The HH-GLI2-CKS1B network regulates the proliferation-to-maturation transition of cardiomyocytes.

Cardiomyocyte (CM) proliferation and maturation are highly linked processes, however, the extent to which these processes are controlled by a single signaling axis is unclear. Here, we show the previously undescribed role of Hedgehog (HH)-GLI2-CKS1B cascade in regulation of the toggle between CM proliferation and maturation. Here we show downregulation of GLI-signaling in adult human CM, adult murine CM, and in late-stage hiPSC-CM leading to their maturation. In early-stage hiPSC-CM, inhibition of HH- or GLI-proteins enhanced CM maturation with increased maturation indices, increased calcium handling, and transcriptome. Mechanistically, we identified CKS1B, as a new effector of GLI2 in CMs. GLI2 binds the CKS1B promoter to regulate its expression. CKS1B overexpression in late-stage hiPSC-CMs led to increased proliferation with loss of maturation in CMs. Next, analysis of datasets of patients with heart disease showed a significant enrichment of GLI2-signaling in patients with ischemic heart failure (HF) or dilated-cardiomyopathy (DCM) disease, indicating operational GLI2-signaling in the stressed heart. Thus, the Hh-GLI2-CKS1B axis regulates the proliferation-maturation transition and provides targets to enhance cardiac tissue engineering and regenerative therapies.

Medical cannabis for children: Evidence and recommendations.

Interest in using cannabis products for a medical purpose in children under the age of 18 years is increasing. There are many medical cannabis products available that can include cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC), or both. Despite many therapeutic claims, there are few rigorous studies to inform the dosing, safety, and efficacy of medical cannabis in paediatric clinical practice. This statement reviews the current evidence and provides recommendations for using medical cannabis in children. Longer-term (2-year) reports support the sustained tolerability and efficacy of cannabidiol therapy for patients with Lennox-Gastaut and Dravet syndromes. CBD-enriched cannabis extracts containing small amounts of THC have been evaluated in a small number of paediatric patients, and further research is needed to inform clinical practice guidelines. Given the widespread use of medical cannabis in Canada, paediatricians should be prepared to engage in open, ongoing discussions with families about its potential benefits and risks, and develop individualized plans that monitor efficacy, reduce harms, and mitigate drug-drug interactions.

Les données probantes et les recommandations sur le cannabis à des fins médicales chez les enfants.

L'intérêt envers l'utilisation des produits du cannabis à des fins médicales chez les enfants de moins de 18 ans augmente. De nombreux produits du cannabis à des fins médicales contiennent du cannabidiol, du delta-9-tétrahydrocannabinol ou ces deux produits. Malgré les nombreuses prétentions thérapeutiques, peu d'études rigoureuses guident la posologie, l'innocuité et l'efficacité du cannabis à des fins médicales en pédiatrie clinique. Le présent document de principes passe en revue les données probantes à jour et expose les recommandations sur l'utilisation du cannabis à des fins médicales chez les enfants. Les rapports à plus long terme (deux ans) souscrivent à la tolérabilité et à l'efficacité soutenues d'un traitement au cannabidiol chez les patients ayant le syndrome de Lennox-Gastaut ou le syndrome de Dravet. Les extraits de cannabis enrichis de cannabidiol qui renferment de petites quantités de delta-9-tétrahydrocannabinol ont été évalués auprès d'un petit nombre de patients d'âge pédiatrique, et d'autres recherches devront être réalisées pour éclairer les guides de pratique clinique. Étant donné l'utilisation répandue du cannabis à des fins médicales au Canada, les pédiatres devraient être prêts à participer à des échanges ouverts et continus avec les familles au sujet de ses avantages potentiels et de ses risques, ainsi qu'à préparer des plans individuels en vue d'en surveiller l'efficacité, de réduire les méfaits et de limiter les interactions médicamenteuses.

The use of prescription medications and non-prescription medications during lactation in a prospective Canadian cohort study.

