Cannabis Hyperemesis Syndrome in a Recently Abstinent Chronic User: Assessment and Intervention.

BACKGROUND: Cannabis Hyperemesis Syndrome (CHS) is a condition characterized by episodic bursts of vomiting and abdominal pain linked to cannabis use. The clinical picture mimics an acute abdomen and is often misdiagnosed, especially when the patient avoids reporting their cannabis use for legal reasons. CASE REPORT: We report on the case of a 33-year-old man that was brought to the emergency room with a history of 3 days of non-bloody, non-projectile, and non-bilious brownish vomit, coupled with severe epigastric and left hypochondriac pain, and a slight fever. He was a daily cannabis user for several years and had stopped using a week or so before the onset of the symptoms, as he was traveling to a country with more restrictive cannabis laws. His condition deteriorated rapidly, followed by emergency room attendance, thorough diagnostic work-up, and unsuccessful interventions, including intravenous treatment with the anti-emetic Ondansetron. The patient was referred to a psychiatrist after a suspected psychogenic etiology by the medical team. The history was suggestive of CHS and also included anxious, depressed mood with 'brain fog'. The abdominal pain was the most severe complaint. A combination of tramadol, promethazine, and mirtazapine given on an outpatient basis led to full recovery within 10 days. CONCLUSION: CHS can occur soon after the interruption of chronic cannabis use and overlap with withdrawal symptom. A combination of anti-histaminergic, opioid-based medication, and antidepressant mirtazapine seemed an effective treatment of CHS, which resulted in a relatively quick recovery.

High-salt diet induces microbiome dysregulation, neuroinflammation and anxiety in the chronic period after mild repetitive closed head injury in adolescent mice.

The associations between human concussions and subsequent sequelae of chronic neuropsychiatric and cardiovascular diseases such as hypertension have been reported; however, little is known about the underlying biological processes. We hypothesized that dietary changes, including a high-salt diet, disrupt the bidirectional gut-brain axis, resulting in worsening neuroinflammation and emergence of cardiovascular and behavioural phenotypes in the chronic period after repetitive closed head injury in adolescent mice. Adolescent mice were subjected to three daily closed head injuries, recovered for 12 weeks and then maintained on a high-salt diet or a normal diet for an additional 12 weeks. Experimental endpoints were haemodynamics, behaviour, microglial gene expression (bulk RNA sequencing), brain inflammation (brain tissue quantitative PCR) and microbiome diversity (16S RNA sequencing). High-salt diet did not affect systemic blood pressure or heart rate in sham or injured mice. High-salt diet increased anxiety-like behaviour in injured mice compared to sham mice fed with high-salt diet and injured mice fed with normal diet. Increased anxiety in injured mice that received a high-salt diet was associated with microgliosis and a proinflammatory microglial transcriptomic signature, including upregulation in interferon-gamma, interferon-beta and oxidative stress-related pathways. Accordingly, we found upregulation of tumour necrosis factor-alpha and interferon-gamma mRNA in the brain tissue of high salt diet-fed injured mice. High-salt diet had a larger effect on the gut microbiome composition than repetitive closed head injury. Increases in gut microbes in the families Lachnospiraceae, Erysipelotrichaceae and Clostridiaceae were positively correlated with anxiety-like behaviours. In contrast, Muribaculaceae, Acholeplasmataceae and Lactobacillaceae were negatively correlated with anxiety in injured mice that received a high-salt diet, a time-dependent effect. The findings suggest that high-salt diet, administered after a recovery period, may affect neurologic outcomes following mild repetitive head injury, including the development of anxiety. This effect was linked to microbiome dysregulation and an exacerbation of microglial inflammation, which may be physiological targets to prevent behavioural sequelae in the chronic period after mild repetitive head injury. The data suggest an important contribution of diet in determining long-term outcomes after mild repetitive head injury.

World addiction medicine reports: formation of the International Society of Addiction Medicine Global Expert Network (ISAM-GEN) and its global surveys.

Addiction medicine is a dynamic field that encompasses clinical practice and research in the context of societal, economic, and cultural factors at the local, national, regional, and global levels. This field has evolved profoundly during the past decades in terms of scopes and activities with the contribution of addiction medicine scientists and professionals globally. The dynamic nature of drug addiction at the global level has resulted in a crucial need for developing an international collaborative network of addiction societies, treatment programs and experts to monitor emerging national, regional, and global concerns. This protocol paper presents methodological details of running longitudinal surveys at national, regional, and global levels through the Global Expert Network of the International Society of Addiction Medicine (ISAM-GEN). The initial formation of the network with a recruitment phase and a round of snowball sampling provided 354 experts from 78 countries across the globe. In addition, 43 national/regional addiction societies/associations are also included in the database. The surveys will be developed by global experts in addiction medicine on treatment services, service coverage, co-occurring disorders, treatment standards and barriers, emerging addictions and/or dynamic changes in treatment needs worldwide. Survey participants in categories of (1) addiction societies/associations, (2) addiction treatment programs, (3) addiction experts/clinicians and (4) related stakeholders will respond to these global longitudinal surveys. The results will be analyzed and cross-examined with available data and peer-reviewed for publication.

