient's native platelets were HPA-1a positive. The patient was diagnosed with PLS. RESULTS: The patient's treatment course included 57 units of platelets transfused, emergency splenectomy, rituximab, plasma exchange, intravenous immunoglobulin (IVIG), eltrombopag, romiplostim, and efgartigimod. DISCUSSION: The synergistic effect of efgartigimod with eltrombopag and romiplostim most likely resolved the patient's thrombocytopenia. This case represents a novel use of efgartigimod in the treatment of passenger lymphocyte syndrome following liver transplant.

The mental health of officials who regularly examine child sexual abuse material: strategies for harm mitigation.

BACKGROUND: The current study aims to better understand the mental health and subjective well-being of investigators and forensic examiners exposed to child sexual abuse material (CSAM) by examining which components of this work are associated with elevated mental health conditions and decreased well-being, as well as the intra-personal and organizational variables that may mitigate harm and improve well-being. METHODS: Police investigators, forensic examiners, and others connected with the criminal justice system from across the United States who were exposed to CSAM as part of their professions (N = 500) completed an anonymous online survey. Participants were recruited through connections with the National Criminal Justice Training Center. RESULTS: Duration, frequency, amount, and content of CSAM exposure was not related to poorer mental health with the exception of exposure to violent CSAM which was related to elevated post-traumatic stress symptoms. Several agency-level practices and policies, such as the availability of an Officer Wellness Program and more frequently knowing the final case resolution, were related to better mental health and well-being. Harm mitigation strategies, such as talking to other officers investigating the case and taking breaks from the material being viewed, were also related to better mental health. CONCLUSIONS: Findings indicate that police agencies have options for implementing agency-level procedures and practices that have the potential to reduce the negative impact of CSAM investigations. Additionally, many investigators use strategies that are correlated with greater well-being, suggesting opportunities for improving training programs.

Determining residual gastric volume in healthy children using ultrasound.

PURPOSE: Fasting guidelines for children recommend restricting clear fluids for one or two hours before a procedure to reduce pulmonary aspiration. Gastric volumes < 1.5 mL·kg-1 do not seem to present an increased risk of pulmonary aspiration. Our aim was to quantify the time to achieve a gastric volume < 1.5 mL·kg-1 after clear fluid ingestion in children. METHODS: We conducted a prospective observational study in healthy volunteers aged 1-14 yr. Participants followed American Society of Anesthesiologists fasting guidelines prior to data collection. Gastric ultrasound (US) was performed in the right lateral decubitus (RLD) position to determine the antral cross-sectional area (CSA). Following baseline measurements, participants consumed 250 mL of a clear fluid. We then performed gastric US at four time intervals: 30, 60, 90, and 120 min. Data were collected following a predictive model for gastric volume estimation using the formula: volume (mL) = -7.8 + (3.5 × RLD CSA) + (0.127) × age (months). RESULTS: We recruited 33 healthy children aged 2-14 yr. The mean gastric volume per weight (mL·kg-1) at baseline was 0.51 mL·kg-1 (95% confidence interval [CI], 0.46 to 0.57). The mean gastric volume was 1.55 mL·kg-1 (95% CI, 1.36 to 1.75) at 30 min, 1.17 mL·kg-1 (95% CI, 1.01 to 1.33) at 60 min, 0.76 mL·kg-1 (95% CI, 0.67 to 0.85) at 90 min, and 0.58 mL·kg-1 (95% CI, 0.52 to 0.65) at 120 min. CONCLUSION: Our results show that total gastric fluid volume was < 1.5 mL·kg-1 after 60 min, suggesting that current fasting guidelines for children could be liberalized.