BACKGROUND: A lack of safety data on postpartum medication use presents a potential barrier to breastfeeding and may result in infant exposure to medications in breastmilk. The type and extent of medication use by lactating women requires investigation. METHODS: Data were collected from the CHILD Cohort Study which enrolled pregnant women across Canada between 2008 and 2012. Participants completed questionnaires regarding medications and non-prescription medications used and breastfeeding status at 3, 6 and 12 months postpartum. Medications, along with self-reported reasons for medication use, were categorized by ontologies [hierarchical controlled vocabulary] as part of a large-scale curation effort to enable more robust investigations of reasons for medication use. RESULTS: A total of 3542 mother-infant dyads were recruited to the CHILD study. Breastfeeding rates were 87.4%, 75.3%, 45.5% at 3, 6 and 12 months respectively. About 40% of women who were breastfeeding at 3 months used at least one prescription medication during the first three months postpartum; this proportion decreased over time to 29.5% % at 6 months and 32.8% at 12 months. The most commonly used prescription medication by breastfeeding women was domperidone at 3 months (9.0%, n = 229/2540) and 6 months (5.6%, n = 109/1948), and norethisterone at 12 months (4.1%, n = 48/1180). The vast majority of domperidone use by breastfeeding women (97.3%) was for lactation purposes which is off-label (signifying unapproved use of an approved medication). Non-prescription medications were more often used among breastfeeding than non-breastfeeding women (67.6% versus 48.9% at 3 months, p < 0.0001), The most commonly used non-prescription medications were multivitamins and Vitamin D at 3, 6 and 12 months postpartum. CONCLUSIONS: In Canada, medication use is common postpartum; 40% of breastfeeding women use prescription medications in the first 3 months postpartum. A diverse range of medications were used, with many women taking more than one prescription and non-prescription medicines. The most commonly used prescription medication by breastfeeding women were domperidone for off-label lactation support, signalling a need for more data on the efficacy of domperidone for this indication. This data should inform research priorities and communication strategies developed to optimize care during lactation.

Acute Emergence of the Intestinal Pathobiome after Postinjury Pneumonia.

BACKGROUND: Previous preclinical studies have demonstrated sex-specific alterations in the gut microbiome following traumatic injury or sepsis alone; however, the impact of host sex on dysbiosis in the setting of postinjury sepsis acutely is unknown. We hypothesized that multicompartmental injury with subsequent pneumonia would result in host sex-specific dysbiosis. METHODS: Male and proestrus female Sprague-Dawley rats (n = 8/group) were subjected to either polytrauma (PT) (lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofracture), PT plus 2-hours daily restraint stress (PT/RS), PT with postinjury day 1 pseudomonas aeruginosa pneumonia (PT + PNA), PT/RS with pneumonia (PT/RS + PNA), or naive controls. Fecal microbiome was measured on days 0 and 2 using high-throughput 16S rRNA sequencing and QIIME2 bioinformatics analyses. Microbial α-diversity was assessed using Chao1 (number of different unique species) and Shannon (species richness and evenness) indices. ß-diversity was assessed using principal coordinate analysis. Significance was defined as p < 0.05. RESULTS: All groups had drastic declines in the Chao1 (α-diversity) index compared to naïve controls (p < 0.05). PT + PNA and PT/RS + PNA resulted in different ß-diversity arrays compared to uninfected counterparts (PT, PT/RS) (p = 0.001). Postinjury sepsis cohorts showed a loss of commensal bacteria along with emergence of pathogenic bacteria, with blooms of Proteus in PT + PNA and Escherichia-Shigella group in PT/RS + PNA compared to other cohorts. At day 2, PT + PNA resulted in ß-diversity which was unique between males and females (p = 0.004). Microbiome composition in PT + PNA males was dominated by Anaerostipes and Parasuterella whereas females had increased Barnesiella and Oscillibacter. PT/RS males had an abundance of Gastranaerophilales and Muribaculaceae. CONCLUSIONS: Multicompartmental trauma complicated by sepsis significantly diminishes diversity and alters microbial composition towards a severely dysbiotic state early after injury, which varies between males and females. These findings highlight the role of sex in postinjury sepsis and the pathobiome which may influence outcomes after severe trauma and sepsis. LEVEL OF EVIDENCE: Not applicable - basic science.

Removing barriers to accessing medical cannabis for paediatric patients.

