Stability of Nano-Emulsified Cannabidiol in Acidic Foods and Beverages.

Introduction: Food and beverage products containing cannabidiol (CBD) is a growing industry, but some CBD products contain Δ9-tetrahydrocannabinol (Δ9-THC), despite being labeled as "THC-free". As CBD can convert to Δ9-THC under acidic conditions, a potential cause is the formation of Δ9-THC during storage of acidic CBD products. In this study, we investigated if acidic products (pH ≤ 4) fortified with CBD would facilitate conversion to THC over a 2-15-month time period. Materials and Methods: Six products, three beverages (lemonade, cola, and sports drink) and three condiments (ketchup, mustard, and hot sauce), were purchased from a local grocery store and fortified with a nano-emulsified CBD isolate (verified as THC-free by testing). The concentrations of CBD and Δ9-THC were measured by Gas Chromatography Flame Ionization Detector (GC-FID) and Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), respectively, for up to 15 months at room temperature. Results: Coefficients of variation (CVs) of initial CBD concentrations by GC-FID were <10% for all products except ketchup (18%), showing homogeneity in the fortification. Formation of THC was variable, with the largest amount observed after 15 months in fortified lemonade #2 (3.09 mg Δ9-THC/serving) and sports drink #2 (1.18 mg Δ9-THC/serving). Both beverages contain citric acid, while cola containing phosphoric acid produced 0.10 mg Δ9-THC/serving after 4 months. The importance of the acid type was verified using acid solutions in water. No more than 0.01 mg Δ9-THC/serving was observed with the condiments after 4 months. Discussion: Conversion of CBD to THC can occur in some acidic food products when those products are stored at room temperature. Therefore, despite purchasing beverages manufactured with a THC-free nano-emulsified form of CBD, consumers might be at some risk of unknowingly ingesting small amounts of THC. The results indicate that up to 3 mg Δ9-THC from conversion can be present in a serving of CBD-lemonade. Based on the previous studies, 3 mg Δ9-THC might produce a positive urine sample (≥15 ng/mL THC carboxylic acid) in some individuals. Conclusion: Consumers must exert caution when consuming products with an acidic pH (≤4) that suggests that they are "THC-Free," because consumption might lead to positive drug tests or, in the case of multiple doses, intoxication.

Human Factor Health Data Interoperability.

Comprehensive health data interoperability is recognized as an essential element of high-functioning and accountable health service. Canada is lagging in health data interoperability compared to international comparators, and lacks a comprehensive approach to human factor interoperability, defined as system-level relationships that impact the capacity of health sector stakeholders to adopt harmonized health data standards and technology. Without addressing these system-level relationships, the adoption of harmonized health data standards and technology will be obstructed and Canadians will be underserved. The proposed health data interoperability framework articulates the factors that Canada needs to address to optimize health data design to support quality health programs and services.

Pediatric Cardiac Anesthesia Training and Staffing in the National Health Service.

BACKGROUND: Considerable importance is attached to the process of training, appointing and retaining highly specialized pediatric anesthetists, such as those with a congenital heart disease practice. AIMS: For the 10-year period from April 2012 to March 2022, we wished to establish changes in the absolute number of consultant pediatric cardiac anesthetic posts in NHS Level 1 Centres, turnover in such posts, and what training appointees had received. METHODS: An email survey was sent to the Centre Representative from the Congenital Cardiac Anesthesia Network in each of the eleven NHS Level 1 Pediatric Congenital Heart Disease Centre. Further follow up was completed in order to confirm accuracy of responses. We defined a pediatric cardiac anesthetist as a consultant with a clinical practice including provision of anesthetic management for children undergoing cardiac surgery incorporating the use of cardiopulmonary bypass. RESULTS: The response rate to our survey was 100%. Over the study period the number of consultants increased from 69 to 81, though three posts were unfilled as at March 2022. There were 55 departures and 65 appointees. Five consultants moved between NHS Units. 52 consultants received formal fellowship training and 13 switched into pediatric cardiac anesthesia from an existing general pediatric anesthetic post, with a period of supplementary training within their institution. Appointees reported extensive additional training variably including fellowships in general pediatric anesthesia, adult cardiac anesthesia and pediatric intensive care, both within and outside the United Kingdom. CONCLUSIONS: There has been both an expansion in the number of posts, as well as considerable turnover in consultant posts in the last 10 years. Training standards which support and guide individuals as they develop a practice in this highly specialized field should reflect different routes into the speciality and could be established with the support and advice of the Congenital Cardiac Anesthesia Network.

