A variant of the Mukai pairing via deformation quantization

We give a new method to prove a formula computing a variant of Caldararu's Mukai pairing \cite{Cal1}. Our method is based on some important results in the area of deformation quantization. In particular, part of the work of Kashiwara and Schapira in \cite{KS} as well as an algebraic index theorem of Bressler, Nest and Tsygan in \cite{BNT},\cite{BNT1} and \cite{BNT2} are used. It is hoped that our method is useful for generalization to settings involving certain singular varieties.Comment: 8 pages. Comments and suggestions welcom

The Züri Can study: Can regulated cannabis sales promote lower-risk cannabis use? Mini-review and study protocol

Background and Aims Recreational use of cannabis is illegal in most countries. Despite this, it is the third most commonly used psychoactive substance worldwide. As a result of this discrepancy, a growing number of countries have begun to reassess their legal approach to cannabis in recent years. While the health risks of cannabis and potential harm reduction measures are increasingly well understood, there are still significant gaps in knowledge about which regulatory and supply models are effective in promoting lower-risk cannabis use. In this paper, we outline the Züri Can study, which implements and evaluates a regulatory framework for cannabis sales in the city of Zurich, Switzerland, between 2023 and 2026. In addition, we illustrate how the study addresses current knowledge gaps to provide further insight into the potential future regulation of cannabis in Switzerland. To embed the study in the present scientific and political context, we first provide a brief overview of the state of knowledge on cannabis-related health risks and means of reducing them, along with lessons learned from other countries that have implemented varying regulatory systems. Design and Measurements 2,100 participants will be able to legally purchase cannabis either at a pharmacy, a cannabis social club, or the municipal drug information center over a three-year period. As part of this observational study, participants will be evaluated regarding their cannabis use habits and motives, their knowledge of lower-risk use, and their mental and physical health, among other parameters. Established harm reduction strategies are implemented as an integral part of the study design. Comments The study will contribute to a better understanding of the impact of different cannabis distribution models on cannabis use patterns and related health outcomes. The results are expected to assist Swiss and international policy makers in developing evidence-based and public health-oriented regulatory frameworks for cannabis

A Covering Method for Detecting Genetic Associations between Rare Variants and Common Phenotypes

Genome wide association (GWA) studies, which test for association between common genetic markers and a disease phenotype, have shown varying degrees of success. While many factors could potentially confound GWA studies, we focus on the possibility that multiple, rare variants (RVs) may act in concert to influence disease etiology. Here, we describe an algorithm for RV analysis, RARECOVER. The algorithm combines a disparate collection of RVs with low effect and modest penetrance. Further, it does not require the rare variants be adjacent in location. Extensive simulations over a range of assumed penetrance and population attributable risk (PAR) values illustrate the power of our approach over other published methods, including the collapsing and weighted-collapsing strategies. To showcase the method, we apply RARECOVER to re-sequencing data from a cohort of 289 individuals at the extremes of Body Mass Index distribution (NCT00263042). Individual samples were re-sequenced at two genes, FAAH and MGLL, known to be involved in endocannabinoid metabolism (187Kbp for 148 obese and 150 controls). The RARECOVER analysis identifies exactly one significantly associated region in each gene, each about 5 Kbp in the upstream regulatory regions. The data suggests that the RVs help disrupt the expression of the two genes, leading to lowered metabolism of the corresponding cannabinoids. Overall, our results point to the power of including RVs in measuring genetic associations.National Science Foundation (U.S.) (grant (IIS-0810905)National Institutes of Health (U.S.) (U19 AG023122-05)National Institutes of Health (U.S.) (R01 MH078151-03)Louis & Harold Price FoundationNational Institutes of Health (U.S.) (N01 MH22005)National Institutes of Health (U.S.) (U01-DA024417-01)National Institutes of Health (U.S.) (P50 MH081755-01)National Institutes of Health (U.S.) (R01 AG030474-02)National Institutes of Health (U.S.) (N01 MH022005)National Institutes of Health (U.S.) (R01 HL089655-02)National Institutes of Health (U.S.) (R01 MH080134-03)National Institutes of Health (U.S.) (U54 CA143906-01)National Institutes of Health (U.S.) (UL1 RR025774-03)Scripps Genomic Medicine ProgramNational Human Genome Research Institute (U.S.) (Grant Number T32 HG002295

Neurometabolic Profile of the Amygdala in Smokers Assessed with ¹H-magnetic Resonance Spectroscopy