Medical cannabis (MC) may offer therapeutic benefits for children with complex neurological conditions and chronic diseases. In Canada, parents, and caregivers frequently report encountering barriers when accessing MC for their children. These include negative preconceived notions about risks and benefits, challenges connecting with a knowledgeable healthcare provider (HCP), the high cost of MC products, and navigating MC product shortages. In this manuscript, we explore several of these barriers and provide recommendations to decision-makers to enable a family-centered and evidence-based approach to MC medicine and research for children.

Gut mycobiome dysbiosis after sepsis and trauma.

BACKGROUND: Sepsis and trauma are known to disrupt gut bacterial microbiome communities, but the impacts and perturbations in the fungal (mycobiome) community after severe infection or injury, particularly in patients experiencing chronic critical illness (CCI), remain unstudied. METHODS: We assess persistence of the gut mycobiome perturbation (dysbiosis) in patients experiencing CCI following sepsis or trauma for up to two-to-three weeks after intensive care unit hospitalization. RESULTS: We show that the dysbiotic mycobiome arrays shift toward a pathobiome state, which is more susceptible to infection, in CCI patients compared to age-matched healthy subjects. The fungal community in CCI patients is largely dominated by Candida spp; while, the commensal fungal species are depleted. Additionally, these myco-pathobiome arrays correlate with alterations in micro-ecological niche involving specific gut bacteria and gut-blood metabolites. CONCLUSIONS: The findings reveal the persistence of mycobiome dysbiosis in both sepsis and trauma settings, even up to two weeks post-sepsis and trauma, highlighting the need to assess and address the increased risk of fungal infections in CCI patients.

Posttraumatic pneumonia exacerbates bone marrow erythropoietic dysfunction.

INTRODUCTION: Pneumonia is a common complication after severe trauma that is associated with worse outcomes with increased mortality. Critically ill trauma patients also have persistent inflammation and bone marrow dysfunction that manifests as persistent anemia. Terminal erythropoiesis, which occurs in bone marrow structures called erythroblastic islands (EBIs), has been shown to be impacted by trauma. Using a preclinical model of polytrauma (PT) and pneumonia, we sought to determine the effect of infection on bone marrow dysfunction and terminal erythropoiesis. METHODS: Male and female Sprague-Dawley rats aged 9 to 11 weeks were subjected to either PT (lung contusion, hemorrhagic shock, cecectomy, and bifemoral pseudofracture) or PT with postinjury day 1 Pseudomonas pneumonia (PT-PNA) and compared with a naive cohort. Erythroblastic islands were isolated from bone marrow samples and imaged via confocal microscopy. Hemoglobin, early bone marrow erythroid progenitors, erythroid cells/EBI, and % reticulocytes/EBI were measured on day 7. Significance was defined as p < 0.05. RESULTS: Day 7 hemoglobin was significantly lower in both PT and PT-PNA groups compared with naive (10.8 ± 0.6 and 10.9 ± 0.7 vs. 12.1 ± 0.7 g/dL [ p < 0.05]). Growth of bone marrow early erythroid progenitors (colony-forming units-granulocyte, erythrocyte, monocyte, megakaryocyte; erythroid burst-forming unit; and erythroid colony-forming unit) on day 7 was significantly reduced in PT-PNA compared with both PT and naive. Despite a peripheral reticulocytosis following PT and PT-PNA, the percentage of reticulocytes/EBI was not different between naive, PT, and PT-PNA. However, the number of erythroblasts/EBI was significantly lower in PT-PNA compared with naive (2.9 ± 1.5 [ p < 0.05] vs. 8.9 ± 1.1 cells/EBI macrophage). In addition to changes in EBI composition, EBIs were also found to have significant structural changes following PT and PT-PNA. CONCLUSION: Multicompartmental PT altered late-stage erythropoiesis, and these changes were augmented with the addition of pneumonia. To improve outcomes following trauma and pneumonia, we need to better understand how alterations in EBI structure and function impact persistent bone marrow dysfunction and anemia.

Multicompartmental Trauma Induces Persistent Inflammation and Organ Injury.