A prospective comparison of invasive and non-invasive blood pressure in children undergoing cardiac catheterization.

BACKGROUND: Blood pressure measurement is a standard of monitoring during general anesthesia. Invasive measurement is considered the gold standard but is less commonly used than non-invasive. Automated oscillometric blood pressure devices measure the mean arterial pressure (MAP) and use an algorithm to determine the systolic and diastolic pressures. Few devices have been validated in children, particularly during anesthesia. Few studies have assessed the agreement between invasive and non-invasive blood pressure measurements in children. METHODS: This was a multi-center prospective observational study of children under 16 years undergoing cardiac catheterization with general anesthesia. Paired invasive and non-invasive blood pressure measurements were recorded for each patient during stable periods of the procedure. Correlation within and between sites was assessed with Pearson's correlation coefficient, and agreement was examined using Bland-Altman methodology to determine bias. Agreement during episodes of hypotension and for age and weight was also determined. Bias greater than 5 mmHg and standard deviation greater than 8 mmHg was considered clinically significant. The primary end point was agreement of MAP measurements. RESULTS: A total of 683 paired blood pressure values were collected from 254 children in three pediatric hospitals. Median [IQR] age and weight were 3 [1-7] years and 13.9 [8-23] Kg. The overall bias (SD) for mean arterial pressure values was 7.2 (11.4) mmHg. During hypotension (190 readings), the bias (SD) was 15 (11.0) mmHg. The non-invasive MAP was frequently higher than invasive MAP during infancy, and lower in older children. CONCLUSION: Automated oscillometric blood pressure measurement is unreliable in anesthetized children during cardiac catheterization. Invasive pressure measurement should be considered for high-risk cases.

Study protocol for Attachment & Child Health (ATTACHTM) program: promoting vulnerable Children's health at scale.

BACKGROUND: Children's exposure to toxic stress (e.g., parental depression, violence, poverty) predicts developmental and physical health problems resulting in health care system burden. Supporting parents to develop parenting skills can buffer the effects of toxic stress, leading to healthier outcomes for those children. Parenting interventions that focus on promoting parental reflective function (RF), i.e., parents' capacity for insight into their child's and their own thoughts, feelings, and mental states, may understand help reduce societal health inequities stemming from childhood stress exposures. The Attachment and Child Health (ATTACHTM) program has been implemented and tested in seven rapid-cycling pilot studies (n = 64) and found to significantly improve parents' RF in the domains of attachment, parenting quality, immune function, and children's cognitive and motor development. The purpose of the study is to conduct an effectiveness-implementation hybrid (EIH) Type II study of ATTACHTM to assess its impacts in naturalistic, real-world settings delivered by community agencies rather than researchers under more controlled conditions. METHODS: The study is comprised of a quantitative pre/post-test quasi-experimental evaluation of the ATTACHTM program, and a qualitative examination of implementation feasibility using thematic analysis via Normalization Process Theory (NPT). We will work with 100 families and their children (birth to 36-months-old). Study outcomes include: the Parent Child Interaction Teaching Scale to assess parent-child interaction; the Parental Reflective Function and Reflective Function Questionnaires to assess RF; and the Ages and Stages Questionnaire - 3rd edition to examine child development, all administered pre-, post-, and 3-month-delayed post-assessment. Blood samples will be collected pre- and post- assessment to assess immune biomarkers. Further, we will conduct one-on-one interviews with study participants, health and social service providers, and administrators (total n = 60) from each collaborating agency, using NPT to explore perceptions and experiences of intervention uptake, the fidelity assessment tool and e-learning training as well as the benefits, barriers, and challenges to ATTACHTM implementation. DISCUSSION: The proposed study will assess effectiveness and implementation to help understand the delivery of ATTACHTM in community agencies. TRIAL REGISTRATION: Name of registry: https://clinicaltrials.gov/. REGISTRATION NUMBER: NCT04853888 . Date of registration: April 22, 2021.

