Systematic review of drug-drug interactions of delta-9-tetrahydrocannabinol, cannabidiol, and Cannabis.

Background: The recent exponential increase in legalized medical and recreational cannabis, development of medical cannabis programs, and production of unregulated over-the-counter products (e.g., cannabidiol (CBD) oil, and delta-8-tetrahydrocannabinol (delta-8-THC)), has the potential to create unintended health consequences. The major cannabinoids (delta-9-tetrahydrocannabinol and cannabidiol) are metabolized by the same cytochrome P450 (CYP) enzymes that metabolize most prescription medications and xenobiotics (CYP3A4, CYP2C9, CYP2C19). As a result, we predict that there will be instances of drug-drug interactions and the potential for adverse outcomes, especially for prescription medications with a narrow therapeutic index. Methods: We conducted a systematic review of all years to 2023 to identify real world reports of documented cannabinoid interactions with prescription medications. We limited our search to a set list of medications with predicted narrow therapeutic indices that may produce unintended adverse drug reactions (ADRs). Our team screened 4,600 reports and selected 151 full-text articles to assess for inclusion and exclusion criteria. Results: Our investigation revealed 31 reports for which cannabinoids altered pharmacokinetics and/or produced adverse events. These reports involved 16 different Narrow Therapeutic Index (NTI) medications, under six drug classes, 889 individual subjects and 603 cannabis/cannabinoid users. Interactions between cannabis/cannabinoids and warfarin, valproate, tacrolimus, and sirolimus were the most widely reported and may pose the greatest risk to patients. Common ADRs included bleeding risk, altered mental status, difficulty inducing anesthesia, and gastrointestinal distress. Additionally, we identified 18 instances (58%) in which clinicians uncovered an unexpected serum level of the prescribed drug. The quality of pharmacokinetic evidence for each report was assessed using an internally developed ten-point scale. Conclusion: Drug-drug interactions with cannabinoids are likely amongst prescription medications that use common CYP450 systems. Our findings highlight the need for healthcare providers and patients/care-givers to openly communicate about cannabis/cannabinoid use to prevent unintended adverse events. To that end, we have developed a free online tool (www.CANN-DIR.psu.edu) to help identify potential cannabinoid drug-drug interactions with prescription medications.

Ex Vivo Endotoxin Stimulation of Blood for Predicting Survival in Patients With Sepsis: A Systematic Review.

BACKGROUND: Sepsis is a syndrome characterized by host immune dysfunction, with the extent of immunoparalysis differing among patients. Lipopolysaccharide (LPS) is used commonly to assess the immune function of critically ill patients with sepsis. However, the reliability of this ex vivo diagnostic test in predicting clinical outcomes remains uncertain. RESEARCH QUESTION: Does LPS-induced tumor necrosis factor (TNF) production from the blood of patients with sepsis predict mortality? Secondary outcomes included ICU and hospital stay durations, nosocomial infection rate, and organ recovery rate. STUDY DESIGN AND METHODS: Human sepsis studies from various databases through April 2023 were evaluated. Inclusion criteria encompassed LPS-stimulated blood assays, English language, and reported clinical outcomes. Bias risk was evaluated using the Newcastle-Ottawa scale (NOS). Relationships between TNF production and mortality were analyzed at sepsis onset and during established sepsis, alongside secondary outcomes. RESULTS: Of 11,580 studies, 17 studies (14 adult and three pediatric) were selected for analysis. Although 15 studies were evaluated as moderate to high quality using the NOS, it is important to note that some of these studies also had identifiable biases, such as unclear methods of participant recruitment. Nine studies detailed survival outcomes associated with LPS-induced TNF production at sepsis onset, whereas five studies explored TNF production's relationship with mortality during established sepsis. Trends suggested that lower LPS-induced TNF production correlated with higher mortality. However, heterogeneity in methodologies, especially the LPS assay protocol, hindered definitive conclusions. Publication bias was highlighted using funnel plot analysis. Concerning secondary outcomes, diminished TNF production might signify worsening organ dysfunction, although the link between cytokine production and nosocomial infection varied among studies. INTERPRETATION: For functional immune profiling in sepsis, streamlined research methodologies are essential. This entails organizing cohorts based on microbial sources of sepsis, establishing standardized definitions of immunoparalysis, using consistent types and dosages of immune stimulants, adhering to uniform blood incubation conditions, and adopting consistent clinical outcomes.