INTRODUCTION: Previous preclinical models of multicompartmental injury have investigated its effects for durations of less than 72 h and the long-term effects have not been defined. We hypothesized that a model of multicompartmental injury would result in systemic inflammation and multiorgan dysfunction that persists at 1 wk. METHODS: Male and proestrus female Sprague-Dawley rats (n = 16/group) underwent polytrauma (PT) (unilateral right lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofractures) and were compared to naive controls. Weight, hemoglobin, plasma neutrophil gelatinase-associated lipocalin, and plasma toll-like receptor 4 were evaluated on days two and seven. Bilateral lungs were sectioned, stained and assessed for injury at day seven. Comparisons were performed in Graphpad with significance defined as ∗P <0.05. RESULTS: Rats who underwent PT had significant weight loss and anemia at day 2 (P = 0.001) compared to naïve rats which persisted at day 7 (P = 0.001). PT rats had elevated plasma neutrophil gelatinase-associated lipocalin at day 2 compared to naïve (P <0.0001) which remained elevated at day 7 (P <0.0001). Plasma toll-like receptor 4 was elevated in PT compared to naïve at day 2 (P = 0.03) and day 7 (P = 0.01). Bilateral lungs showed significant injury in PT cohorts at day 7 compared to naïve (P <0.0004). PT males had worse renal function at day seven compared to females (P = 0.02). CONCLUSIONS: Multicompartmental trauma induces systemic inflammation and multiorgan dysfunction without recovery by day seven. However, females demonstrate improved renal recovery compared to males. Long-term assessment of preclinical PT models are crucial to better understand and evaluate future therapeutic immunomodulatory and anti-inflammatory treatments.

Co-designing clinical trials alongside youth with chronic pain.

Youth have a right to participate in research that will inform the care that they receive. Engagement with children and young people has been shown to improve rates of enrollment and retention in clinical trials as well as reduce research waste. The aim of the study is to gain practical insight on the design of trials specifically on (1) recruitment and retention preferences, (2) potential barriers to research, and (3) study design optimization. Based on this youth engagement, we will co-design two clinical trials in headaches with youth. Two recruitment strategies were used to recruit 16 youth from across Canada (aged 15-18 years) from an existing youth group, the KidsCan Young Persons' Research Advisory Group (YPRAG) and a new youth group in collaboration with Solutions for Kids in Pain (SKIP). Four virtual, semi-structured discussion groups were held between April and December 2020, which included pre-circulated materials and utilized two distinct upcoming planned trials as examples for specific methods feedback. Individual engagement evaluations were completed following the final group session using the Public and Patient Engagement Evaluation Tool. Descriptive results were shared with participants prior to publication to ensure appropriate interpretation. The discussion was centred around three themes: recruitment and retention preferences, potential barriers to participation, and study design optimization. Youth indicated that they would prefer to be contacted for a potential study directly by their physician (not over social media), that they would like to develop rapport with study staff, and that one of the barriers to participation is the time commitment. The youth also provided feedback on the design of the clinical trial including outcome measurement tools, data collection, and engagement methods. Feedback on the virtual format of the engagement events indicated that participants appreciated the ease of the online discussion and that the open-ended discussion allowed for easy exchange of ideas. They felt that despite a gender imbalance (towards females) it was an overall inclusive environment. All participants reported believing that their engagement will make a difference to the work of the research team in designing the clinical trials. Perspectives from a diverse group of youth meaningfully improved the design and conduct of two clinical trials for headaches in children. This study provides a framework for future researchers to engage youth in the co-design of clinical trials using online engagement sessions.

Prioritising research funding for cardiovascular disease and diabetes in Australia.

The Targeted Translation Research Accelerator program was created to address cardiovascular disease and diabetes in Australia. To maximise the impact of the considerable investment in this program, a structured prioritisation project was undertaken to determine the highest priority health and medical unmet needs in cardiovascular disease and diabetes. The project was led by Monash University's Behaviour Works Australia in collaboration with Australian National University, Research Australia, and MTPConnect. We conducted an online survey with 318 experts and community representatives to generate a 'long list' of unmet needs for (1) cardiovascular disease; (2) diabetes; and (3) interactions in the pathogenesis of Type 1 diabetes, Type 2 diabetes, and cardiovascular disease. We then convened roundtables of clinical, research, and community leaders to discuss survey results. They prioritised unmet needs against six predefined criteria then discussed results. We present the final priority areas for funding. We demonstrate how a feasible, reproducible, and collaborative prioritisation methodology can be used when designing research funding programs. Such approaches can ensure that funding is directed towards projects that are valuable to the community and reflective of expert opinion.