Prospective national audit of major gastrointestinal complications of transesophageal echocardiography studies in children.

Background: Perioperative trans-esophageal echocardiography ('TEE') is widely used for the assessment of anatomy/repair of congenital cardiac defects. It is recognised that there are risks associated with its use. Aims: We wished, by means of a contemporaneous prospective national audit over a six-month period, to establish what proportion of TEE studies in children are complicated by major upper gastrointestinal or upper aerodigestive tract trauma. Methods: After obtaining appropriate local institutional ethics committee approval, a national prospective audit of the rate and severity of gastrointestinal complications of trans-esophageal echocardiography studies in anaesthetised adult cardiology and cardiac surgical patients was conducted by the Association of Cardiothoracic Anaesthesia and Critical Care in the United Kingdom and Ireland during the twelve months of 2017. During the second six months of the audit, the Congenital Cardiac Anaesthesia Network (an organisation including anaesthetists with a paediatric cardiac anaesthetic practice in all the United Kingdom cardiac surgical centres) prospectively audited the incidence of such complications of TEE studies in children. Results: A total of 1,059 studies were included in this six-month paediatric audit. There were no reports of the specified major complication. Statistical Analysis: The zero incidence of the major complication is consistent with a worst possible incidence of five per thousand TEE examinations. Conclusions: Such potentially reassuring information could be included in discussions with patients or families about the risk of trans-esophageal studies in children.

Initial results from an enhanced recovery program for pediatric cardiac surgical patients.

BACKGROUND: Over recent years, a number of enhanced recovery programs have appeared in first, adult colorectal surgery, and subsequently many other adult surgical specialties. Increasing interest in this approach to perioperative management in children culminated in the recent development of the first enhanced recovery pathway for pediatric intestinal surgery, endorsed by Enhanced Recovery after Surgery Society (ERAS®). In parallel, there has been increasing interest in the refinement of perioperative management of selected pediatric cardiac surgical patients, invariably referred to as "fast track" management. Initiatives have largely focused on duration of postoperative ventilation rather than on a much wider range of perioperative interventions to optimize recovery and ensure timely discharge after surgery. In our institution, a "Level 1" pediatric cardiac surgical center, we assembled a multidisciplinary team to design a comprehensive enhanced recovery pathway, based on ERAS® methodology, for selected cardiac surgical patients. After a lengthy period of planning, staff education, and preparation, we implemented the pathway at the end of November 2019. METHODS: We conducted a prospective audit of the perioperative management and outcomes of the first 88 patients managed according to this enhanced recovery pathway over a 25-month period in our institution. RESULTS: The mean age of the patients was 5.8 years (range 0.5-17.9), and the mean weight was 22.4 kg (range 6.6-57.2). Sixty-eight of the 88 patients were cardiopulmonary bypass cases. A total of 54% of patients received all four defined intraoperative anesthetic interventions (intravenous paracetamol, non-steroidal anti-inflammatory drug, antiemetic if aged more than 4 years, and use of a local anesthetic technique). A total of 89% of patients met the target extubation time of 6 h after administration of protamine. Median postoperative intensive care unit length of stay was 23.5 h (range 15.2-89.5). When compared to a historic control group, this represented a 22% reduction in median intensive care unit stay, although the total hospital length of stay remained unchanged. A total of 83% of patients met the target hospital discharge target of the fifth postoperative day. CONCLUSIONS: These preliminary results suggest that enhanced recovery pathway implementation for selected pediatric cardiac surgical patients is feasible, with acceptable outcomes. They suggest areas for further development and the potential for wider implementation.

Prediction of Bleeding in Pediatric Cardiac Surgery Using Clinical Characteristics and Prospective Coagulation Test Results.