Interventions Addressing Cannabis Use During Pregnancy: A Systematic Review.

OBJECTIVES: The prevalence of cannabis use among pregnant women is increasing in the United States and places mothers and infants at risk of multiple adverse health outcomes. Given the uncertainty expressed by providers regarding how to approach cannabis use during pregnancy and the growing need for a systematic endeavor to curb use in this population, the aim of this study is to conduct a systematic review of interventions focused on reduction in cannabis use during pregnancy. METHODS: We conducted a systematic search of MEDLINE, PsycINFO, CINAHL, Web of Science, SCOPUS, and Cochrane Library to identify studies of interventions that target individuals that engaged in cannabis use during pregnancy. We included studies if they were randomized controlled trials, controlled studies, feasibility studies, pilot studies, as well as observational studies. The primary diagnostic outcome of interest is reduction in cannabis use. RESULTS: We identified 9 studies for inclusion with sample sizes ranging from 15 to 658 pregnant people. Interventions involved brief counseling, cognitive behavioral therapy (CBT), motivational interviewing (MI), motivational enhancement therapy + cognitive behavioral therapy (MET-CBT), computer-delivered psychotherapy, and psychoeducation. The interventions that were effective primarily used MI, CBT, and/or MET. There was just 1 study that implemented a home intervention and one that explored computer-based psychotherapy. CONCLUSIONS: The studies uncovered through this systematic review suggest that interventions involving CBT and/or MI demonstrate promise for decreasing cannabis use during pregnancy. There is a tremendous need for high-quality studies focused on this population, and the potential for remote and computer-based interventions should be explored more fully.

Systematic Review and Meta-analysis: Pharmacological and Nonpharmacological Interventions for Persistent Nonepisodic Irritability.

OBJECTIVE: This meta-analysis examined the efficacy of available pharmacological and nonpharmacological interventions for irritability among youth with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorders (DBD), disruptive mood dysregulation disorder (DMDD), and/or severe mood dysregulation (SMD). METHOD: Literature searches were conducted in October 2020, resulting in 564 abstracts being reviewed to identify relevant papers, with 387 articles being reviewed in full. A random effects model was used for the meta-analysis, with subgroup meta-regressions run to assess effects of study design, intervention type, medication class, and clinical population. RESULTS: A total of 101 studies were included (80 pharmacological, 13 nonpharmacological, 8 combined). Despite high heterogeneity in effects (I2 = 94.3%), pooled posttreatment effect size for decreasing irritability was large (Hedges' g = 1.62). Large effects were found for pharmacological (g = 1.85) and nonpharmacological (g = 1.11) interventions; moderate effects were found for combined interventions relative to monotherapy interventions (g = 0.69). Antipsychotic medications provided the largest effect for reducing irritability relative to all other medication classes and nonpharmacological interventions. A large effect was found for youth with ASD (g = 1.89), whereas a medium effect was found for youth with ADHD/DMDD/DBD/SMD (g = 0.64). CONCLUSION: This meta-analysis provides a comprehensive review of interventions targeting persistent nonepisodic irritability among youth with various psychiatric disorders. Strong evidence was found for medium-to-large effects across study design, intervention type, and clinical populations, with the largest effects for pharmacological interventions, particularly antipsychotic medications and combined pharmacological interventions, and interventions for youth with ASD.

Transformative Learning in Graduate Medical Education: A Scoping Review.

