On-Chip Electrochemical Sensing with an Enhanced Detecting Signal Due to Concentration Polarization-Based Analyte Preconcentration.

Here, we integrated two key technologies within a microfluidic system, an electrokinetic preconcentration of analytes by ion Concentration Polarization (CP) and local electrochemical sensors to detect the analytes, which can synergistically act to significantly enhance the detection signal. This synergistic combination, offering both decoupled and coupled operation modes for continuous monitoring, was validated by the intensified fluorescent intensities of CP-preconcentrated analytes and the associated enhanced electrochemical response using differential pulse voltammetry and chronoamperometry. The system performance was evaluated by varying the location of the active electrochemical sensor, target analyte concentrations, and electrolyte concentration using fluorescein molecules as the model analyte and Homovanillic acid (HVA) as the target bioanalyte within both phosphate-buffered saline (PBS) and artificial sweat solution. The combination of on-chip electrochemical sensing with CP-based preconcentration renders this generic approach adaptable to various analytes. This advanced system shows remarkable promise for enhancing biosensing detection in practical applications while bridging the gap between fundamental research and practical implementation.

A Preclinical Blinded Randomized-Controlled Trial Evaluating the Clinical Relevance of Polyp Size Measurement Using a Virtual Scale Endoscope.

Background: The virtual scale endoscope (VSE) helps endoscopists measure colorectal polyp size more accurately compared to visual assessment (VA). However, previous studies were not adequately powered to evaluate the sizing of polyps at clinically relevant size thresholds and relative accuracy for size subgroups. Methods: We created 64 artificial polyps of varied sizes and Paris class morphology, randomly assigned 1:1 to be measured (383 total measurement datapoints with VSE and VA by 6 endoscopists blinded to true size) in a colon model. We added data from two previous trials (480 measurement datapoints). We evaluated for correct classification of polyps into size groups at 3 mm, 5 mm, 10 mm, and 20 mm size thresholds and the relative size measurement accuracy for diminutive polyps (≤5 mm), small polyps (5-9 mm), large polyps at 10-19 mm, and polyps (≥20). Results: VSE had significantly less size group misclassifications at the 5 mm, and 10 mm thresholds (28 percent vs. 45 percent, P = 0.0159 and 26 percent vs. 44 percent, P = 0.0135, respectively). For the 3 mm and 20 mm thresholds, VSE had lower misclassifications; however, this was not statistically significant (36 percent vs. 46 percent, P = 0.3853 and 38 percent vs. 41 percent, P = 0.2705, respectively). The relative size measurement accuracy was significantly higher for VSE compared to VA for all size subgroups (diminutive (P < 0.01), small polyps (P < 0.01), 10-19 mm (P < 0.01), and ≥20 mm (P < 0.01)). Conclusion: VSE outperforms VA in categorizing polyps into size groups at the clinically relevant size thresholds of 5 mm and 10 mm. Using VSE resulted in significantly higher relative measurement accuracy for all size subgroups.

Medical Trainees' Knowledge and Attitudes Towards Electronic Cigarettes and Hookah: A Multinational Survey Study.

BACKGROUND: The rising prevalence of electronic cigarette (e-cigarette) and hookah use among youth raises questions about medical trainees' views of these products. We aimed to investigate medical trainees' knowledge and attitudes toward e-cigarette and hookah use. METHODS: We used data from a large cross-sectional survey of medical trainees in Brazil, the United States, and India. We investigated demographic and mental health aspects, history of e-cigarettes and tobacco use, knowledge and attitudes toward e-cigarettes and hookah, and sources of information on e-cigarettes and hookah. Although all medical trainees were eligible for the original study, only senior students and physicians-in-training were included in the present analysis. RESULTS: Of 2,036 senior students and physicians-in-training, 27.4% believed e-cigarette use to be less harmful than tobacco smoking. As for hookah use, 14.9% believed it posed a lower risk than cigarettes. More than a third of trainees did not acknowledge the risks of passive e-cigarette use (42.9%) or hookah smoking (35.1%). Also, 32.4% endorsed e-cigarettes to quit smoking, whereas 22.5% felt ill equipped to discuss these tobacco products with patients. Fewer than half recalled attending lectures on these topics, and their most common sources of information were social media (54.5%), Google (40.8%), and friends and relatives (40.3%). CONCLUSIONS: Medical trainees often reported incorrect or biased perceptions of e-cigarettes and hookah, resorted to unreliable sources of information, and lacked the confidence to discuss the topic with patients. An expanded curriculum emphasis on e-cigarette and hookah use might be necessary because failing to address these educational gaps could risk years of efforts against smoking normalization.

