Global epidemiology of cannabis use disorders and its trend from 1990 to 2019: Benchmarking analysis of the global burden of disease study.

Introduction: Cannabis is one of the most widely used psychoactive substances globally, with an increasing trend in its legalization for both medical and recreational purposes in various countries. While cannabis offers potential therapeutic benefits, its regular use can lead to the development of Cannabis Use Disorders (CUDs). Understanding the epidemiology of CUDs is crucial in assessing the public health burden associated with cannabis use. Methods: Epidemiological parameters of CUDs were assessed using the Global Burden of Disease (GBD) methodology across different age-groups, years, sexes, and locations worldwide from 1990-2019. Results: Globally, for both sexes combined, prevalent cases of CUDs increased steadily from 17.1 million(95%UI=12.7-22.8million) in 1990 to 23.8-million(95%UI=17.8-30.9 million) in 2019. All age-adjusted highest number of incidence observed in High-Income-North-America(HINA)(121/100,000), followed by Australasia(100/100,000), Oceania(83.97/100,000), Tropical Latin America(69.59/100,000). Globally, age-standardized disability-adjusted life years rate(ASDR) observed higher in HINA, followed by Australasia, and Western-Europe. In male, all-age incidence counts increased from 1.7 million(95%UI=1.3-2.4million) in 1990 to 2.4 million(95%UI=1.8-3.2 million) in 2019. The highest annual percentage of change in age-standardized incidence rate(ASIR) was found in East-Asia (22%) followed by Middle-East and North-Africa(MENA)(15%). The age group of 15-24 years exhibited the highest burden of CUDs. Conclusion: The widespread occurrence of CUDs on a global scale poses a substantial challenge to public health. Understanding the impact of CUDs and implementing evidence-based interventions is crucial in mitigating the associated individual, societal, and economic burdens. Continued research, collaboration, and knowledge dissemination are essential to inform policies, prevention efforts, and treatment strategies aimed at addressing CUDs on a global-scale.

A young female of Cowden syndrome presenting with Lhermitte-Duclos disease: An illustrative case.

Background: Lhermitte-Duclos Disease (LDD), or dysplastic gangliocytoma, which is a benign hamartomatous condition involving the cerebellum, has a possible association with Cowden syndrome (CS), a rare autosomal dominant disorder due to germline mutations in the phosphatase and tensin homolog (PTEN) tumor-suppressor gene in chromosome 10. Combined CS and LDD cases are rarely reported in the literature. Case Description: We present here a case of a young female patient presented at the emergency department with a severe headache associated with vertigo, vomiting, and cerebellar ataxia. A magnetic resonance imaging scan revealed mixed intensity posterior fossa lesion with almost preserved cerebellar cortical striations. Her facial skin had extensive trichilemmoma. Her symptoms improved after the excision of the posterior fossa lesion through suboccipital craniotomy and histopathology revealed LDD. Conclusion: In a low-resource country where genetic testing for neurosurgical condition is still inadequate, we used the validated Cleveland Clinic Adult Clinical Scoring for PTEN Testing and the patient had an 82-98% chance for a PTEN gene mutation. Finally, she along with her family was adequately counseled and was advised for regular screening and monitoring since it is a premalignant condition where early detection is imperative if any cancer arises in the near future and is now under our follow-up.

Optimization of 5' Untranslated Region of Modified mRNA for Use in Cardiac or Hepatic Ischemic Injury.

Modified mRNA (modRNA) is a gene-delivery platform for transiently introducing a single gene or several genes of interest to different cell types and tissues. modRNA is considered to be a safe vector for gene transfer, as it negligibly activates the innate immune system and does not compromise the genome integrity. The use of modRNA in basic and translational science is rising, due to the clinical potential of modRNA. We are currently using modRNA to induce cardiac regeneration post-ischemic injury. Major obstacles in using modRNA for cardiac ischemic disease include the need for the direct and single administration of modRNA to the heart and the inefficient translation of modRNA due to its short half-life. Modulation of the 5' untranslated region (5' UTR) to enhance translation efficiency in ischemic cardiac disease has great value, as it can reduce the amount of modRNA needed per delivery and will achieve higher and longer protein production post-single delivery. Here, we identified that 5' UTR, from the fatty acid metabolism gene carboxylesterase 1D (Ces1d), enhanced the translation of firefly luciferase (Luc) modRNA by 2-fold in the heart post-myocardial infarction (MI). Moreover, we identified, in the Ces1d, a specific RNA element (element D) that is responsible for the improvement of modRNA translation and leads to a 2.5-fold translation increment over Luc modRNA carrying artificial 5' UTR, post-MI. Importantly, we were able to show that 5' UTR Ces1d also enhances modRNA translation in the liver, but not in the kidney, post-ischemic injury, indicating that Ces1d 5' UTR and element D may play a wider role in translation of protein under an ischemic condition.

Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction.

BACKGROUND: Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI. METHODS: We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI. RESULTS: We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils. CONCLUSIONS: Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.

Deprescribing as a Clinical Improvement Focus.