RéSUMé: OBJECTIF: Les directives de jeûne pour les enfants recommandent de restreindre les liquides clairs pendant une ou deux heures avant une intervention pour réduire l'aspiration pulmonaire. Des volumes gastriques < 1,5 mL·kg−1 ne semblent pas présenter un risque accru d'aspiration pulmonaire. Notre objectif était de quantifier le temps nécessaire pour atteindre un volume gastrique < 1,5 mL·kg−1 après ingestion de liquides clairs chez les enfants. MéTHODE: Nous avons mené une étude observationnelle prospective chez des volontaires en bonne santé âgé·es de 1 à 14 ans. Les participant·es ont suivi les directives de jeûne de l'American Society of Anesthesiologists avant la collecte de données. L'échographie gastrique a été réalisée en décubitus latéral droit (DLD) pour déterminer la section transversale antrale. Après les mesures initiales, les participant·es ont consommé 250 mL d'un liquide clair. Nous avons ensuite réalisé une échographie gastrique à quatre intervalles de temps : 30, 60, 90 et 120 minutes. Les données ont été recueillies selon un modèle prédictif pour l'estimation du volume gastrique à l'aide de la formule : volume (mL) = −7,8 + (3,5 × section transversale antrale en DLD) + (0,127) × âge (mois). RéSULTATS: Nous avons recruté 33 enfants en bonne santé âgé·es de 2 à 14 ans. Le volume gastrique moyen par poids (mL·kg−1) au début de l'intervention était de 0,51 mL·kg−1 (intervalle de confiance [IC] à 95 %, 0,46 à 0,57). Le volume gastrique moyen était de 1,55 mL·kg−1 (IC 95 %, 1,36 à 1,75) à 30 min, 1,17 mL·kg−1 (IC 95 %, 1,01 à 1,33) à 60 min, 0,76 mL·kg−1 (IC 95 %, 0,67 à 0,85) à 90 min, et 0,58 mL·kg−1 (IC 95 %, 0,52 à 0,65) à 120 min. CONCLUSION: Nos résultats montrent que le volume total de liquide gastrique était < 1,5 mL·kg−1 après 60 min, suggérant que les directives actuelles de jeûne pour les enfants pourraient être libéralisées.

Understanding equitable and affirming communication moments and relationship milestones during the intensive care unit journey: findings from stage 1 of a design thinking project.

PURPOSE: Communication is vital to facilitate patient and family-centred care (PFCC) and to build trusting relationships between intensive care unit (ICU) health care providers, the patient, and their loved ones in the ICU. The focus of this investigation was to identify, define, and refine key moments of communication, connection, and relationship building in the ICU through a lens of Equity, Diversity, Decolonization, and Inclusion (EDDI) to encourage meaningful communication and development of trusting relationships. METHODS: We conducted 13 journey mapping interviews with ICU health care providers, patients, and their loved ones as the first stage in a design thinking project. We used directed content analysis to identify intersections where principles of EDDI directly or indirectly impacted communication, relationships, and trust throughout the ICU journey. To serve diverse patients and their loved ones, accessibility, inclusivity, and cultural safety were foundational pillars of the design thinking project. RESULTS: Thirteen ICU health care providers, patients, and their loved ones participated in journey mapping interviews. We defined and refined 16 communication moments and relationship milestones in the journey of a patient through the ICU (e.g., admission, crises, stabilization, discharge), and intersections where EDDI directly or indirectly impacted communication and connection during the ICU journey. CONCLUSION: Our findings highlight that diverse intersectional identities impact communication moments and relationship milestones during an ICU journey. To fully embrace a paradigm of PFCC, consideration should be given to creating an affirming and safe space for patients and their loved ones in the ICU.

RéSUMé: OBJECTIF : La communication est essentielle pour faciliter les soins axés sur la patientèle et la famille et pour établir des relations de confiance entre les prestataires de soins de santé de l'unité de soins intensifs (USI), la patientèle, et ses proches à l'USI. L'objectif de cette enquête était d'identifier, de définir et de peaufiner les moments clés de communication, de connexion et de création de relation aux soins intensifs sous l'angle de l'équité, de la diversité, de l'inclusion et de la décolonisation (EDID) afin d'encourager une communication profonde et la création de relations de confiance. MéTHODE: Nous avons mené 13 entretiens de cartographie du parcours avec des prestataires de soins et des patient·es de l'USI ainsi qu'avec leurs proches dans le cadre de la première étape d'un projet de réflexion conceptuelle. Nous avons utilisé l'analyse de contenu dirigée pour identifier les intersections où les principes de l'EDID ont eu un impact direct ou indirect sur la communication, les relations et la confiance tout au long du parcours aux soins intensifs. L'accessibilité, l'inclusivité et la sécurité culturelle ont constitué des piliers fondamentaux du projet de réflexion conceptuelle pour desservir une patientèle diverse et ses proches. RéSULTATS: Treize prestataires de soins et patient·es de l'USI et leurs proches ont participé à des entrevues de cartographie du parcours. Nous avons défini et affiné 16 moments de communication et jalons de la relation dans le parcours d'un·e patient·e à l'USI (p. ex. admission, crises, stabilisation, congé) et les intersections où l'EDID a eu une incidence directe ou indirecte sur la communication et la connexion pendant le parcours aux soins intensifs. CONCLUSION: Nos résultats soulignent que les diverses identités intersectionnelles ont un impact sur les moments de communication et les jalons de la relation lors d'une trajectoire aux soins intensifs. Pour adopter pleinement un paradigme de soins axés sur la patientèle et sa famille, il faudrait envisager de créer un espace d'affirmation et de sécurité pour les patient·es et leurs proches à l'unité de soins intensifs.