Patterns of cannabis use, perception of harm, and perceived impact of legislative change in an online sample of young adults from Lebanon: insight on recreational users versus dual motive users.

BACKGROUND: Lebanon remains as one of the major sources of cannabis worldwide. In 2020, its government passed a legislation enabling the cultivation of local medicinal cannabis. This first study following the legislative change examines the overlapping use of cannabis for recreational/medicinal purposes and characteristics of the distinct cannabis user types. METHODS: A total of 1230 young adults (18-24 years) filled an anonymous online survey in early 2020. RESULTS: Young adults in the sample were distributed as follows: 33% 18-20 years; 60% males; 94% Lebanese; 75% students; and 89% living with family. The older young adults (21-24), males, those employed, living with non-family members, and who perceived themselves as being a little/lot richer than most were statistically significantly more present in the cannabis user subtypes (recreational only or recreational/medicinal) than non-cannabis users. When dual recreational/medicinal users are compared to recreational users only, the latter seemed to have a more conservative profile of behaviours, attitudes, and perceptions and acts of harm. The prevalence ratio comparing the prevalence of users supporting consuming cannabis "once or twice" in dual motive users vs. recreational users only was 1.13 for "once or twice", 1.25 for "occasionally", 1.64 for "regularly", and 2.4 for "daily". Any other illicit drug use was reported by 1% of the non-cannabis users, 36% of the recreational users only, and 58% of the recreational/medicinal users (p-value < 0.01). Similarly, any prescription drug use was reported by 3% of the non-cannabis users, 16% of the recreational users only, and 28% of both recreational/medicinal users (p-value < 0.01). CONCLUSION: The interface between recreational and medicinal cannabis use is complex. Dual motive users may warrant special attention as a subpopulation of cannabis users. This is relevant to contexts experiencing medicinal cannabis legislation changes, such as Lebanon, as policymakers and implementers should be sensitized to the emerging evidence for more data-informed policy changes.

Infection and inflammation: New perspectives on Alzheimer's disease.

Neuroinflammation has been recognized as a component of Alzheimer's Disease (AD) pathology since the original descriptions by Alois Alzheimer and a role for infections in AD pathogenesis has long been hypothesized. More recently, this hypothesis has gained strength as human genetics and experimental data suggest key roles for inflammatory cells in AD pathogenesis. To review this topic, Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium: "Infection and Inflammation: New Perspectives on Alzheimer's Disease (AD)." Participants considered current evidence for and against the hypothesis that AD could be caused or exacerbated by infection or commensal microbes. Discussion focused on connecting microglial transcriptional states to functional states, mouse models that better mimic human immunity, the potential involvement of inflammasome signaling, metabolic alterations, self-reactive T cells, gut microbes and fungal infections, and lessons learned from Covid-19 patients with neurologic symptoms. The content presented in the symposium, and major topics raised in discussions are reviewed in this summary of the proceedings.

CRISPR-Cas knockout of miR21 reduces glioma growth.

Non-coding RNAs, including microRNAs (miRNAs), support the progression of glioma. miR-21 is a small, non-coding transcript involved in regulating gene expression in multiple cellular pathways, including the regulation of proliferation. High expression of miR-21 has been shown to be a major driver of glioma growth. Manipulating the expression of miRNAs is a novel strategy in the development of therapeutics in cancer. In this study we aimed to target miR-21. Using CRISPR genome-editing technology, we disrupted the miR-21 coding sequences in glioma cells. Depletion of this miRNA resulted in the upregulation of many downstream miR-21 target mRNAs involved in proliferation. Phenotypically, CRISPR-edited glioma cells showed reduced migration, invasion, and proliferation in vitro. In immunocompetent mouse models, miR-21 knockout tumors showed reduced growth resulting in an increased overall survival. In summary, we show that by knocking out a key miRNA in glioma, these cells have decreased proliferation capacity both in vitro and in vivo. Overall, we identified miR-21 as a potential target for CRISPR-based therapeutics in glioma.

Repetitive Mild Closed Head Injury in Adolescent Mice Is Associated with Impaired Proteostasis, Neuroinflammation, and Tauopathy.

Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1ß processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphosphorylated tau, and changes in expression of proteins suggestive of impaired translation in males but not in females. At 6 months, injured IL-1 receptor 1 (IL-1R1) KO mice, which are protected from postinjury cognitive deficits, had decreased accumulation of pro-IL-1ß and misfolded tau in cortex and cerebellum, suggesting that IL-1R1 is upstream of inflammasome priming (defined as increase in pro-IL-1ß) and abnormal tau phosphorylation. Together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurologic dysfunction and neurodegeneration.SIGNIFICANCE STATEMENT Repetitive mild closed head injury in adolescent male mice leads to impaired proteostasis, tau phosphorylation, and inflammasome activation in neurons later in adulthood through mechanisms involving IL-1 receptor 1. The data are the first to link repetitive mild traumatic brain injury in adolescence to neurodegeneration and suggest molecular targets and pathways to prevent neurologic sequelae in the chronic period after injuries.

Minimum and optimal numbers of psychiatric beds: expert consensus using a Delphi process.

The required minimum number of psychiatric inpatient beds is highly debated and has substantial resource implications. The present study used the Delphi method to try to reach a global consensus on the minimum and optimal psychiatric bed numbers. An international board of scientific advisors nominated the Delphi panel members. In the first round, the expert panel provided responses exploring estimate ranges for a minimum to optimal numbers of psychiatric beds and three levels of shortage. In a second round, the panel reconsidered their responses using the input from the total group to achieve consensus. The Delphi panel comprised 65 experts (42% women, 54% based in low- and middle-income countries) from 40 countries in the six regions of the World Health Organization. Sixty psychiatric beds per 100 000 population were considered optimal and 30 the minimum, whilst 25-30 was regarded as mild, 15-25 as moderate, and less than 15 as severe shortage. This is the first expert consensus on minimum and optimal bed numbers involving experts from HICs and LMICs. Many high-income countries have psychiatric bed numbers that fall within the recommended range. In contrast, the number of beds in many LMIC is below the minimum recommended rate.

SCARF1-Induced Efferocytosis Plays an Immunomodulatory Role in Humans, and Autoantibodies Targeting SCARF1 Are Produced in Patients with Systemic Lupus Erythematosus.

Deficiency in the clearance of cellular debris is a major pathogenic factor in the emergence of autoimmune diseases. We previously demonstrated that mice deficient for scavenger receptor class F member 1 (SCARF1) develop a lupus-like autoimmune disease with symptoms similar to human systemic lupus erythematosus (SLE), including a pronounced accumulation of apoptotic cells (ACs). Therefore, we hypothesized that SCARF1 will be important for clearance of ACs and maintenance of self-tolerance in humans, and that dysregulation of this process could contribute to SLE. In this article, we show that SCARF1 is highly expressed on phagocytic cells, where it functions as an efferocytosis receptor. In healthy individuals, we discovered that engagement of SCARF1 by ACs on BDCA1+ dendritic cells initiates an IL-10 anti-inflammatory response mediated by the phosphorylation of STAT1 and STAT3. Unexpectedly, there was no significant difference in SCARF1 expression in samples of patients with SLE compared with healthy donor samples. However, we detected anti-SCARF1 autoantibodies in 26% of patients with SLE, which was associated with dsDNA Ab positivity. Furthermore, our data show a direct correlation of the levels of anti-SCARF1 in the serum and defects in the removal of ACs. Depletion of Ig restores efferocytosis in SLE serum, suggesting that defects in the removal of ACs are partially mediated by SCARF1 pathogenic autoantibodies. Our data demonstrate that human SCARF1 is an AC receptor in dendritic cells and plays a role in maintaining tolerance and homeostasis.

Predictors of admission to an assertive outreach service for psychosis in Lebanon.

