Project description:Background and aimsDrug checking services provide people who use drugs with chemical analysis results of their drug samples while simultaneously monitoring the unregulated drug market. We sought to identify and synthesize literature on the following domains: (a) the influence of drug checking services on the behaviour of people who use drugs; (b) monitoring of drug markets by drug checking services; and (c) outcomes related to models of drug checking services.MethodsSystematic review. A systematic literature search was conducted in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PsycINFO, Scopus, Web of Science and Dissertations and Theses Global. Eligible studies were peer-reviewed articles and conference abstracts or grey literature, published in any language since 1990 and including original data on the domains. We assessed risk of bias for quantitative peer-reviewed articles reporting on behaviour or models of drug checking services using National Institutes of Health tools.ResultsWe screened 2463 titles and abstracts and 156 full texts, with 90 studies meeting inclusion criteria. Most (n = 65, 72.2%) were from Europe and used cross-sectional designs (n = 79, 87.7%). Monitoring of drug markets by drug checking services (n = 63, 70%) was the most reported domain, followed by the influence of drug checking services on behaviour (n = 31, 34.4%), including intent to use, actual use and disposal of the drug, and outcomes related to models of drug checking services (n = 17, 18.9%). The most common outcome measures were detection of unexpected substances (n = 50, 55.6%), expected substances (n = 44, 48.9%), new psychoactive substances (n = 40, 44.4%) and drugs of concern (n = 32, 36.5%) by drug checking services.ConclusionsDrug checking services appear to influence behavioural intentions and the behaviour of people who use drugs, particularly when results from drug checking services are unexpected or drugs of concern. Monitoring of drug markets by drug checking services is well established in Europe, and increasingly in North America. Concerns about drug contents and negative health consequences facilitate the use of drug checking services; lack of concern; trust in drug sellers; lack of accessibility of drug checking services; and legal and privacy concerns are barriers to use.
Project description:In patients with diabetes, where cardiovascular morbidity is highly prevalent, recent cardiovascular outcomes trials have identified therapies in the modern glucagon-like peptide 1 receptor agonist (GLP-1RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) classes that significantly reduce cardiovascular events. A number of drugs in both classes have demonstrated reductions in the risk of the composite outcome of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death). In addition, SGLT2i drugs have a substantial impact on hospitalization for heart failure. Because GLP-1RA and SGLT2i are effective in reducing cardiovascular events, independent of their effects on blood glucose, cardiologists should be familiar with how to use them. This review outlines the evidence of cardiovascular benefit for current GLP-1RA and SGLT2i drugs, practical information for prescribing them, and putative mechanisms, so that these therapies can be incorporated along with antihypertensives, statins, and antiplatelet therapies into the routine care of patients.
Project description:BackgroundIn North America, overdose rates have steeply risen over the past five years, largely due to the ubiquity of illicitly manufactured fentanyls in the drug supply. Drug checking services (DCS) represent a promising harm reduction strategy and characterizing experiences of use and interest among people who inject drugs (PWID) is a priority.MethodsBetween February-October 2022, PWID participating in a cohort study in San Diego, CA and Tijuana, Mexico completed structured surveys including questions about DCS, socio-demographics and substance use behaviors. We used Poisson regression to assess factors associated with lifetime DCS use and characterized experiences with DCS and interest in free access to DCS.ResultsOf 426 PWID, 72% were male, 59% Latinx, 79% were experiencing homelessness and 56% ever experienced a nonfatal overdose. One third had heard of DCS, of whom 57% had ever used them. Among the latter, most (98%) reported using fentanyl test strips (FTS) the last time they used DCS; 66% did so less than once per month. In the last six months, respondents used FTS to check methamphetamine (48%), heroin (30%) or fentanyl (29%). Relative to White/non-Latinx PWID, those who were non-White/Latinx were significantly less likely to have used DCS [adjusted risk ratio (aRR): 0.22; 95% CI: 0.10, 0.47), as were PWID experiencing homelessness (aRR:0.45; 95% CI: 0.28, 0.72). However, a significant interaction indicated that non-White/Latinx syringe service program (SSP) clients were more likely to have used DCS than non-SSP clients (aRR: 2.79; CI: 1.09, 7.2). Among all PWID, 44% expressed interest in free access to FTS, while 84% (of 196 PWID) expressed interest in advanced spectrometry DCS to identify and quantify multiple substances.ConclusionsOur findings highlight low rates of DCS awareness and utilization, inequities by race/ethnicity and housing situation, high interest in advanced spectrometry DCS versus FTS, and the potential role of SSPs in improving access to DCS, especially among racial/ethnic minorities.