BACKGROUND: Transformative learning (TL) is an educational theory focused on deep fundamental shifts in an individual's worldview. Such shifts are well known to occur within graduate medical education (GME). However, TL in GME has yet to be formally explored. OBJECTIVE: We performed a scoping review of the literature on TL within GME to identify areas where trainees currently experience or have potential to experience TL, and to explore areas where fostering TL has been used as a pedagogical tool. METHODS: In January 2020, we searched 7 databases to identify literature on TL in GME. Additional articles were identified by hand-searching the Journal of Graduate Medical Education. RESULTS: A total of 956 articles were identified through database search with 3 unique articles found via hand-searching. Abstracts and manuscripts were screened by 2 authors and disagreements arbitrated by a third, yielding 28 articles for our analysis. The main components of TL (disorienting dilemma, reflection, discourse, action) took various forms. TL was closely linked with professionalism training and professional identity formation. Training programs in primary care fields were most frequently referenced. Often, trainees were experiencing TL without recognition of the theory by their educators. Gaps in the graduate medical education literature exist pertaining to TL in venues such as diversity, equity, and inclusion. CONCLUSIONS: Our scoping review uncovered the following themes: TL and professionalism, TL and primary care, and TL by other names. TL is likely occurring but going unrecognized in some settings.

A Systematic Scoping Review of How Healthcare Organizations Are Facilitating Access to Fruits and Vegetables in Their Patient Populations.

BACKGROUND: There is compelling evidence on the impact of diet as preventative medicine, and with rising health care costs healthcare organizations are attempting to identify interventions to improve patient health outcomes. OBJECTIVES: The purpose of this systematic scoping review was to characterize existing healthcare organization-based interventions to improve access to fruits and vegetables (F&V) for their patient populations. In addition, we aimed to review the impact of identified interventions on dietary intake and health outcomes. METHODS: Titles and abstracts were searched in PubMed® (MEDLINE®), Embase®, CINAHL®, and the Cochrane Library® from 1 January 1990 to 31 December 2019. To be selected for inclusion, original studies must have included a healthcare organization and have had a programmatic focus on increasing access to or providing fresh F&V to patients in an outpatient, naturalistic setting. The Effective Public Health Practice Project tool was used to assess study quality in 6 domains (selection bias, study design, confounders, blinding, data collection methods, and withdrawals and dropouts). RESULTS: A total of 8876 abstracts were screened, yielding 44 manuscripts or abstracts from 27 programs. Six program models were identified: 1) a cash-back rebate program, 2) F&V voucher programs, 3) garden-based programs, 4) subsidized food box programs, 5) home-delivery meal programs, and 6) collaborative food pantry-clinical programs. Only 6 of 27 studies included a control group. The overall quality of the studies was weak due to participant selection bias and incomplete reporting on data collection tools, confounders, and dropouts. Given the heterogeneity of outcomes measured and weak study quality, conclusions regarding dietary and health-related outcomes were limited. CONCLUSIONS: Healthcare-based initiatives to improve patient access to F&V are novel and have promise. However, future studies will need rigorous study designs and validated data collection tools, particularly related to dietary intake, to better determine the effect of these interventions on health-related outcomes.

A meta-analysis and systematic review of venous thromboembolism prophylaxis in patients undergoing vascular surgery procedures.