Solriamfetol for Attention-Deficit/Hyperactivity Disorder in Adults: A Double-Blind Placebo-Controlled Pilot Study.

Objective: Some individuals with attention-deficit/hyperactivity disorder (ADHD) may not tolerate or adequately respond to currently available treatments. This study examined whether solriamfetol could have a favorable pattern of effects and tolerability as a treatment for ADHD in adults.Methods: Sixty adults with DSM-5 ADHD participated from August 2021 through January 2023 in a remotely conducted, randomized, double-blind, placebo-controlled, 6-week dose-optimization trial of 75 mg or 150 mg of solriamfetol. Measures included the Adult ADHD Investigator Symptom Rating Scale (AISRS), which was our primary outcome measure, as well as the Clinical Global Impressions scale (CGI), vital signs, the Global Assessment of Functioning (GAF), the Behavior Rating Inventory of Executive Function-Adult Form (BRIEF-A), the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), and a modified Adult ADHD Self-Report Scale (MASRS).Results: Solriamfetol was well tolerated, with no significant effect on mean heart rate (+3.7 vs +2.2 bpm, P = .5609), systolic blood pressure (+2.4 vs +1.5 mm Hg, P = .6474), or diastolic blood pressure (+1.1 vs +1.5 mm Hg, P = .8117). There was no statistically significant treatment effect on occurrence of adverse events. Compared to individuals on placebo, individuals on solriamfetol treatment experienced adverse events at a rate of at least 10 percentage points higher in the categories of decreased appetite, headache, gastrointestinal, insomnia, increased energy, cardiovascular, and neurologic. Compared to individuals on placebo, by study endpoint, a greater proportion of individuals in the treatment group met the a priori-defined treatment response (CGI score indicating much or very much improved and AISRS score reduced ≥ 25%: 45% vs 6.9%, P = .0020); those treated with solriamfetol also had greater improvement in total AISRS scores by week 3 through week 6 (P = .0012; week 6 effect size = 1.09). Significantly more solriamfetol-treated adults than placebo-treated adults had 0.5-standard deviation improvement in T-score on the BRIEF-A Global Executive Composite (P = .0173); those treated with solriamfetol also had greater mean change in GAF score (-4.8 vs -0.3, P = .0006) and greater mean MASRS total score change (P = .0047; effect size = 1.23). Mean ESS score improved more with solriamfetol than with placebo (P = .0056), but this difference did not predict AISRS response (P = .3735). There was no significant association between solriamfetol and change in PSQI scores.Conclusions: Solriamfetol may be a novel and effective treatment for the management of ADHD in adults. Further replication in larger trials is indicated.Trial Registration: ClinicalTrials.gov identifier: NCT04839562.

Vaping and Hookah Use Among Medical Trainees: A Multinational Survey Study.