Project description:Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis.
Project description:Addiction prioritizes drug use over innate needs by "hijacking" brain circuits that direct motivation, but how this develops remains unclear. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we find that drugs of abuse augment ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell-type-specific manner. Combining "FOS-Seq", CRISPR-perturbations, and snRNA-seq, we identify Rheb as a shared molecular substrate that regulates cell-type-specific signal transductions in NAc while enabling drugs to suppress natural reward responses. Retrograde circuit mapping pinpoints orbitofrontal cortex which, upon activation, mirrors drug effects on innate needs. These findings deconstruct the dynamic, molecular, and circuit basis of a common reward circuit, wherein drug value is scaled to promote drug-seeking over other, normative goals.
Project description:Neural networks (NN) are taking over ever more decisions thus far taken by humans, even though verifiable system-level guarantees are far out of reach. Neither is the verification technology available, nor is it even understood what a formal, meaningful, extensible, and scalable testbed might look like for such a technology. The present paper is a modest attempt to improve on both the above aspects. We present a family of formal models that contain basic features of automated decision making contexts and which can be extended with further orthogonal features, ultimately encompassing the scope of autonomous driving. Due to the possibility to model random noise in the decision actuation, each model instance induces a Markov decision process (MDP) as verification object. The NN in this context has the duty to actuate (near-optimal) decisions. From the verification perspective, the externally learnt NN serves as a determinizer of the MDP, the result being a Markov chain which as such is amenable to statistical model checking. The combination of a MDP and a NN encoding the action policy is central to what we call “deep statistical model checking” (DSMC). While being a straightforward extension of statistical model checking, it enables to gain deep insight into questions like “how high is the NN-induced safety risk?”, “how good is the NN compared to the optimal policy?” (obtained by model checking the MDP), or “does further training improve the NN?”. We report on an implementation of DSMC inside TheModestToolset in combination with externally learnt NNs, demonstrating the potential of DSMC on various instances of the model family.
Project description:Approximately half a million people are thought to develop multidrug-resistant tuberculosis annually. Barely 20% of these people currently receive recommended treatment and only about 10% are successfully treated. Poor access to treatment is probably driving the current epidemic, via ongoing transmission. Treatment scale-up is hampered by current treatment regimens, which are lengthy, expensive, poorly tolerated and difficult to administer in the settings where most patients reside. Although new drugs provide an opportunity to improve treatment regimens, current and planned clinical trials hold little promise for developing regimens that will facilitate prompt treatment scale-up. In this article we argue that clinical trials, while necessary, should be complemented by timely, large-scale, operational research that will provide programmatic data on the use of new drugs and regimens while simultaneously improving access to life-saving treatment. Perceived risks - such as the rapid development of resistance to new drugs - need to be balanced against the high levels of mortality and transmission that will otherwise persist. Doubling access to treatment and increasing treatment success could save approximately a million lives over the next decade.
Project description:Decreased light transmittance through the ocular lens, termed cataract, is a leading cause of low vision and blindness worldwide. Cataract causes significantly decreased quality of life, particularly in the elderly. Environmental risk factors, including aging, UV exposure, diabetes, smoking and some prescription drugs, are all contributors to cataract formation. In particular, drug-induced cataract represents a poorly-addressed source of cataract. To better understand the potential impact of prescription drugs on cataract, we analyzed publicly-available drug prescriptions data from the Australian Pharmaceutical Benefits Scheme. The data was analyzed for the 5-year period from July 2014 to June 2019. Analyses included the number of prescriptions for each drug, as well as the associated government and total prescription costs. The drugs chosen for analysis belonged to any of four broad categories-those with known, probable, possible or uncertain association with cataract in patients. The analyses revealed high prescription rates and costs for drugs in the Known category (e.g., steroids) and Possible category (e.g., psychotropic drugs). Collectively, these data provide valuable insights into specific prescription drugs that likely contribute to the increasing annual burden of new cataract cases. These data highlight the need-as well as new, stem cell-based opportunities-to elucidate molecular mechanisms of drug-induced cataract formation.