Identifying behaviors that characterize emergence delirium: An observational study.

BACKGROUND: Diagnostic criteria for emergence agitation are sensitive but not specific; they misclassify patients who are angry or upset as having emergence delirium. AIMS: The aim of this three-phase study was to determine expert agreement on the behaviors that differentiate children with emergence delirium from those without. METHODS: In the first phase of this observational study, pediatric dental patients were video recorded while awakening from anesthesia. In the second phase, salient 10 s segments of the recordings showing patient activity were shown to an expert audience of pediatric dentists, anesthesiologists and Post Anesthetic Care nurses, who scored the recordings as showing or not showing "true emergence delirium." In phase 3, the video segments were assessed by three research assistants using a behavior checklist for features that discriminate between those scored "true emergence delirium" and those scored "NOT true emergence delirium" by the experts. RESULTS: One hundred and fifty-four pediatric dental patients were included. Subsequently, an expert audience consisting of 10 anesthesiologists, 12 anesthesiology residents, 3 pediatric dentists, and 4 experienced Post Anesthesia Care Unit nurses rated each 10-second video segment. This resulted in three groups of patients: a group for whom all experts agreed was "True emergence delirium" (n = 33; CI 21 to 45), a group for whom all agreed was "Not True emergence delirium" (n = 120; CI 107 to 133), and a group where experts disagreed (n = 11; CI 4 to 18). Three research assistants then completed a behavior checklist for each of the 33 "True emergence delirium" video segments and matched "Not True" controls. Twenty-four behaviors were identified as significantly different between videos scored True emergence delirium and those scored Not True emergence delirium. Research assistants reached almost perfect agreement (0.81-1.00) on one behavior, and substantial agreement (0.61-0.80) on seven behaviors that characterized "True emergence delirium." CONCLUSIONS: Eight behaviors that differentiate pediatric dental patients with emergence delirium from those without were found. These discriminators may be used to develop a scale that will lead to better diagnosis and treatment of emergence delirium.

Enhanced Crystallinity of Covalent Organic Frameworks Formed Under Physical Confinement by Exfoliated Graphene.

The polymerization of 1,4-benzenediboronic acid (BDBA) on mica to form a covalent organic framework (COF-1) reveals a dramatic increase in crystallinity when physically confined by exfoliated graphene. COF-1 domains formed under graphene confinement are highly geometric in shape and on the order of square micrometers in size, while outside of the exfoliated flakes, the COF-1 does not exhibit long-range mesoscale structural order, according to atomic force microscopy imaging. Micro-Fourier transform infrared spectroscopy confirms the presence of COF-1 both outside and underneath the exfoliated graphene flakes, and density functional theory calculations predict that higher mobility and self-assembly are not causes of this higher degree of crystallinity for the confined COF-1 domains. The most likely origin of the confined COF-1's substantial increase in crystallinity is from enhanced dynamic covalent crystallization due to the water confined beneath the graphene flake.

Comparative risk of pulmonary adverse events with transfusion of pathogen reduced and conventional platelet components.

BACKGROUND: Platelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion. STUDY DESIGN: An open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality. RESULTS: By modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio = 0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p = .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p = .151; odds ratio = 0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p = .256); and allergic TR were significantly less with PRPC (p = .006). PC and RBC use were not increased with PRPC. DISCUSSION: PRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.

Competence of anesthesiology residents following a longitudinal point-of-care ultrasound curriculum.