Tobacco smoking is one of the main causes of premature death worldwide and quitting success remains low, highlighting the need to understand the neurobiological mechanisms underlying relapse. Preclinical models have shown that the amygdala and glutamate play an important role in nicotine addiction. The aims of this study were to compare glutamate and other metabolites in the amygdala between smokers and controls, and between different smoking states. Furthermore, associations between amygdalar metabolite levels and smoking characteristics were explored. A novel non-water-suppressed proton magnetic resonance spectroscopy protocol was applied to quantify neurometabolites in 28 male smokers (≥15 cigarettes/day) and 21 non-smoking controls, matched in age, education, verbal IQ, and weekly alcohol consumption. Controls were measured once (baseline) and smokers were measured in a baseline state (1–3 h abstinence), during withdrawal (24 h abstinence) and in a satiation state (directly after smoking). Baseline spectroscopy data were compared between groups by independent t-tests or Mann-Whitney-U tests. Smoking state differences were investigated by repeated-measures analyses of variance (ANOVAs). Associations between spectroscopy data and smoking characteristics were explored using Spearman correlations. Good spectral quality, high anatomical specificity (98% mean gray matter) and reliable quantification of most metabolites of interest were achieved in the amygdala. Metabolite levels did not differ between groups, but smokers showed significantly higher glutamine levels at baseline than satiation. Glx levels were negatively associated with pack-years and smoking duration. In summary, this study provides first insights into the neurometabolic profile of the amygdala in smokers with high anatomical specificity. By applying proton magnetic resonance spectroscopy, neurometabolites in smokers during different smoking states and non-smoking controls were quantified reliably. A significant shift in glutamine levels between smoking states was detected, with lower concentrations in satiation than baseline. The negative association between Glx levels and smoking quantity and duration may imply altered glutamate homeostasis with more severe nicotine addiction

Cue-induced cocaine craving enhances psychosocial stress and vice versa in chronic cocaine users

Stress and craving, it has been found, contribute to the development and maintenance of and relapse in cocaine use disorder. Chronic cocaine users (CU), previous research has shown, display altered physiological responses to psychosocial stress and increased vegetative responding to substance-related cues. However, how psychosocial stress and cue-induced craving interact in relation to the CU’s physiological responses remains largely unknown. We thus investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. In a crossed and balanced design, the participants were randomly exposed to a video-based cocaine-cue paradigm and the Trier Social Stress Test (TSST) or vice versa to investigate possible mutually augmenting effects of both stressors on physiological stress responses. Over the course of the experimental procedure, plasma cortisol, ACTH, noradrenaline, subjective stress, and craving were assessed repeatedly. To estimate the responses during the cocaine-cue paradigm and TSST, growth models and discontinuous growth models were used. Overall, though both groups did not differ in their endocrinological responses to the TSST, CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU, but when the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. In CU, cocaine-cues robustly evoked craving but no physiological stress response, while cue-induced craving was intensified after the TSST. Taken together, though CU did not show an altered acute stress response during the TSST, stress and craving together seemed to have mutually augmenting effects on their stress response

Cue-induced cocaine craving enhances psychosocial stress and vice versa in chronic cocaine users.

Stress and craving, it has been found, contribute to the development and maintenance of and relapse in cocaine use disorder. Chronic cocaine users (CU), previous research has shown, display altered physiological responses to psychosocial stress and increased vegetative responding to substance-related cues. However, how psychosocial stress and cue-induced craving interact in relation to the CU's physiological responses remains largely unknown. We thus investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. In a crossed and balanced design, the participants were randomly exposed to a video-based cocaine-cue paradigm and the Trier Social Stress Test (TSST) or vice versa to investigate possible mutually augmenting effects of both stressors on physiological stress responses. Over the course of the experimental procedure, plasma cortisol, ACTH, noradrenaline, subjective stress, and craving were assessed repeatedly. To estimate the responses during the cocaine-cue paradigm and TSST, growth models and discontinuous growth models were used. Overall, though both groups did not differ in their endocrinological responses to the TSST, CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU, but when the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. In CU, cocaine-cues robustly evoked craving but no physiological stress response, while cue-induced craving was intensified after the TSST. Taken together, though CU did not show an altered acute stress response during the TSST, stress and craving together seemed to have mutually augmenting effects on their stress response

Cannabidiol in foods and food supplements : evaluation of health risks and health claims

Background: Cannabidiol (CBD) is a cannabinoid present in the hemp plant (Cannabis sativa L.). Non-medicinal CBD oils with typically 5–40% CBD are advertised for various alleged positive health effects. While such foodstuffs containing cannabinoids are covered by the Novel Food Regulation in the European Union (EU), none of these products have yet been authorized. Nevertheless, they continue to be available on the European market. Methods: The Permanent Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) reviewed the currently available data on adverse and potential beneficial effects of CBD in the dose range relevant for foods. Results: Increased liver enzyme activities were observed in healthy volunteers following administration of 4.3 mg CBD/kg bw/day and higher for 3–4 weeks. As lower doses were not tested, a no observed adverse effect level (NOAEL) could not be derived, and the dose of 4.3 mg/kg bw/day was identified as the lowest observed adverse effect level (LOAEL). Based on the CBD content and dose recommendations of CBD products on the market, the SKLM considered several exposure scenarios and concluded that the LOAEL for liver toxicity may be easily reached, e.g., via consumption of 30 drops of an oil containing 20% CBD, or even exceeded. A critical evaluation of the available data on potential beneficial health effects of CBD in the dose range at or below the LOAEL of 4.3 mg/kg bw/day revealed no scientific evidence that would substantiate health claims, e.g., in relation to physical performance, the cardiovascular, immune, and nervous system, anxiety, relaxation, stress, sleep, pain, or menstrual health. Conclusions: The SKLM concluded that consumption of CBD-containing foods/food supplements may not provide substantiated health benefits and may even pose a health risk to consumers