Bleeding caused by coagulopathy is common in children undergoing cardiac surgery and causes adverse outcomes. Coagulation testing assists selection of treatments to stop bleeding but has an uncertain role for predicting bleeding. We aimed to evaluate how well prospective coagulation testing predicted excessive bleeding during and after cardiac surgery compared to prediction using clinical characteristics alone. The study was a single-center, prospective cohort study in children having a range of cardiac surgery procedures with coagulation testing at anesthetic induction and immediately after cardiopulmonary bypass. The primary outcome was clinical concern about bleeding (CCB), a composite of either administration of prohemostatic treatments in response to bleeding or a high chest drain volume after surgery. In 225 children, CCB occurred in 26 (12%) during surgery and in 68 (30%) after surgery. Multivariable fractional polynomial models using the clinical characteristics of the children alone predicted CCB during surgery (c-statistic 0.64; 95% confidence interval 0.53, 0.76) and after surgery (0.74; 0.67, 0.82). Incorporating coagulation test results into these models improved prediction (c-statistics 0.79; 0.70, 0.87, and 0.80; 0.74, 0.87, respectively). However, this increased the overall proportion of children classified correctly as CCB or not CCB during surgery by only 0.9% and after surgery by only 0.4%. Incorporating coagulation test results into predictive models had no effect on prediction of blood transfusion or postoperative complications. Prospective coagulation testing marginally improves prediction of CCB during and after cardiac surgery but the clinical impact of this is small when compared to prediction using clinical characteristics.

Lateralized evoked responses in parietal cortex demonstrate visual short-term memory deficits in first-episode schizophrenia.

Working memory dysfunction may be central to neurocognitive deficits in schizophrenia. Maintenance of visual information in working memory, or visual short-term memory (vSTM), is linked to general cognitive dysfunction and predicts functional outcome. Lateralized change-detection tasks afford investigation of the contralateral delay activity (CDA), a useful tool for investigating vSTM dysfunction. Previous work suggests "hyperfocusing" of attention in schizophrenia, such that CDA is increased when a single item is maintained in vSTM but reduced for multiple items. If observed early in the disease, vSTM dysfunction may be a key feature of schizophrenia or target for intervention. We investigated CDA during lateralized vSTM of one versus three items using sensor-level electroencephalography and source-level magnetoencephalography in 26 individuals at their first episode of schizophrenia-spectrum psychosis (FESz) and 26 matched healthy controls. FESz were unable to modulate CDA with increased memory load - high-load CDA was reduced and low-load CDA was increased compared to controls. Further, sources of CDA in posterior parietal cortex were reduced in FESz and indices of working memory were correlated with neurocognitive deficits and symptom severity. These results support working memory maintenance dysfunction as a central and early component to the disorder. Targeted intervention focusing on vSTM deficits may be warranted to alleviate downstream effects of this disability.

The relationship between serum adipokines and glucose homeostasis in normal-weight and obese patients on hemodialysis: a preliminary study.

PURPOSE: Insulin resistance (IR) is a prevalent disorder in advanced renal failure irrespective of diabetes. Adipokines might play a role in IR, which has not been well-documented in uremic conditions. This study investigated the relationship of Zinc-α2-glycoprotein (ZAG), adipose triglyceride lipase (ATGL), and adipolin with glucose-insulin homeostasis in normal weight (NW) and obese (OB) patients with hemodialysis. METHODS: In this cross-sectional study, 59 patients (29 NW; 18.5 ≤ BMI < 25 kg/m2, and 30 OB; BMI ≥ 30 kg/m2) were studied. Anthropometries, circulating ZAG, adipolin, ATGL, free fatty acids (FFAs), fasting blood glucose (FBG), insulin, and homeostasis model assessment of IR (HOMA)-IR were assessed. RESULTS: There were no significant differences in age, gender, hemodialysis duration, dialysis adequacy and diabetes between the two groups. ZAG (100.9 ± 37.1 vs. 107.5 ± 30.5 ng/mL, P = 0.03) and adipolin (12.4 ± 1.6 vs. 13.2 ± 2.8 ng/mL, P = 0.002) concentrations were significantly lower, and FFAs (228.1 ± 112.6 vs. 185 ± 119 ng/mL, P = 0.014) were significantly higher in the OB than NW group. No significant differences were observed in ATGL, FBG, insulin and HOMA-IR between the two groups. Patients with lower IR had higher ZAG (112.9 ± 31.7 vs. 94.9 ± 34.5 ng/mL; P = 0.046), lower FFAs (167.8 ± 98.4 vs. 249.9 ± 120.8 ng/mL; P = 0.004), and marginally lower ATGL (9.1 ± 5.2 vs. 12.3 ± 9.6 mIU/mL; P = 0.079) concentrations than those with higher IR. ZAG was negatively (r = - 0.323, P = 0.018 and r = - 0.266, P = 0.054) and FFAs were positively (r = 0.321, P = 0.019 and r = 0.353, P = 0.009) correlated with insulin and HOMA-IR, respectively. ATGL was directly correlated with FFAs (r = 0.314, P = 0.018). CONCLUSIONS: Novel adipokines, ZAG and ATGL, might contribute to glucose-insulin homeostasis in hemodialysis. Understanding potential causative, diagnostic or therapeutic roles of adipokines in IR require further studies.