PURPOSE: Point-of-care ultrasound (POCUS) facilitates diagnostic, procedural, and resuscitative applications in anesthesiology. Structured POCUS curricula improve learner satisfaction, test scores, and clinical management, but the learning curve towards competency and retention of skills over time remain unknown. METHODS: We conducted a prospective observational study to determine when anesthesiology trainees enrolled in a POCUS curriculum achieve competency in POCUS skills. We also investigated the learning curve of trainees' competency using a POCUS-specific competency-based medical education assessment. The structured, longitudinal POCUS curriculum included online lectures, journal articles, live model scanning sessions, video review of cases, and a portfolio of supervised scans. Point-of-care ultrasound scanning sessions on standardized patients were conducted in the simulation lab for 2.5 hr a week and each resident completed eight sessions (20 hr) per academic year. At each scanning session, timed image acquisition scores were collected and POCUS skills entrustment scale evaluations were conducted. The primary outcome was the number of supervised scans and sessions required to achieve a mean entrustment score of 4 ("may use independently"). Secondary outcomes included image acquisition scores and retention of skills after six months. RESULTS: The mean (standard deviation) number of supervised scans required for trainees (n = 29) to reach a mean entrustment score of ≥ 4 was 36 (10) scans over nine sessions for rescue echo. A mean entrustment score of ≥ 4 was observed for lung ultrasound after a mean (SD) of 8 (3) scans over two sessions. CONCLUSIONS: Our study shows that anesthesiology residents can achieve competence in rescue echo and lung ultrasound through participation in a structured, longitudinal POCUS curriculum, and outlines the learning curve for progression towards competency.

RéSUMé: OBJECTIF: L'échographie ciblée (POCUS) facilite les applications diagnostiques, procédurales et de réanimation en anesthésiologie. Les programmes de cours structurés en échographie ciblée améliorent la satisfaction des apprenants ainsi que leurs résultats aux examens et leur prise en charge clinique, mais nous connaissons mal la courbe d'apprentissage vers la compétence et le maintien des compétences au fil du temps. MéTHODE: Nous avons réalisé une étude observationnelle prospective afin de déterminer quand les stagiaires en anesthésiologie inscrits à un programme d'échographie ciblée atteignaient les compétences dans ce domaine. Nous avons également étudié la courbe d'apprentissage des compétences des résidents à l'aide d'une évaluation de la formation médicale fondée sur les compétences spécifique à l'échographie ciblée. Le programme d'échographie ciblée structuré et longitudinal comprenait des cours en ligne, des articles de revues, des séances d'examens d'échographie modèles en direct, une revue vidéo de cas et un portefeuille d'examens échographiques supervisés. Des séances d'échographie ciblée sur des patients standardisés ont été réalisées dans le laboratoire de simulation pendant 2,5 heures par semaine et chaque résident a suivi huit séances (20 heures) par année scolaire. À chaque session d'examen échographique, des scores chronométrés d'acquisition d'images ont été colligés et des évaluations d'échelle de confiance des compétences d'échographie ciblée ont été réalisées. Le critère d'évaluation principal était le nombre d'examens et de séances d'échographie supervisés requis pour obtenir un score moyen de confiance de 4 (« peut réaliser une échographie indépendamment ¼). Les critères d'évaluation secondaires comprenaient les scores d'acquisition d'images et le maintien des compétences après six mois. RéSULTATS: Le nombre moyen (écart type) d'examens supervisés requis pour les résidents (n = 29) pour atteindre un score de confiance moyen ≥ 4 était de 36 (10) examens sur neuf sessions pour l'échographie de sauvetage. Un score de confiance moyen ≥ 4 a été observé pour l'échographie pulmonaire après une moyenne (ET) de 8 (3) examens sur deux séances. CONCLUSION: Notre étude montre que les résidents en anesthésiologie peuvent acquérir des compétences en échographie de sauvetage et en échographie pulmonaire en participant à un cours d'échographie ciblée structuré et longitudinal, et décrit la courbe d'apprentissage pour la progression vers la compétence.

The Use of General Anesthesia for Pediatric Dentistry in Saskatchewan: A Retrospective Study.