OBJECTIVE: Perioperative venous thromboembolism (VTE) is generally considered preventable. Whereas the non-vascular surgery literature is rich in providing data about the impact of VTE prophylaxis on VTE outcomes, vascular surgery data are relatively sparse on this topic. This study sought to evaluate the evidence for VTE prophylaxis specifically for the population of vascular surgery patients. METHODS: A systematic search was conducted in MEDLINE, Cochrane, and Embase databases in December 2018. Included were studies reporting primary and secondary outcomes for common vascular surgery procedures (open aortic operation, endovascular aneurysm repair [EVAR], peripheral artery bypass, amputation, venous reflux operation). A meta-analysis was performed comparing the patients who did not receive VTE prophylaxis and had VTE complications with patients who developed VTE despite receiving prophylaxis. RESULTS: From 3757 uniquely identified articles, 42 publications met the criteria for inclusion in this review (1 for the category of all vascular operations, 5 for open aortic reconstructions, 2 for EVAR, 1 for open aortic surgery or EVAR, 3 for abdominal or bypass surgery, 2 for peripheral bypass surgery, 2 for amputations, 1 for vascular trauma, and 25 for surgical treatment of superficial venous disease). Five studies met the criteria for inclusion in the meta-analysis. The results demonstrated slightly lower relative risk for development of VTE among patients receiving VTE prophylaxis (relative risk, 0.70; 95% confidence interval, 0.26-1.87). After open aortic reconstruction, the risk of VTE is 13% to 18% and is not reduced by VTE prophylaxis. For EVAR patients, the risk of VTE without prophylaxis is 6%. For patients undergoing peripheral bypass surgery and not receiving therapeutic or prophylactic anticoagulation, the risk of VTE is <2%. For patients undergoing amputations, VTE prophylaxis reduces the risk of VTE. For patients undergoing surgical treatment of superficial venous disease, there is an abundance of literature exploring the utility of VTE prophylaxis, but the evidence is conflicting; some studies demonstrated a benefit, whereas others showed no reduction of VTE with prophylaxis. CONCLUSIONS: Overall, there is a paucity of literature that addresses the effectiveness of VTE prophylaxis specifically in the population of vascular surgery patients. Our meta-analysis of the literature does not demonstrate a statistically significant benefit of VTE prophylaxis among the vascular surgery patients evaluated; however, it does suggest a low incidence of VTE among patients who receive VTE prophylaxis. Clinicians should identify the patients at high risk for development of postoperative VTE as the risk-benefit ratio may favor VTE prophylaxis in a selected group of patients. Clinicians should use their judgment and established VTE risk prediction models to assess VTE risk for patients. Vascular surgeons should consider reporting VTE incidence as a secondary outcome in publications.

The role of pemetrexed in recurrent epithelial ovarian cancer: A scoping review.

Ovarian cancer is the leading cause of mortality among gynecologic malignancies, with most cases diagnosed at an advanced stage. Despite an initial response, most develop a recurrence and subsequent resistance to standard therapies. Pemetrexed (AlimtaTM) is a new generation multi-targeted antifolate initially approved for the treatment of malignant pleural mesothelioma. In recent years, it has shown promise in the treatment of recurrent epithelial ovarian cancer. In this review, we outline the current literature and discuss the future of pemetrexed in the setting of recurrent epithelial ovarian cancer.

Determinants of behavioral and psychological symptoms of dementia: A scoping review of the evidence.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are prevalent in people with neurodegenerative diseases. PURPOSE: In this scoping review the Kales, Gitlin and Lykestos framework is used to answer the question: What high quality evidence exists for the patient, caregiver and environmental determinants of five specific BPSD: aggression, agitation, apathy, depression and psychosis? METHOD: An a priori review protocol was developed; 692 of 6013 articles retrieved in the search were deemed eligible for review. Gough's Weight of Evidence Framework and the Cochrane Collaboration's tool for assessing risk of bias were used. The findings from 56 high quality/low bias articles are summarized. DISCUSSION: Each symptom had its own set of determinants, but many were common across several symptoms: neurodegeneration, type of dementia, severity of cognitive impairments, and declining functional abilities, and to a lesser extent, caregiver burden and communication. CONCLUSION: Research and policy implications are relevant to the National Plan to Address Alzheimer's Disease.

Implementing and Sustaining Evidence Based Practice Through a Nursing Journal Club.