The increased use of E-cigarettes and hookah among young consumers represents a public health concern. This study aimed to investigate the frequency and patterns of use of E-cigarettes and hookah among medical trainees. This cross-sectional multinational online survey included medical students, residents, and fellows in Brazil, the U.S., and India between October 2020 and November 2021. Information on sociodemographics; mental health; and E-cigarettes, hookah, tobacco, marijuana, and alcohol use were collected. Generalized structural equation models were used in 2022 to explore the factors associated with current vaping and current hookah use (ongoing monthly/weekly/daily use). People reporting previous sporadic/frequent use or those who never used/only tried it once were the reference group. Overall, 7,526 participants were recruited (Brazil=3,093; U.S.=3,067; India=1,366). The frequency of current vaping was 20% (Brazil), 11% (U.S.), and <1% (India), and current hookah use was 10% (Brazil), 6% (U.S.), and 1% (India). Higher family income (OR=6.35, 95% CI=4.42, 9.12), smoking cigarettes (OR=5.88, 95% CI=4.88, 7.09) and marijuana (OR=2.8, 95% CI=2.35, 3.34), and binge drinking (OR=3.03, 95% CI=2.56, 3.59) were associated with current vaping. The same was true for hookah use: higher family income (OR=2.69, 95% CI=1.75, 4.14), smoking cigarettes (OR=3.20, 95% CI=2.53, 4.06), smoking marijuana (OR=4.17, 95% CI=3.35, 4.19), and binge drinking (OR=2.42, 95% CI=1.96, 2.99). In conclusion, E-cigarettes and hookah were frequently used by Brazilian and American trainees, sharply contrasting with data from India. Cultural aspects and public health policies may explain the differences among countries. Addressing the problems of hookah and E-cigarette smoking in this population is relevant to avoid the renormalization of smoking.

The GABA and GABA-Receptor System in Inflammation, Anti-Tumor Immune Responses, and COVID-19.

GABA and GABAA-receptors (GABAA-Rs) play major roles in neurodevelopment and neurotransmission in the central nervous system (CNS). There has been a growing appreciation that GABAA-Rs are also present on most immune cells. Studies in the fields of autoimmune disease, cancer, parasitology, and virology have observed that GABA-R ligands have anti-inflammatory actions on T cells and antigen-presenting cells (APCs), while also enhancing regulatory T cell (Treg) responses and shifting APCs toward anti-inflammatory phenotypes. These actions have enabled GABAA-R ligands to ameliorate autoimmune diseases, such as type 1 diabetes (T1D), multiple sclerosis (MS), and rheumatoid arthritis, as well as type 2 diabetes (T2D)-associated inflammation in preclinical models. Conversely, antagonism of GABAA-R activity promotes the pro-inflammatory responses of T cells and APCs, enhancing anti-tumor responses and reducing tumor burden in models of solid tumors. Lung epithelial cells also express GABA-Rs, whose activation helps maintain fluid homeostasis and promote recovery from injury. The ability of GABAA-R agonists to limit both excessive immune responses and lung epithelial cell injury may underlie recent findings that GABAA-R agonists reduce the severity of disease in mice infected with highly lethal coronaviruses (SARS-CoV-2 and MHV-1). These observations suggest that GABAA-R agonists may provide off-the-shelf therapies for COVID-19 caused by new SARS-CoV-2 variants, as well as novel beta-coronaviruses, which evade vaccine-induced immune responses and antiviral medications. We review these findings and further advance the notions that (1) immune cells possess GABAA-Rs to limit inflammation in the CNS, and (2) this natural "braking system" on inflammatory responses may be pharmacologically engaged to slow the progression of autoimmune diseases, reduce the severity of COVID-19, and perhaps limit neuroinflammation associated with long COVID.

Examination of methadone involved overdoses during the COVID-19 pandemic.

BACKGROUND: The US opioid overdose epidemic continues to escalate. The restrictions on methadone availability including take-home dosing were loosened during the COVID-19 pandemic although there have been concerns about the high street value of diverted methadone. This report examined how fatal overdoses involving methadone have changed over the past two-decades including during the pandemic. METHODS: The CDC's Wide-ranging Online Data for Epidemiologic Research (WONDER) was used to find the unintentional methadone related overdose death rate from 1999 to 2020. Unintentional methadone deaths were defined using the ICD X40-44 codes with only data for methadone (T40.3). Data from the DEA's Automation of Reports and Consolidated Orders System (ARCOS) on methadone overall use, opioid treatment programs use, and pain management use was gathered for all states for 2020 and corrected for population. RESULTS: There have been dynamic changes over the past two-decades in methadone overdoses. Overdoses increased from 1999 (0.9/million) to 2007 (15.9) and declined until 2019 (6.5). Overdoses in 2020 (9.6) were 48.1% higher than in 2019 (t(50) = 3.05, p < .005). The state level correlations between overall methadone use (r(49) = +0.75, p < .001), and opioid treatment program use (r(49) = +0.77, p < .001) with overdoses were positive, strong, and statistically significant. However, methadone use for pain treatment was not associated with methadone overdoses (r(49) = -0.08). CONCLUSIONS: Overdoses involving methadone significantly increased by 48.1% in 2020 relative to 2019. Policy changes that were implemented following the COVID-19 pandemic involving methadone take-homes may warrant further study before they are made permanent.