Sex-specific intestinal dysbiosis persists after multicompartmental injury.

BACKGROUND: Preclinical studies of the gut microbiome after severe traumatic injury have demonstrated severe dysbiosis in males, with sex-specific microbial differences up to 2 days after injury. However, the impact of host sex on injury-driven dysbiosis over time remains unknown. We hypothesized that sex-specific differences in intestinal microbiome diversity and composition after traumatic injury with and without stress would persist after 7 days. METHODS: Male and proestrus female Sprague-Dawley rats (n = 8/group) were subjected to either polytrauma (lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofractures), polytrauma plus chronic restraint stress, or naïve controls. The fecal microbiome was measured on days 0, 3, and 7 using 16S rRNA sequencing and Quantitative Insights into Microbial Ecology bioinformatics analyses. Microbial alpha-diversity (Chao1 and Shannon indices) and beta-diversity were assessed. Analyses were performed in GraphPad and "R," with significance defined as P < .05. RESULTS: Polytrauma and polytrauma plus chronic restraint stress reduced alpha-diversity (Chao1, Shannon) within 3 days postinjury, which persisted up to day 7 in both sexes; polytrauma and polytrauma plus chronic restraint stress females had significantly decreased Chao1 compared to male counterparts at day 7 (P = .02). At day 7, the microbiome composition in polytrauma females had higher proportion of Mucispirillum, whereas polytrauma plus chronic restraint stress males demonstrated elevated abundance of Ruminococcus and Akkermansia. CONCLUSION: Multicompartmental trauma induces intestinal dysbiosis that is sex-specific with persistence of decreased diversity and unique "pathobiome" signatures in females after 1 week. These findings underline sex as an important biological variable that may influence variable host-specific responses and outcomes after severe trauma and critical illness. This underscores the need to consider precision medicine strategies to ameliorate these outcomes.

Anemia Recovery After Lung Contusion, Hemorrhagic Shock, and Chronic Stress Is Gender-Specific in a Rat Model.

Background: Severe trauma and hemorrhagic shock lead to persistent anemia. Although biologic gender is known to modulate inflammatory responses after critical illness, the impact of gender on anemia recovery after injury remains unknown. The aim of this study was to identify gender-specific differences in anemia recovery after critical illness. Materials and Methods: Male and proestrus female Sprague-Dawley rats (n = 8-9 per group) were subjected to lung contusion and hemorrhagic shock (LCHS) or LCHS with daily chronic stress (LCHS/CS) compared with naïve. Hematologic data, bone marrow progenitor growth, and bone marrow and liver gene transcription were analyzed on day seven. Significance was defined as p < 0.05. Results: Males lost substantial weight after LCHS and LCHS/CS compared with naïve males, while female LCHS rats did not compared with naive counterparts. Male LCHS rats had a drastic decrease in hemoglobin from naïve males. Male LCHS/CS rats had reduced colony-forming units-granulocyte, -erythrocyte, -monocyte, -megakaryocyte (CFU-GEMM) and burst-forming unit-erythroid (BFU-E) when compared with female counterparts. Naïve, LCHS, and LCHS/CS males had lower serum iron than their respective female counterparts. Liver transcription of BMP4 and BMP6 was elevated after LCHS and LCHS/CS in males compared with females. The LCHS/CS males had decreased expression of bone marrow pro-erythroid factors compared with LCHS/CS females. Conclusions: After trauma with or without chronic stress, male rats demonstrated increased weight loss, substantial decrease in hemoglobin level, dysregulated iron metabolism, substantial suppression of bone marrow erythroid progenitor growth, and no change in transcription of pro-erythroid factors. These findings confirm that gender is an important variable that impacts anemia recovery and bone marrow dysfunction after traumatic injury and shock in this rat model.

Examining the Role of Race in End-of-Life Care in the Intensive Care Unit: A Single-Center Observational Study.