Schizophrenia is a chronic, debilitating mental illness that contributes significantly to the global burden of disease. Assertive outreach treatment for patients with schizophrenia and psychotic disorders has been implemented to improve treatment adherence and outcomes. The suitability of this model of care outside the western context has not been fully established. We describe the characteristics of 45 patients enrolled in the Psychosis Recovery Outreach Program (PROP), a program developed at a leading psychiatric facility in Lebanon. We collected twelve-month data for patients and used logistic regression models to identify predictor variables for enrollment in the service compared to those receiving standard treatment. Patients were mostly males (77.8%), younger than 39 years (80%), of college or higher education (68.2%), and diagnosed with schizophrenia (46.7%) or schizoaffective disorder (48.9%). About one-quarter (22.7%) had a comorbid cannabis use disorder. A majority received more than one oral antipsychotic (75.6%) while half (51.1%) were maintained on a long-acting injectable (LAI) antipsychotic. The following variables were significant predictors of enrollment in PROP: having a comorbid cannabis use disorder (OR 2.83 [1.25 - 6.37]), being prescribed a LAI antipsychotic (OR 9.99 [4.93-20.24]) or more than one oral antipsychotic (OR 4.57 [2.22-9.39]), visiting the emergency department more than once (OR 8.7 [2.64-28.68]), and admission to the psychiatry unit (OR 13.91 [3.17-60.94]). In addition, those following up in PROP were younger and less likely to be in the oldest age group (over 54 years) [OR 0.11 (0.01-0.93)], less likely to be females (OR 0.39 [0.18-0.81]), and less likely to be diagnosed with "other psychotic disorder" as compared to schizophrenia (OR 0.14 [0.03 - 0.62]). Our findings highlight that the assertive outreach model of care is applicable to its target population in the context of psychiatric care in Lebanon, namely young individuals with psychosis, higher comorbidities and a severe course of illness.

Legalizing Medical Cannabis in Lebanon: the Complex Interface Between Medicine, Law, Ethics, and Economics.

In April 2020, after decades of discussions and controversy, the Lebanese parliament voted a law legalizing the cultivation, production, and sale of cannabis for medicinal purposes. Although the law leaves several unanswered questions and awaits implementation, the symbolic nature of this step in recognizing a positive role of cannabis in the local economy is significant on a regional level. The Arab world has traditionally been conservative when it comes to all drugs-related policies. Cannabis is largely demonized with heavy sentences served to anyone suspected of using selling, let alone planting cannabis. Despite a few countries considered producers and consumers of substances, governing authorities have remained immune to the liberalization trend encountered in western countries. The social experiment taking place in Lebanon is fraught with risks, given the unstable political situation and chronic economic challenges. The reactions to the law have been mixed with several scientific bodies such as the Lebanese Psychiatric Society criticizing the absence of proper consultation of stakeholders. The absence of consistency in enforcing established drugs policies or seriously debating the decriminalization of cannabis use raises concerns over the establishment of a two-tier approach toward drugs, driven solely by economic imperatives.

Responding to a Major Disaster: The Trauma Assessment and Support Clinic in Beirut.

The Beirut port explosion on August 4, 2020, traumatized the Lebanese population. It also revealed a lack of disaster mental health preparedness in a country subject to significant political, economic, and security challenges. The Trauma Assessment and Support Clinic at the American University of Beirut Medical Center was one of many initiatives set up nationally as a dedicated emergency benevolent service. The authors recommend anticipating the psychiatric consequences of such rare events at a professional and systemic level. The experiences of clinicians and the challenges faced in Lebanon can guide the improvement of disaster mental health care on a global level.

Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis.

Traumatic brain injury (TBI) is a leading cause of death and disability with no specific effective therapy, in part because disease driving mechanisms remain to be elucidated. Receptor interacting protein kinases (RIPKs) are serine/threonine kinases that assemble multi-molecular complexes that induce apoptosis, necroptosis, inflammasome and nuclear factor kappa B activation. Prior studies using pharmacological inhibitors implicated necroptosis in the pathogenesis of TBI and stroke, but these studies cannot be used to conclusively demonstrate a role for necroptosis because of the possibility of off target effects. Using a model of cerebral contusion and RIPK3 and mixed lineage kinase like knockout (MLKL-/-) mice, we found evidence for activation of RIPK3 and MLKL and assembly of a RIPK1-RIPK3-MLKL necrosome complex in pericontusional brain tissue. Phosphorylated forms of RIPK3 and MLKL were detected in endothelium, CD11b + immune cells, and neurons, and RIPK3 was upregulated and activated in three-dimensional human endothelial cell cultures subjected to CCI. RIPK3-/- and MLKL-/- mice had reduced blood-brain barrier damage at 24 h (p < 0.05), but no differences in neuronal death (6 h, p = ns in CA1, CA3 and DG), brain edema (24 h, p = ns), or lesion size (4 weeks, p = ns) after CCI. RIPK3-/-, but not MLKL-/- mice, were protected against postinjury motor and cognitive deficits at 1-4 weeks (RIPK3-/- vs WT: p < 0.05 for group in wire grip, Morris water maze hidden platform trials, p < 0.05 for novel object recognition test, p < 0.01 for rotarod test). RIPK3-/- mice had reduced infiltrating leukocytes (p < 0.05 vs WT in CD11b + cells, microglia and macrophages), HMGB1 release and interleukin-1 beta activation at 24-48 h (p < 0.01) after CCI. Our data indicate that RIPK3 contributes to functional outcome after cerebral contusion by mechanisms involving inflammation but independent of necroptosis.