A GABA-receptor agonist reduces pneumonitis severity, viral load, and death rate in SARS-CoV-2-infected mice.

Gamma-aminobutyric acid (GABA) and GABA-receptors (GABA-Rs) form a major neurotransmitter system in the brain. GABA-Rs are also expressed by 1) cells of the innate and adaptive immune system and act to inhibit their inflammatory activities, and 2) lung epithelial cells and GABA-R agonists/potentiators have been observed to limit acute lung injuries. These biological properties suggest that GABA-R agonists may have potential for treating COVID-19. We previously reported that GABA-R agonist treatments protected mice from severe disease induced by infection with a lethal mouse coronavirus (MHV-1). Because MHV-1 targets different cellular receptors and is biologically distinct from SARS-CoV-2, we sought to test GABA therapy in K18-hACE2 mice which develop severe pneumonitis with high lethality following SARS-CoV-2 infection. We observed that GABA treatment initiated immediately after SARS-CoV-2 infection, or 2 days later near the peak of lung viral load, reduced pneumonitis severity and death rates in K18-hACE2 mice. GABA-treated mice had reduced lung viral loads and displayed shifts in their serum cytokine/chemokine levels that are associated with better outcomes in COVID-19 patients. Thus, GABA-R activation had multiple effects that are also desirable for the treatment of COVID-19. The protective effects of GABA against two very different beta coronaviruses (SARS-CoV-2 and MHV-1) suggest that it may provide a generalizable off-the-shelf therapy to help treat diseases induced by new SARS-CoV-2 variants and novel coronaviruses that evade immune responses and antiviral medications. GABA is inexpensive, safe for human use, and stable at room temperature, making it an attractive candidate for testing in clinical trials. We also discuss the potential of GABA-R agonists for limiting COVID-19-associated neuroinflammation.

Perspective and practice patterns of mediastinal staging among thoracic surgeons.

Background: Accurate mediastinal staging of lung cancer patients is critical for determining appropriate treatment. Mediastinoscopy and endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration are the most commonly utilized techniques. Limited data exist on training and practice trends among thoracic surgeons. We aimed to determine training and practice patterns and find whether there is a paradigm shift in mediastinal staging after the introduction of EBUS into practice among thoracic surgeons in the United States. Methods: 28-question survey was constructed querying demographic, training, and practice patterns with mediastinoscopy and EBUS and was sent to practicing thoracic surgeons in the United States. Descriptive statistics were used to summarize quantitative data. Results: Ninety-eight responded with a 93% completion rate. Eighty-seven percent of respondents received training in EBUS and 70% perform EBUS routinely. All respondents believe EBUS should be incorporated into thoracic surgery training curriculums. Majority of those who prefer EBUS feel EBUS is safer than mediastinoscopy, allows access to lymph nodes stations or lesions inaccessible by mediastinoscopy and prefer EBUS to avoid re-do mediastinoscopy and in irradiated mediastinum. Majority of those who prefer mediastinoscopy reported they perform more accurate staging compared to EBUS, that mediastinoscopy is more accurate in diagnosing lymphoma or sarcoidosis and that frozen section can be done at the same interval as resection. Among surgeons who prefer EBUS, 94% biopsy 3 or more lymph node stations, 86% routinely biopsy hilar (N1) nodes while 8% never biopsy N1 nodes. Of surgeons who prefer mediastinoscopy. Ninety-seven percent biopsy 3 or more lymph node stations, only 27% routinely biopsy N1 nodes and 70% never biopsy N1 nodes. Conclusions: EBUS is used frequently by thoracic surgeons in their practice for mediastinal staging. Methods of obtaining proficiency in EBUS widely varied among surgeons. In addition to mediastinoscopy, dedicated EBUS training should be incorporated into thoracic surgery training curriculums.