Gender-Related Differences of Tachykinin NK2 Receptor Expression and Activity in Human Colonic Smooth Muscle.

The tachykinin NK2 receptor plays a key role in gastrointestinal motor function. Enteric neurons release neurokinin A (NKA), which activates NK2 receptors on gastrointestinal smooth muscle, leading to contraction and increased motility. In patients with diarrhea-predominant irritable bowel syndrome, the NK2 receptor antagonist ibodutant had a greater therapeutic effect in females than males. The present study aimed to determine whether gender influences the expression and activity of NK2 receptors in human colonic smooth muscle. In vitro functional studies were performed to examine the contractile responses of colonic muscle strips to NKA and the selective NK2 receptor agonist [Lys5,MeLeu9,Nle10]NKA(4-10). Contractions were also measured in the presence of ibodutant to determine its antagonistic potency. The signal transduction pathways coupled to NK2 receptor activation were investigated using second messenger inhibitors. Western blot and fluorescent immunohistochemistry were conducted to determine the protein expression and localization of NK2 receptors. NK2 receptor-mediated contractility was greater in females compared with males. When against NKA, ibodutant was more potent in females. NK2 receptor expression increased with age in females, but not in males. Phospholipase C-mediated signaling was less prominent in females compared with males, whereas Ca2+ sensitization via Rho kinase and protein kinase C appeared to be the dominant pathway in both genders. The distribution of NK2 receptors in the human colon did not differ between the genders. Overall, gender differences exist in the expression and activity of NK2 receptors in colonic smooth muscle. These gender distinctions should be considered in the therapeutic development of NK2 receptor agents. SIGNIFICANCE STATEMENT: The tachykinin NK2 receptor has been identified as a therapeutic target for the treatment of bowel and bladder dysfunctions. The present study has revealed gender-related variations in NK2 receptor activity, signaling transduction pathways, antagonist potency, and changes in expression with age. These factors may underlie the gender differences in the treatment of diarrhea-predominant irritable bowel syndrome with NK2 receptor antagonists. Our findings highlight that gender differences should be considered in the therapeutic development of NK2 receptor agents.

Panel 8: Vaccines and immunology.

OBJECTIVE: To review and highlight significant advances made towards vaccine development and understanding of the immunology of otitis media (OM) since the 19th International Symposium on Recent Advances in Otitis Media (ISOM) in 2015, as well as identify future research directions and knowledge gaps. DATA SOURCES: PubMed database, National Library of Medicine. REVIEW METHODS: Key topics were assigned to each panel member for detailed review. Draft reviews were collated, circulated, and thoroughly discussed when the panel met at the 20th ISOM in June 2019. The final manuscript was prepared with input from all panel members. CONCLUSIONS: Since 2015 there have been a number of studies assessing the impact of licensed pneumococcal vaccines on OM. While these studies have confirmed that these vaccines are effective in preventing carriage and/or disease caused by vaccine serotypes, OM caused by non-vaccine serotype pneumococci and other otopathogens remains a significant health care burden globally. Development of multi-species vaccines is challenging but essential to reducing the global burden of OM. Influenza vaccination has been shown to prevent acute OM, and with novel vaccines against nontypeable Haemophilus influenzae (NTHi), Moraxella catarrhalis and Respiratory Syncytial Virus (RSV) in clinical trials, the potential to significantly prevent OM is within reach. Research into alternative vaccine delivery strategies has demonstrated the power of maternal and mucosal vaccination for OM prevention. Future OM vaccine trials must include molecular diagnostics of middle ear effusion, for detection of viruses and bacteria that are persisting in biofilms and to enable accurate assessment of vaccine impact on OM etiology. Understanding population differences in natural and vaccine-induced immune responses to otopathogens is also important for development of the most effective OM vaccines. Improved understanding of the interaction between otopathogens will also advance development of effective therapies and encourage the assessment of the indirect benefits of vaccination. IMPLICATIONS FOR PRACTICE: While NTHi and M. catarrhalis are the predominant otopathogens, funding opportunities to drive vaccine development for these species are limited due to a focus on prevention of childhood mortality rather than morbidity. Delivery of a comprehensive report on the high financial and social costs of OM, including the potential for OM vaccines to reduce antibiotic use and subsequent development of antimicrobial resistance (AMR), would likely assist in engaging stakeholders to recognize the value of prevention of OM and increase support for efforts on OM vaccine development. Vaccine trials with OM prevention as a clinical end-point are challenging, however a focus on developing assays that measure functional correlates of protection would facilitate OM vaccine development.