INTRODUCTION: The rate of general anesthesia (GA) use for pediatric dental treatment in Saskatchewan is among the highest in Canada. Although the prevalence of and risk factors for early childhood caries (ECC) has been reviewed nationally, few studies have focused on Saskatchewan. The objective of this study was to determine the prevalence of and predictive factors for dental treatment under GA in Saskatchewan. METHODS: This retrospective review focused on pediatric patients who required dental treatment under GA in Saskatchewan between 2015 and 2018. Demographic, dental diagnostic and treatment data and number of previous exposures to GA were collected and analyzed. RESULTS: We reviewed 570 patient records. Dental treatment needs among the sample were complex; children had 10.85 ± 3.56 (mean ± standard deviation) teeth treated, for an average cost of $3231.72 ± $898.95 per child. Children who lived in less accessible or remote locations had a significantly higher caries experience, number of teeth treated and cost of treatment. In addition, children who lived in such locations were more likely to have had previous dental treatment under GA (odds ratio [OR] 1.29, 95% CI 1.029-1.645) compared with those who lived in easily accessible/accessible areas (OR 0.81, 95% CI 0.700-0.953). CONCLUSION: Our findings confirm previous research that children who require dental treatment under GA have extensive caries and treatment needs. Our results suggest that children who live in less accessible and more remote areas of the province have a higher burden of disease and are more likely to require repeated GA exposures for dental treatment.

Integration of hatha yoga and evidence-based psychological treatments for common mental disorders: An evidence map.

BACKGROUND: Interest in the use of yoga to enhance engagement with and augment the benefits of psychological treatment has grown. However, a systematic approach to reviewing existing research examining the use of yoga with psychological treatment is lacking. MATERIALS AND METHODS: This mapping review identified and synthesised research trialling yoga as an integrated or adjunct therapy with evidence-based psychological interventions for the treatment of anxiety, depression, PTSD, and eating disorders. RESULTS: Overall, the review identified ten published and three unpublished studies, representing either single group or small quasi-experimental research designs. DISCUSSION: Limited but promising findings were shown for yoga with CBT for anxiety and depression, and the integration of yoga within intensive treatment models for PTSD. CONCLUSIONS: Future research is encouraged to focus on controlled trials that enable examination of the component effect of yoga when applied with evidence-based psychological treatment and acceptability and feasibility data to further knowledge regarding a role for yoga in clinical practice.

Inhibition of calcium-calmodulin-dependent phosphodiesterase (PDE1) suppresses inflammatory responses.

A novel, potent, and highly specific inhibitor of calcium-calmodulin-dependent phosphodiesterases (PDE) of the PDE1 family, ITI-214, was used to investigate the role of PDE1 in inflammatory responses. ITI-214 dose-dependently suppressed lipopolysaccharide (LPS)-induced gene expression of pro-inflammatory cytokines in an immortalized murine microglial cell line, BV2 cells. RNA profiling (RNA-Seq) was used to analyze the impact of ITI-214 on the BV2 cell transcriptome in the absence and the presence of LPS. ITI-214 was found to regulate classes of genes that are involved in inflammation and cell migration responses to LPS exposure. The gene expression changes seen with ITI-214 treatment were distinct from those elicited by inhibitors of other PDEs with anti-inflammatory activity (e.g., a PDE4 inhibitor), indicating a distinct mechanism of action for PDE1. Functionally, ITI-214 inhibited ADP-induced migration of BV2 cells through a P2Y12-receptor-dependent pathway, possibly due to increases in the extent of cAMP and VASP phosphorylation downstream of receptor activation. Importantly, this effect was recapitulated in P2 rat microglial cells in vitro, indicating that these pathways are active in native microglial cells. These studies are the first to demonstrate that inhibition of PDE1 exerts anti-inflammatory effects through effects on microglia signaling pathways. The ability of PDE1 inhibitors to prevent or dampen excessive inflammatory responses of BV2 cells and microglia provides a basis for exploring their therapeutic utility in the treatment of neurodegenerative diseases associated with increased inflammation and microglia proliferation such as Parkinson's disease and Alzheimer's disease.

Cognitive Event-Related Potential Responses Differentiate Older Adults with and without Probable Mild Cognitive Impairment.

Background: Older adults rarely seek cognitive assessment, but often visit other healthcare professionals (e.g., audiologists). Noninvasive clinical measures within the scopes of practice of those professions sensitive to cognitive impairment are needed. Purpose: This study examined the differences of probable mild cognitive impairment (MCI) on latency and mean amplitude of the P3b auditory event-related potential. Method: Fifty-four participants comprised two groups according to cognitive status (cognitively normal older adults [CNOA], n = 25; probable MCI, n = 29). P3b was recorded using an oddball paradigm for speech (/ba/, /da/) and non-speech (1000, 2000 Hz) stimuli. Amplitudes and latencies were compared from six electrodes (FPz, Fz, FCz, Cz, CPz, Pz) between groups across stimulus probability and type. Results: CNOA participants had larger P3b mean amplitudes for deviant stimuli than those with probable MCI. Group effects of latency were isolated to deviant stimuli at FCz only when those with unclear P3bs were included. Findings did not covary with age or education. Overall, CNOAs showed a large P3b oddball effect while those with probable MCI did not. Conclusions: P3b can be used to show electrophysiological differences between older adults with and without probable MCI. These results support the development of educational materials targeting professionals using auditory-evoked potentials.