Designing Personalized Antigen-Specific Immunotherapies for Autoimmune Diseases-The Case for Using Ignored Target Cell Antigen Determinants.

We have proposed that antigen-specific immunotherapies (ASIs) for autoimmune diseases could be enhanced by administering target cell antigen epitopes (determinants) that are immunogenic but ignored by autoreactive T cells because these determinants may have large pools of naïve cognate T cells available for priming towards regulatory responses. Here, we identified an immunogenic preproinsulin determinant (PPIL4-20) that was ignored by autoimmune responses in type 1 diabetes (T1D)-prone NOD mice. The size of the PPIL4-20-specific splenic naive T cell pool gradually increased from 2-12 weeks in age and remained stable thereafter, while that of the major target determinant insulin B-chain9-23 decreased greatly after 12 weeks in age, presumably due to recruitment into the autoimmune response. In 15-16 week old mice, insulin B-chain9-23/alum immunization induced modest-low level of splenic T cell IL-10 and IL-4 responses, little or no spreading of these responses, and boosted IFNγ responses to itself and other autoantigens. In contrast, PPIL4-20/alum treatment induced robust IL-10 and IL-4 responses, which spread to other autoantigens and increased the frequency of splenic IL-10-secreting Treg and Tr-1-like cells, without boosting IFNγ responses to ß-cell autoantigens. In newly diabetic NOD mice, PPIL4-20, but not insulin B-chain9-23 administered intraperitoneally (with alum) or intradermally (as soluble antigen) supplemented with oral GABA induced long-term disease remission. We discuss the potential of personalized ASIs that are based on an individual's naïve autoantigen-reactive T cell pools and the use of HLA-appropriate ignored autoantigen determinants to safely enhance the efficacy of ASIs.

GABA Administration Ameliorates Sjogren's Syndrome in Two Different Mouse Models.

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltrates in the salivary and lachrymal glands resulting in oral and ocular dryness. There are no clinically approved therapies to slow the progression of SS. Immune cells possess receptors for the neurotransmitter GABA (GABA-Rs) and their activation has immunoregulatory actions. We tested whether GABA administration has potential for amelioration of SS in NOD.B10-H2b and C57BL/6.NOD-Aec1Aec2 mice, two spontaneous SS models. Oral GABA treatment was initiated (1) after the development of sialadenitis but before the onset of overt symptoms, or (2) after the appearance of overt symptoms. When assessed weeks later, GABA-treated mice had greater saliva and tear production, as well as quicker times to salvia flow, in both SS mouse models. This was especially evident when GABA treatment was initiated after the onset of overt disease. This preservation of exocrine function was not accompanied by significant changes in the number or area of lymphocytic foci in the salivary or lachrymal glands of GABA-treated mice and we discuss the possible reasons for these observations. Given that GABA-treatment preserved saliva and tear production which are the most salient symptoms of SS and is safe for consumption, it may provide a new approach to help ameliorate SS.

Personalized Remote Mobile Surveys of Adult ADHD Symptoms and Function: A Pilot Study of Usability and Utility for Pharmacology Monitoring.

OBJECTIVE: Validate the usability and treatment-sensitivity of a remote SMS-based ADHD monitoring method. METHOD: 206 adults taking stimulants for ADHD participated. Participants selected ADHD symptoms and functional impairments that they anticipated to be stimulant-sensitive, which were rated via mobile messages up to 20 times over 10 days. RESULTS: A majority of participants found it only somewhat or not at all difficult to identify an ADHD symptom sensitive to presence of stimulant medication, and 79% responded to at least one survey message. As expected, a majority of participants endorsed it was "easy" to participate, and less burdensome than a paper diary. Surveys significantly discriminated between on and off medication states, both between days, and within the same day. CONCLUSION: Our findings suggest SMS-based monitoring of patient-selected ADHD-related challenges is both feasible and sensitive to stimulant treatment. This remote assay method may be a meaningful adjunct to in-visit treatment monitoring.