Self-regulation of the dopaminergic reward circuit in cocaine users with mental imagery and neurofeedback

BACKGROUND: Enhanced drug-related reward sensitivity accompanied by impaired sensitivity to non-drug related rewards in the mesolimbic dopamine system are thought to underlie the broad motivational deficits and dysfunctional decision-making frequently observed in cocaine use disorder (CUD). Effective approaches to modify this imbalance and reinstate non-drug reward responsiveness are urgently needed. Here, we examined whether cocaine users (CU) can use mental imagery of non-drug rewards to self-regulate the ventral tegmental area and substantia nigra (VTA/SN). We expected that obsessive and compulsive thoughts about cocaine consumption would hamper the ability to self-regulate the VTA/SN activity and tested if real-time fMRI (rtfMRI) neurofeedback (NFB) can improve self-regulation of the VTA/SN. METHODS: Twenty-two CU and 28 healthy controls (HC) were asked to voluntarily up-regulate VTA/SN activity with non-drug reward imagery alone, or combined with rtfMRI NFB. RESULTS: On a group level, HC and CU were able to activate the dopaminergic midbrain and other reward regions with reward imagery. In CU, the individual ability to self-regulate the VTA/SN was reduced in those with more severe obsessive-compulsive drug use. NFB enhanced the effect of reward imagery but did not result in transfer effects at the end of the session. CONCLUSION: CU can voluntary activate their reward system with non-drug reward imagery and improve this ability with rtfMRI NFB. Combining mental imagery and rtFMRI NFB has great potential for modifying the maladapted reward sensitivity and reinstating non-drug reward responsiveness. This motivates further work to examine the use of rtfMRI NFB in the treatment of CUD

Psoriasis and Hypertension Severity: Results from a Case-Control Study

BACKGROUND: Epidemiologic studies have provided new insights into the association between psoriasis and cardiovascular diseases. Previous population studies have examined hypertension frequency in psoriasis patients. However, the relationship between severity of hypertension and psoriasis has not been characterized. OBJECTIVE: We sought to investigate whether patients with psoriasis have more difficult-to-manage hypertension compared to non-psoriatic hypertensive patients. APPROACH: We performed a case-control study using the University of California Davis electronic medical records. The cases were defined as patients diagnosed with both psoriasis and hypertension, and controls were defined as patients with hypertension and without psoriasis. In this identified population, 835 cases were matched on age, sex, and body mass index (BMI) to 2418 control patients. KEY RESULTS: Treatment with multiple anti-hypertensives was significantly associated with the presence of psoriasis using univariate (p < 0.0001) and multivariable analysis, after adjusting for diabetes, hyperlipidemia, and race (p < 0.0001). Compared to hypertensive patients without psoriasis, psoriasis patients with hypertension were 5 times more likely to be on a monotherapy antihypertensive regimen (95% CI 3.607.05), 9.5 times more likely to be on dual antihypertensive therapy (95% CI 6.68-13.65), 16.5 times more likely to be on triple antihypertensive regimen (95% CI 11.01-24.84), and 19.9 times more likely to be on quadruple therapy or centrally-acting agent (95% CI 10.58-37.33) in multivariable analysis after adjusting for traditional cardiac risk factors. CONCLUSIONS: Psoriasis patients appear to have more difficult-to-control hypertension compared to non-psoriatic, hypertensive patients

Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics

BACKGROUND: Recently, it has been shown that increasing body mass index (BMI) in asthma is associated with reduced exhaled NO. Our objective in this study was to determine if the BMI-related changes in exhaled NO differ across asthmatics and controls, and to determine if these changes are related to increased airway oxidative stress and systemic levels of leptin and adiponectin. METHODS: Observational study of the association of BMI, leptin, and adiponectin with exhaled nitric oxide (NO) and exhaled 8-isoprostanes in 67 non-smoking patients with moderate to severe persistent asthma during baseline conditions and 47 controls. Measurements included plasma levels of leptin, adiponectin, exhaled breath condensates for 8-isoprostanes, exhaled NO, pulmonary function tests, and questionnaires regarding asthma severity and control. RESULTS: In asthmatics, BMI and the ratio of leptin to adiponectin were respectively associated with reduced levels of exhaled NO (β = -0.04 [95% C.I. -0.07, -0.1], p < 0.003) and (β = -0.0018 [95% C.I. -0.003, -0.00034], p = 0.01) after adjusting for confounders. Also, BMI was associated with increased levels of exhaled 8-isoprostanes (β = 0.30 [95% C.I. 0.003, 0.6], p = 0.03) after adjusting for confounders. In contrast, we did not observe these associations in the control group of healthy non-asthmatics with a similar weight distribution. CONCLUSION: In adults with stable moderate to severe persistent asthma, but not in controls, BMI and the plasma ratio of leptin/adiponectin is associated with reduced exhaled NO. Also, BMI is associated with increased exhaled 8-isoprostanes. These results suggest that BMI in asthmatics may increase airway oxidative stress and could explain the BMI-related reductions in exhaled NO