Background: Prior studies have shown variation in the intensity of end-of-life care in intensive care units (ICUs) among patients of different races. Objective: We sought to identify variation in the levels of care at the end of life in the ICU and to assess for any association with race and ethnicity. Design: An observational, retrospective cohort study. Settings: A tertiary care center in Boston, MA. Participants: All critically ill patients admitted to medical and surgical ICUs between June 2019 and December 2020. Exposure: Self-identified race and ethnicity. Main Outcome and Measure: The primary outcome was death. Secondary outcomes included "code status," markers of intensity of care, consultation by the Palliative care service, and consultation by the Ethics service. Results: A total of 9083 ICU patient encounters were analyzed. One thousand two hundred fifty-nine patients (14%) died in the ICU; the mean age of patients was 64 years (standard deviation 16.8), and 44% of patients were women. A large number of decedents (22.7%) did not have their race identified. These patients had a high rate of interventions at death. Code status varied by race, with more White patients designated as "Comfort Measures Only" (CMO) (74%) whereas more Black patients were designated as "Do Not Resuscitate/Do Not Intubate (DNR/DNI) and DNR/ok to intubate" (12.1% and 15.7%) at the end of life; after adjustment for age and severity of illness, there were no statistical differences by race for the use of the CMO code status. Use of dialysis at the end of life varied by self-identified race. Specifically, Black and Unknown patients were more likely to receive renal replacement therapy, even after adjustment for age and severity of illness (24% and 20%, p = 0.003). Conclusions: Our data describe a gap in identification of race and ethnicity, as well as differences at the end of life in the ICU, especially with respect to code status and certain markers of intensity.

Protocol for a randomized control trial of the Building Regulation in Dual Generations Program (BRIDGE): preventing the intergenerational transmission of mental illness in at-risk preschool children.

BACKGROUND: Since the onset of the COVID-19 pandemic, the worldwide prevalence of maternal depression has risen sharply; it is now estimated that one quarter of mothers experience clinically significant depression symptoms. Exposure to maternal depression during early childhood increases the risk for the development of childhood mental illness (MI) in offspring, with altered parenting practices mediating the association between maternal depression and child outcomes. Dual-generation interventions, which aim to simultaneously treat parent and child mental health, show promise for improving outcomes for mothers with depression and their young children. The Building Regulation in Dual Generations (BRIDGE) program combines Dialectical Behavior Therapy (DBT) and parenting skills training to concurrently treat maternal depression and improve parenting practices. In pilot within-group studies, BRIDGE has led to large reductions in maternal depression and child MI symptoms. The aim of the current study is to evaluate the efficacy of BRIDGE in reducing maternal depression and child MI symptoms (primary outcomes) as well as parenting stress and harsh parenting (secondary outcomes). METHODS: A three-armed randomized control trial with equal group sizes will be conducted to compare the efficacy of (1) BRIDGE (DBT + parenting skills), (2) DBT skills training, and (3) services-as-usual. Participants (n = 180) will be mothers of 3- to 5-year-old children who report elevated depression symptoms. Those randomized to BRIDGE or DBT skills training will complete a 16-week group therapy intervention. Assessments will be administered at pre-intervention(T1) post-intervention (T2), and 6-month follow-up (T3). DISCUSSION: Dual-generation programs offer an innovative approach to prevent the intergenerational transmission of mental illness. The current study will add to the evidence base for BRIDGE by comparing it to a stand-alone mental health intervention and a services-as-usual group. These comparisons will provide valuable information on the relative efficacy of including parenting support in a mental health intervention for parents. The results will contribute to our understanding of how maternal depression affects children's development and how intervening at both a mental health and parenting level may affect child and family outcomes. TRIAL REGISTRATION: Name of registry: Clinical Trials Protocol Registration and Results System; trial registration number: NCT05959538; date of registry: July 24, 2023; available: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05959538.

Cannabinoids for symptom management in children with cancer: A systematic review and meta-analysis.