Are auditory processing and cognitive performance assessments overlapping or distinct? Parsing the auditory behaviour of older adults.

OBJECTIVE: Auditory processing predicts cognitive decline, including dementia, in older adults. Auditory processing involves the understanding, interpretation, and communication of auditory information. Cognition is linked to auditory processing; however, it is disputed whether auditory processing is a separate construct distinct from cognition. The purpose of this study was to determine if auditory processing is distinct from cognition in older adults. DESIGN: Participants completed 14 cognitive and auditory processing assessments. Assessments were subjected to exploratory factor analysis with principal components extraction and varimax rotation with Kaiser normalisation. Study sample: 213 community-dwelling older adults (M = 71.39 years, 57% female, 93% Caucasian, M = 16 years education) with and without mild cognitive impairment (MCI) participated. RESULTS: Four factors were identified, explaining 66.3% of the total variance: (1) executive functions, visual processing speed, and dichotic auditory processing, (2) auditory processing of degraded speech, (3) memory, and (4) auditory temporal processing of nonspeech. CONCLUSIONS: Two domains of auditory processing (processing degraded speech and temporal processing) account for unique variance to which cognitive measures are not sensitive, while measures of auditory dichotic processing appear to be tapping similar abilities as measures of cognition. Older adults who perform poorly on dichotic measures should be screened for cognitive impairment.

Video Modeling and Video Feedback to Reduce Time to Perform Intravenous Cannulation in Medical Students: A Randomized-Controlled Mixed-Methods Study.

PURPOSE: Combined video modeling (VM) and video feedback (VF) may be more beneficial than traditional feedback when teaching procedural skills. This study examined whether repeated VM and VF compared with VM alone reduced the time required for medical students to perform peripheral intravenous (IV) cannulation. METHODS: Twenty-five novice medical students were randomly assigned to groups in a one-way blinded embedded mixed-methods study to perform IV cannulation. Participants received standardized instruction and performed IV cannulation on each other while being audio-video recorded. They were assigned to review a video of an expert performing IV cannulation (VM alone), or both the expert video and a video of their own most recent IV cannulation (VM+VF), before returning to perform another IV cannulation. This was repeated for a total of four IV cannulation encounters and three video reviews. A post-test interview was also conducted and analyzed qualitatively using thematic content analysis. RESULTS: The median [interquartile range] time required to perform IV cannulation in the final encounter was significantly different between the VM+VF group vs VM alone group (126 [93-226] sec vs 345 [131-537] sec, respectively; median difference, 111 sec; 95% confidence interval, 8 to 391; P = 0.02). There was no significant difference in IV cannulation success between VM alone and VM+VF in the final encounter (75% vs 85% respectively; P = 0.65). For the VM+VF group, the time to perform IV cannulation was reduced after the final encounter compared with the baseline encounter (P = 0.002), which was not true of the VM alone group (P = 0.35). CONCLUSION: Video modeling and feedback shortened time to IV skill completion, reduced complications, and improved satisfaction in novice medical students.