LFP clustering in cortex reveals a taxonomy of Up states and near-millisecond, ordered phase-locking in cortical neurons.

During slow-wave sleep and anesthesia, mammalian cortex exhibits a synchronized state during which neurons shift from a largely nonfiring to a firing state, known as an Up-state transition. Up-state transitions may constitute the default activity pattern of the entire cortex (Neske GT. Front Neural Circuits 9: 88, 2016) and could be critical to understanding cortical function, yet the genesis of such transitions and their interaction with single neurons is not well understood. It was recently shown that neurons firing at rates >2 Hz fire spikes in a stereotyped order during Up-state transitions (Luczak A, McNaughton BL, Harris KD. Nat Rev Neurosci 16: 745-755, 2015), yet it is still unknown if Up states are homogeneous and whether spiking order is present in neurons with rates <2 Hz (the majority). Using extracellular recordings from anesthetized cats and mice and from naturally sleeping rats, we show for the first time that Up-state transitions can be classified into several types based on the shape of the local field potential (LFP) during each transition. Individual LFP events could be localized in time to within 1-4 ms, more than an order of magnitude less than in previous studies. The majority of recorded neurons synchronized their firing to within ±5-15 ms relative to each Up-state transition. Simultaneous electrophysiology and wide-field imaging in mouse confirmed that LFP event clusters are cortex-wide phenomena. Our findings show that Up states are of different types and point to the potential importance of temporal order and millisecond-scale signaling by cortical neurons.NEW & NOTEWORTHY During cortical Up-state transitions in sleep and anesthesia, neurons undergo brief periods of increased firing in an order similar to that occurring in awake states. We show that these transitions can be classified into distinct types based on the shape of the local field potential. Transition times can be defined to <5 ms. Most neurons synchronize their firing to within ±5-15 ms of the transitions and fire in a consistent order.

Anesthetist-delivered intraoperative transesophageal echocardiography in pediatric cardiac surgery.

This article reviews the evidence for anesthetist-delivered perioperative transesophageal echocardiography for children undergoing cardiac surgery. It addresses the additional issues of training, developing practice, accreditation, and the requirement for collaboration with pediatric cardiologists, surgeons and other members of the perioperative team. Finally an overview of the potential structure of an anesthetist-delivered perioperative transesophageal echocardiography service is presented.

Mesoscale brain explorer, a flexible python-based image analysis and visualization tool.

Imaging of mesoscale brain activity is used to map interactions between brain regions. This work has benefited from the pioneering studies of Grinvald et al., who employed optical methods to image brain function by exploiting the properties of intrinsic optical signals and small molecule voltage-sensitive dyes. Mesoscale interareal brain imaging techniques have been advanced by cell targeted and selective recombinant indicators of neuronal activity. Spontaneous resting state activity is often collected during mesoscale imaging to provide the basis for mapping of connectivity relationships using correlation. However, the information content of mesoscale datasets is vast and is only superficially presented in manuscripts given the need to constrain measurements to a fixed set of frequencies, regions of interest, and other parameters. We describe a new open source tool written in python, termed mesoscale brain explorer (MBE), which provides an interface to process and explore these large datasets. The platform supports automated image processing pipelines with the ability to assess multiple trials and combine data from different animals. The tool provides functions for temporal filtering, averaging, and visualization of functional connectivity relations using time-dependent correlation. Here, we describe the tool and show applications, where previously published datasets were reanalyzed using MBE.