BACKGROUND: Despite the widespread use of medical cannabis, little is known regarding the safety, efficacy, and dosing of cannabis products in children with cancer. The objective of this study was to systematically appraise the existing published literature for the use of cannabis products in children with cancer. METHODS: This systematic review, registered with the International Prospective Register of Systematic Reviews (CRD42020187433), searched four databases: MEDLINE, Embase, PsycINFO, and the Cochrane Library. Abstracts and full texts were screened in duplicate. Data on types of cannabis products, doses, formulations, frequencies, routes of administration, indications, and clinical and demographic details as well as reported efficacy outcomes were extracted. Data on cannabinoid-related adverse events were also summarized. RESULTS: Out of 34,611 identified citations, 19 unique studies with a total of 1927 participants with cancer were included: eight retrospective chart reviews, seven randomized controlled trials, two open-label studies, and two case reports. The included studies reported the use of various cannabis products for the management of symptoms. Cannabinoids were commonly used for the management of chemotherapy-induced nausea and vomiting (11 of 19 [58%]). In controlled studies, somnolence, dizziness, dry mouth, and withdrawal due to adverse events were more commonly associated with the use of cannabinoids. Across all included studies, no serious cannabis-related adverse events were reported. CONCLUSIONS: Although there is evidence to support the use of cannabis for symptom management, in children with cancer, there is a lack of rigorous evidence to inform the dosing, safety, and efficacy of cannabinoids. Because of the increasing interest in using cannabis, there is an urgent need for more research on medical cannabis in children with cancer.

NARROWING THE GAP: PRECLINICAL TRAUMA WITH POSTINJURY SEPSIS MODEL WITH INCREASED CLINICAL RELEVANCE.

ABSTRACT: Background : Overall outcomes for trauma patients have improved over time. However, mortality for postinjury sepsis is unchanged. The use of relevant preclinical studies remains necessary to understand mechanistic changes after injury and sepsis at the cellular and molecular level. We hypothesized that a preclinical rodent model of multicompartmental injury with postinjury pneumonia and chronic stress would replicate inflammation and organ injury similar to trauma patients in the intensive care unit. Methods : Male and proestrus female Sprague-Dawley rats ( n = 16/group) were subjected to either polytrauma (PT) (lung contusion, hemorrhagic shock, cecectomy, and bifemoral pseudofracture), PT with daily chronic restraint stress (PT/CS), PT with postinjury day one Pseudomonas pneumonia (PT + PNA), PT/CS with pneumonia (PT/CS + PNA) or naive controls. Weight, white blood cell count, plasma toll-like receptor 4 (TLR4), urine norepinephrine (NE), hemoglobin, serum creatinine, and bilateral lung histology were evaluated. Results : PT + PNA and PT/CS + PNA groups lost more weight compared with those without sepsis (PT, PT/CS) and naive rats ( P < 0.03). Similarly, both PT + PNA and PT/CS + PNA had increased leukocytosis and plasma TLR4 compared with uninfected counterparts. Urine NE was elevated in PT + PNA and PT/CS + PNA compared with naive ( P < 0.03), with PT/CS + PNA exhibiting the highest levels. PT/CS + PNA exhibited worse acute kidney injury with elevated serum creatinine compared with PT/CS ( P = 0.008). PT/CS + PNA right and left lung injury scores were worse than PT + PNA ( P < 0.01). Conclusions : Sepsis, with postinjury pneumonia, induced significant systemic inflammation, organ dysfunction following polytrauma and chronic stress. Advanced animal models that replicate the critically ill human condition will help overcome the classic limitations of previous experimental models and enhance their translational value.

Medical cannabis in schools: A qualitative study on the experiences of clinicians.

Objectives: Guidance is lacking for medical cannabis use in Canadian schools in both legislation and approach; the impact of ambiguous policy on patient care is unknown. A qualitative study was undertaken to explore the experiences of clinicians who care for school-aged children who take medical cannabis. Methods: Semi-structured interviews were recorded and transcribed verbatim. Qualitative content analysis performed using the Dedoose qualitative software ascribed meaning units and codes, which were further consolidated into categories and subcategories. Results: Thirteen physicians were interviewed virtually, representing seven provinces in Canada. The physicians provided care for between five and hundreds of school-aged children who took medical cannabis. The most common indications were refractory seizure disorders and autism. The interviews provided rich descriptions on perceptions of medical cannabis in schools, and in general. Five overarching categories were identified across both domains including variability, challenges (subcategories: lack of knowledge, stigma, lack of policy, and pragmatic challenges), potential solutions (subcategories: treat it like other medications, communication, education, and family support), positive experiences and improvements over time. Conclusion: In Canada, cannabis-based medicine use in schools still faces important challenges. Effective education, communication, family support and policy refinements that allow cannabis to be treated like other prescription medications are recommended to improve the status quo. These findings will guide the C4T Medical Cannabis in Schools Working Group's future priorities and initiatives.