RéSUMé: OBJECTIF: La combinaison d'une vidéo de démonstration (VD) et d'une vidéo de rétroaction (VR) pourrait être plus efficace que la rétroaction traditionnelle pour l'enseignement des habiletés nécessaires pour des procédures. Cette étude a cherché à savoir si la répétition d'une VD et d'une VR réduisait davantage le temps nécessaire à des étudiants en médecine pour effectuer une canulation intraveineuse périphérique (IV) par rapport à la seule VD. MéTHODES: Vingt-cinq étudiants en médecine novices ont été assignés par randomisation à des groupes d'une étude utilisant différentes méthodes intégrées d'apprentissage avec insu unilatéral pour la réalisation d'une canulation IV. Les participants ont reçu un enseignement standardisé et ont réalisé une canulation IV sur un autre participant tout en étant filmés (audio-vidéo). Selon leur groupe, ils devaient visionner la vidéo d'un expert effectuant une canulation IV (groupe VD uniquement) ou voir la vidéo de l'expert et une vidéo de leur plus récente canulation IV (groupe VD + VR) avant d'effectuer une autre canulation IV. La procédure a été répétée (total de 4 tentatives de canulations et 3 séances de vidéos). Un entretien post test a été également mené et analysé du point de vue qualitatif au moyen d'une analyse thématique du contenu. RéSULTATS: Le temps médian [plage interquartile] nécessaire pour effectuer la canulation IV au cours de la dernière tentative a été significativement différent entre le groupe VD+VR et le groupe VD seule (respectivement, 126 secondes [93 à 226 s] contre 345 s [131 à 537 s]; différence des médianes, 111 s; intervalle de confiance à 95 % : 8 à 391; P = 0,02). Il n'y a pas eu de différence significative entre le taux de réussite des canulations entre le groupe VD seule et le groupe VD+VR (respectivement, 75 % contre 85 %; P = 0,65). Pour le groupe VD+VR, le temps nécessaire à la canulation IV au moment de la dernière tentative a été plus court par rapport au temps mis au cours de la première tentative (P = 0,002), ce qui n'a pas été le cas pour le groupe VD seule (P = 0,35). CONCLUSION: La vidéo de démonstration et la vidéo de rétroaction ont permis de raccourcir le temps de réalisation des habiletés d'une canulation IV, ont réduit les complications et amélioré la satisfaction des étudiants en médecine novices.

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition.

BACKGROUND: Phosphodiesterase type-1 (PDE1) hydrolyzes cAMP and cGMP and is constitutively expressed in the heart, although cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly expresses PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined the acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs, and rabbits, in normal and failing hearts, and explored its regulatory pathways. METHODS: Conscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously±dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of ß-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left ventricular myocytes. RESULTS: In normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to ß-adrenergic receptor agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbits, ß-adrenergic receptor blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas ß-adrenergic receptor agonism (isoproterenol) or PDE3 inhibition (cilostamide) increased both. Unlike cilostamide, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only cilostamide increased calcium transients. CONCLUSIONS: PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via ß-adrenergic receptors or PDE3 modulation. ITI-214, which has completed phase I trials, may provide a novel therapy for HF.

Perianesthetic Implications and Considerations for Myasthenia Gravis.

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease in which antibodies against the post-nicotinic acetylcholine receptor at the neuromuscular junction develop. Although the exact cause of MG remains unknown, the thymus is a common factor in many cases. Patients with underlying junctional disease, such as MG, have greater anesthesia-related risks because of their known predisposition toward prolonged muscle weakness. Medications given in the perioperative period, such as anesthetic agents, antibiotics, cardiovascular drugs, and corticosteroids, affect neuromuscular transmission that contributes to muscle weakness. Judicious use of neuromuscular blocking agents for patients with MG must be considered. This patient population is at high risk for respiratory failure, and therefore must be carefully assessed throughout the perioperative period to ensure that a regular spontaneous respiratory pattern is sufficient to provide adequate oxygenation. Perianesthesia providers must consider anesthetic, ventilatory, and pharmacologic implications when proposing, providing, and recovering anesthesia for the patient with MG.

Temperature sensitive point mutations in fission yeast tropomyosin have long range effects on the stability and function of the actin-tropomyosin copolymer.

The actin cytoskeleton is modulated by regulatory actin-binding proteins which fine-tune the dynamic properties of the actin polymer to regulate function. One such actin-binding protein is tropomyosin (Tpm), a highly-conserved alpha-helical dimer which stabilises actin and regulates interactions with other proteins. Temperature sensitive mutants of Tpm are invaluable tools in the study of actin filament dependent processes, critical to the viability of a cell. Here we investigated the molecular basis of the temperature sensitivity of fission yeast Tpm mutants which fail to undergo cytokinesis at the restrictive temperatures. Comparison of Contractile Actomyosin Ring (CAR) constriction as well as cell shape and size revealed the cdc8.110 or cdc8.27 mutant alleles displayed significant differences in their temperature sensitivity and impact upon actin dependent functions during the cell cycle. In vitro analysis revealed the mutant proteins displayed a different reduction in thermostability, and unexpectedly yield two discrete unfolding domains when acetylated on their amino-termini. Our findings demonstrate how subtle changes in structure (point mutations or acetylation) alter the stability not simply of discrete regions of this conserved cytoskeletal protein but of the whole molecule. This differentially impacts the stability and cellular organisation of this essential cytoskeletal protein.