Addressing psychiatric care in conflict zones: recommendations for the Arab region.

The Arab world has struggled with conflict and political turmoil for several decades, rendering its already underdeveloped mental healthcare system unable to serve the psychiatric needs of victims of violence and trauma, with consequences that extend far beyond the cessation of hostilities. This role has become incumbent on international relief agencies, which have expanded mental health programmes in countries of conflict and refuge. Although their intervention has overall been positive, their mission is usually short term, leaving countries unable to maintain these advantages when the funding ends. The authors advocate for a sustainable framework that emphasises a larger role for regional and local actors. Expertise that is culturally and socially grounded could take the initiative in research, training and deployment in collaboration with non-governmental organisations, allowing for comprehensive development of the mental health sector.

Comorbidities and Age Are Associated With Persistent COVID-19 PCR Positivity.

Objectives: The impact of demographics and comorbidities on the duration of COVID-19 nasopharyngeal swab PCR positivity remains unclear. The objective of our analysis is to determine the impact of age, intensive care unit (ICU) admission, comorbidities, and ethnicity on the duration of COVID-19 PCR positivity among hospitalized patients in a large group of hospital. Method: We studied 530 patients from a large hospital system and time to SARS-CoV-2 virus RNA PCR negativity at any-time during hospitalization or following discharge from the hospital was the primary endpoint. We included patients 18 years or older who tested positive for COVID-19 during an inpatient, outpatient, or emergency room visit between February 1, 2020, and April 14, 2020. Results: Overall, 315 (59.4%) of our patient population continued to have a positive SARS-CoV-2 virus RNA PCR 4 weeks after the initial positive test. We found that age>70 years, chronic kidney disease, hypertension, hyperlipidemia, obesity, or coronary artery disease are associated with persistent PCR positivity for more than 4 weeks after initial diagnosis. Conclusion: Age, and the presence of co-morbidities should be taken into consideration when interpreting a positive COVID PCR test.

Comparative Analysis Identifies Similarities between the Human and Murine Microglial Sensomes.

One of the essential functions of microglia is to continuously sense changes in their environment and adapt to those changes. For this purpose, they use a set of genes termed the sensome. This sensome is comprised of the most abundantly expressed receptors on the surface of microglia. In this study, we updated previously identified mouse microglial sensome by incorporating an additional published RNAseq dataset into the data-analysis pipeline. We also identified members of the human microglial sensome using two independent human microglia RNAseq data sources. Using both the mouse and human microglia sensomes, we identified a key set of genes conserved between the mouse and human microglial sensomes as well as some differences between the species. We found a key set of 57 genes to be conserved in both mouse and human microglial sensomes. We define these genes as the "microglia core sensome". We then analyzed expression of genes in this core sensome in five different datasets from two neurodegenerative disease models at various stages of the diseases and found that, overall, changes in the level of expression of microglial sensome genes are specific to the disease or condition studied. Our results highlight the relevance of data generated in mice for understanding the biology of human microglia, but also stress the importance of species-specific gene sets for the investigation of diseases involving microglia. Defining this microglial specific core sensome may help identify pathological changes in microglia in humans and mouse models of human disease.

Repetitive Traumatic Brain Injury Causes Neuroinflammation before Tau Pathology in Adolescent P301S Mice.

Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.

The ICD-11 classification of gender incongruence of adolescence and adulthood: adequacy among transgender people in Lebanon.

The aim of this study was to evaluate the adequacy of the then proposed International Classification of Diseases version 11 (ICD-11) diagnostic guidelines for Gender Incongruence of Adolescence and Adulthood in a sample of transgender people accessing multi-disciplinary health care services at specialised organisations in Lebanon. The cross-sectional study reported here was part of the ICD-11 field test studies that took place in several countries. Twenty-eight Arab transgender adults residing in Lebanon were recruited after giving consent to participate in a structured interview with a mental health professional. The questions asked of them consisted of the following: socio-demographic data; medical history related to gender identity; experiences of gender incongruence; psychological distress; rejection; violence; and functional impairment. Results showed that Arab transgender individuals living in Lebanon report being the victims of violence, abuse, discrimination and rejection from family, peers and society in general. As a result, they develop psychological distress that is better explained by the social context in which they live, rather than by their transgender identity. Reformulating ICD-10 Transsexualism as Gender Incongruence of Adolescence and Adulthood in ICD-11 and moving this diagnosis out of the chapter on mental disorders chapter would be favourable to the Lebanese sample.