OBJECTIVES: Polypharmacy is a concern in the practice of geriatrics because of consequences such as adverse drug events and poorer quality of life. Deprescribing, a response to polypharmacy, refers to the systematic, programmed, and appropriate reduction in drug number and dose. Although now broadly recognized, challenges exist in practice for effective implementation. This study was conducted to determine the deprescribing success rate and relate it to drug classes and clinical settings, and to identify factors that influence the deprescribing process. DESIGN: As a performance improvement (PI) project, fellows in geriatric medicine, under supervision of faculty geriatricians, attempted deprescribing during at least 1 encounter daily at 2 long-term care (LTC) facilities and an outpatient geriatrics clinic (C) in Bronx, New York, from August 2018 to January 2019. Deprescribing was initiated following discussion and consent from patient or caregiver. Following the data collection, involved fellows and faculty physicians participated in a survey to identify factors that influenced the process. RESULTS: Out of 449 encounters, 383 encounters were included for analysis. Average patient age was 78.2 years (LTC: 77.9, C: 79.1). Average patient comorbidities was 6.5 (LTC: 6.7, C: 5.8). Deprescribing was successful in 90.1% of encounters (LTC: 96.9%, C: 67.4%). On average, 1.3 medications were deprescribed per encounter (LTC: 1.4, C: 1.0). Analgesics (32.2%), multivitamin-minerals supplements (29.7%), lipid-lowering agents (22.9%), antihistamines (46.7%), and acid blockers (26.2%) had highest success. CONCLUSIONS AND IMPLICATIONS: Deprescribing is possible in practice in both LTC and community settings at each encounter, until it is no longer applicable. Factors that contribute to successful deprescribing primarily include meaningful and earnest provider effort, ideally in collaboration with interdisciplinary team members (nurses, pharmacists, social worker, and others), besides interactions with consultants for the patient. Certain medication classes such as vitamins, minerals, analgesics, and proton pump inhibitors can be deprescribed with high success, as noted in our study, whereas antipsychotic agents, antidepressants, and ophthalmic preparations, prescribed by specialists, proved harder to deprescribe. An understanding of barriers to deprescribing (outlined in the article) and addressing them are crucial in enabling success. The study demonstrates that as a performance improvement project in collaborative effort with multiple disciplines, deprescribing is possible in health care. Factors promoting success and barriers to deprescribing are detailed. Appropriate deprescribing has the potential to help lower adverse drug events, costs of care, and possibly improve quality of life.

Race/Ethnicity Moderates the Association Between Psychosocial Resilience and Movement-Evoked Pain in Knee Osteoarthritis.

OBJECTIVE: Racial/ethnic disparities in pain are well-recognized, with non-Hispanic blacks (NHBs) experiencing greater pain severity and pain-related disability than non-Hispanic whites (NHWs). Although numerous risk factors are posited as contributors to these disparities, there is limited research addressing how resilience differentially influences pain and functioning across race/ethnicity. Therefore, this study examined associations between measures of psychosocial resilience, clinical pain, and functional performance among adults with knee osteoarthritis (OA), and assessed the moderating role of race/ethnicity on these relationships. METHODS: In a secondary analysis of the Understanding Pain and Limitations in Osteoarthritic Disease (UPLOAD-2) study, 201 individuals with knee OA (NHB = 105, NHW = 96) completed measures of resilience (ie, trait resilience, optimism, positive well-being, social support, positive affect) and clinical pain, as well as a performance-based measure assessing lower-extremity function and movement-evoked pain. RESULTS: Bivariate analyses showed that higher levels of psychosocial resilience were associated with lower clinical pain and disability and more optimal physical functioning. NHBs reported greater pain and disability, poorer lower-extremity function, and higher movement-evoked pain compared with NHWs; however, measures of psychosocial resilience were similar across race/ethnicity. In moderation analyses, higher optimism and positive well-being were protective against movement-evoked pain in NHBs, whereas higher levels of positive affect were associated with greater movement-evoked pain in NHWs. CONCLUSION: Our findings underscore the importance of psychosocial resilience on OA-related pain and function and highlight the influence of race/ethnicity on the resilience-pain relationship. Treatments aimed at targeting resilience may help mitigate racial/ethnic disparities in pain.

Examining the Impact of a Resilience-Based Hope Intervention on Pain-Evoked Cortisol Response.

Temporomandibular disorder (TMD) is an orofacial pain condition often resulting in functional impairment and pain-related disability. Given the relationship between stress and pain in TMD, it has been suggested that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (e.g., cortisol responsivity) could contribute to the onset and maintenance of the condition. Research has shown that therapies to control pain and stress can improve quality of life in patients with persistent pain, with recent evidence supporting resilience as a potential target of intervention. However, no studies have systematically examined whether a resilience intervention has efficacy in modulating neuroendocrine functioning in TMD. Therefore, the primary objective of this pilot study was to investigate the effects of a resilience-based hope intervention on pain-evoked cortisol levels in individuals with TMD. Twenty-nine participants were randomized to a 3-session intervention intended to increase hope or a control intervention targeting pain and stress education. Prior to and after the intervention, participants attended two experimental sessions whereby salivary cortisol was obtained after the induction of a painful, cold-water procedure. While there were no intervention group differences in pain-evoked cortisol response, greater situational and dispositional hope were associated with lower levels of cortisol. Overall, findings suggest that positive emotional resources may attenuate heightened neuroendocrine activity; however, further research is needed to determine the physiological benefits of resilience-oriented therapies.