BACKGROUND: The outcomes based emphasis in nursing and health care delivery requires identification of best available evidence in order to produce quality, safe, and effective patient care. Finding, critiquing, and ultimately implementing the best available evidence for practice is a formidable task for many clinical nurses. Development and implementation of a nursing journal club (NJC) became one organization's successful attempt to help clinical nurses better understand and use best available evidence in actual practice. METHODS: The process and structure for the NJC evolved from an additional activity scheduled outside of work to a fully established endeavor of Nursing Research and Evidence Based Practice Council (NR&EBP). The Nursing Professional Practice Model was foundational to establishing the NJC as a formal component within the NR&EBP Council shared governance structure. Efforts to embed the NJC included taking advantage of resources available at an academic medical center and incorporating them into the council structure. RESULTS: Successful outcomes of the NJC include a quarterly schedule, with topics selected in advance that are based on nursing department as well as organizational driven goals and initiatives. The structure and process in place has eliminated frequently mentioned deterrents to evidence based practice such as not enough time, lack of knowledge, or no immediate application to practice. CONCLUSIONS: Incorporating the NJC as a component of NR&EBP Council has provided clinical nurses time away from clinical care that supports scholarship for nursing practice. Committed leadership and garnering of available resources have been key factors for success.

Starting a Fee-Based Systematic Review Service.

The George T. Harrell Health Sciences Library at Penn State College of Medicine began a fee-based systematic review service, a model for cost recovery, in October 2013. This article describes the library's experience in establishing, introducing, and promoting the new service, which follows the Institute of Medicine's recommended standards for performing systematic reviews. The goal is to share this information with librarians who are contemplating starting such a service.

Olfactory dysfunction in Multiple Sclerosis: A scoping review of the literature.

OBJECTIVE: Olfactory dysfunction in Multiple Sclerosis (MS) has been reported, but results have been inconsistent. In this review we describe, synthesize, and interpret the existing literature on olfactory dysfunction in Multiple Sclerosis and identify gaps in the current level of knowledge. METHODS: The study design was a scoping review of the literature covering several study designs. Systematic Searches of the PubMed, CINAHL, Cochrane Library, Web of Science, PsycARTICLES, PsycINFO and Google Scholar databases were conducted that included key words related to Multiple Sclerosis and Olfaction Disorders. Literature that met the criteria of pertaining to both Multiple Sclerosis and olfactory dysfunction was identified, with the aim of providing an overview of the extent and types of research available in this area. RESULTS: Sixty-one reports were identified in the initial search, with 40 meeting the study criteria. Twenty-five clinical studies were included. Among them, 23 studies measured for olfactory dysfunction in MS patients, ten evaluated MRI correlates of olfactory dysfunction, and five evaluated neurophysiology correlates of olfactory dysfunction. Six of the included studies were abstracts. In addition, thirteen reviews/commentaries and two case studies were included. The majority of the studies identified some degree of olfactory dysfunction in MS patients, and various aspects and correlations with olfactory impairment were observed. CONCLUSIONS: The overall weight of the literature suggests that olfactory dysfunction may occur in MS. Although there is variability in reported frequency, the more robust studies suggest the prevalence is significant, ranging from 20% to 45% in the MS population. Despite this, the mechanisms are unknown and the clinical relevance of this association has not been well explored. Interesting findings relating mood disorders, cognition, and olfactory dysfunction in MS are also suggested but remain poorly developed and require further investigation. Future studies are also warranted to understand the dynamic changes in olfactory function during the course of MS, and to correlate olfactory function with relapses/disease activity.

Worldwide need for a comprehensive database of stability data for pharmaceuticals stored in uncontrolled environments.

Developing a database to compile all known, relevant information on the stability of pharmaceuticals in tropical environments would vastly increase access to this information, improving safety and reducing cost. Many studies have examined the stability of pharmaceuticals stored under conditions that exceed manufacturer specifications, but this information is published across so many journals and Websites that it can be virtually inaccessible to clinics or suppliers needing to make pharmaceutical inventory management decisions. We have made progress toward the completion of a database of this nature, but resources and abilities of international public health organizations will be needed to bring the database fully to fruition.