Lung Chordoma: A Discussion.

Chordomas are rare neoplasms arising from remnants of the notochord. We report a case of a 61-year-old woman who underwent workup for bariatric surgery and was found to have bilateral pulmonary nodules on a computed tomographic scan. Video-assisted thoracoscopic wedge resections were performed, and immunohistochemical stains confirmed the diagnosis of chordoma in all lesions. Much of our current knowledge of chordomas comes from axial and extra-axial, nonpulmonary presentations. Surgery appears to be the best treatment option because these tumors are generally chemoresistant. However, there are limited numbers of case reports of this entity.

Declines and regional variation in opioid distribution by U.S. hospitals.

ABSTRACT: The United States is enduring a preventable opioid crisis, particularly involving a population being treated in a hospital setting, a subset of whom may escalate to illicit opioids. This project analyzed trends in distribution of opioids by hospitals in the United States. Opioids monitored included buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, powdered opium, remifentanil, and tapentadol. The Automation of Reports and Consolidated Orders System (ARCOS) reports on substances controlled by the Drug Enforcement Administration. National data from ARCOS reports 5 and 7 from 2000 to 2019 were used for an observational study on hospital opioid distribution. Morphine milligram equivalents (MMEs) were calculated using oral conversion factors. The MME per person per state was calculated to compare data from the peak year, 2012, with data from 2019. Opioid use peaked in 2012, with a -46.6% decline from 2012 to 2019. Half (25) of the states have seen a decrease of -50% or greater. Of the opioid compounds observed, buprenorphine has seen increased (+122.5%) hospital use from 2012 to 2019. All other opioids have been experiencing a decline (≥50%), particularly hydromorphone (-49.9%), oxymorphone (-57.7%), methadone (-58.7%), morphine (-66.9%), codeine (-67.5%), and meperidine (-77.6%). There was a 6-fold difference in population-corrected use of opioids in 2019 between the lowest (6.8 MME/person in New Jersey) and highest (Alaska = 39.6) states. This study demonstrates the considerable progress made thus far by hospitals in curbing the U.S. opioid crisis.

GABAA-Receptor Agonists Limit Pneumonitis and Death in Murine Coronavirus-Infected Mice.

There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.

Exploring exchange and direct procurement strategies for Natufian food processing tools of el-Wad Terrace, Israel.

We present the results of a detailed geochemical provenance study of 54 Natufian (ca. 15,000-11,700 cal. BP) basalt pestles from the site of el-Wad Terrace (EWT), Israel. It is the first time precise locations from where basalt raw materials were derived are provided. The results indicate that the Natufian hunter-gatherers used multiple sources of basaltic rocks, distributed over a large area surrounding the Sea of Galilee. This area is located at a considerable distance from EWT, ca. 60-120 km away, in a region where contemporaneous Natufian basecamps are few. We consider two possible models that suggest vehicles for the transportation of these artifacts to EWT, namely the exchange obtaining model (EOM) and the direct procurement model (DPM). We argue that these mechanisms are not mutually exclusive and may have operated together. We also suggest that at a time of increasing Natufian territoriality, a large area around the Sea of Galilee remained unclaimed. The paper concludes with a brief discussion of the implications for the two models. In particular, we note that the DPM implies that technological know-how for pestle production was maintained within the EWT community.

Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis.

Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood-brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing-remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.

Opioid Mortality Following Implementation of Medical Cannabis Programs in the United States.

INTRODUCTION: The United States is in the midst of an opioid overdose epidemic. Emerging evidence suggests that medical cannabis (MC) may reduce use of opioids for pain in some individuals, with potential impacts on opioid-related overdose. However, there may be other important differences between states that did, and did not, adopt MC. METHODS: This study evaluated differences following legal MC sales on US opioid-related overdose deaths, corrected for population, from 1999 to 2017 using an interrupted time series. Comparisons by MC status were also made for Medicaid expansion and the Centers for Disease Control death certificate reporting quality (0: