An Assessment of the One-Month Effectiveness of Telehealth Treatment for Opioid Use Disorder Using the Brief Addiction Monitor.

OBJECTIVES: Telehealth treatment with medication for opioid use disorder (teleMOUD) was made possible with regulations following the COVID-19 pandemic that permitted prescribing buprenorphine without an in-person visit. This study evaluates the self-reported outcomes of patients treated by teleMOUD using the Brief Addiction Monitor (BAM), a 17-question tool that assesses drug use, cravings, physical and psychological health, and psychosocial factors to produce 3 subset scores: substance use, risk factors, and protective factors. METHODS: Patients treated by a teleMOUD provider group operating in >30 states were asked to complete an app-based version of BAM at enrollment and at 1 month. Patients who completed both assessments between June 2022 and March 2023 were included. RESULTS: A total of 2556 patients completed an enrollment BAM and 1447 completed both assessments. Mean number of days from baseline BAM to follow-up was 26.7 days. Changes were significantly different across most questions. The substance use subscale decreased from mean 2.6 to 0.8 (P < .001), the risk factors subscale decreased from mean 10.3 to 7.5 (P < .001), and the protective factors subscale increased from mean 14.3 to 15.0. (P < .001). Substance use and risk factor subscale changes were significant across all sex and age groups, while protective factors subscale did not improve for those <25 and >54 years. Patient reports of at least 1 day of illegal use or misuse decreased, including marijuana (28.1% vs 9.0%), cocaine/crack (3.9% vs 2.6%), and opioids (49.8% vs 10.5%). CONCLUSIONS: Among patients treated by teleMOUD who completed assessments at enrollment and 1 month, there was improvement in drug use, risk factor, and protective factor scores.

Treatment of poppy seed tea misuse with buprenorphine in a telehealth practice: a case series.

BACKGROUND: Poppy seed tea (PST) is a legally obtainable source of opiates made from the seeds of the opium poppy. Our large telehealth opioid use disorder (OUD) provider group has treated several patients with PST misuse. METHODS: We retrospectively identified patients with primary PST use disorder treated with buprenorphine in a telehealth-only practice with first visits between January 2021 and December 2022. Patients were identified by having the word "poppy" in their enrollment note, and then charts were reviewed to determine which patients had primary PST misuse. Demographics, buprenorphine doses, and retention in treatment were recorded. RESULTS: We identified 18 patients treated for PST use disorder. Fifteen (83.3%) identified as male, mean age was 40.4 (standard deviation 8.8) years, and patients resided in 10 different U.S. states. Median starting buprenorphine dose was 2 mg (interquartile range (IQR) 2-2.5 mg). Median stabilizing dose of buprenorphine was 16 mg daily (IQR 15-20.5 mg). As of June 2023, 5 patients (27.8%) were still in active treatment. Two patients (11.1%) had completed a planned, elective taper. Ten patients (55.6%) had unplanned discontinuation from treatment, and 3 patients (16.7%) discontinued for other reasons. CONCLUSIONS: To our knowledge, this is the largest case series describing PST misuse in the U.S., and the first to demonstrate its treatment in the telehealth setting. PST use disorder is treatable with buprenorphine with doses similar to treatment of other opioid use disorders. Clinicians who treat patients with OUD should be aware of PST use disorder and its treatment.

Cocaine Exposure Increases Excitatory Synaptic Transmission and Intrinsic Excitability in the Basolateral Amygdala in Male and Female Rats and across the Estrous Cycle.

INTRODUCTION: Sex and ovarian hormones influence cocaine seeking and relapse vulnerability, but less is known regarding the cellular and synaptic mechanisms contributing to these behavioral sex differences. One factor thought to influence cue-induced seeking behavior following withdrawal is cocaine-induced changes in the spontaneous activity of pyramidal neurons in the basolateral amygdala (BLA). However, the mechanisms underlying these changes, including potential sex or estrous cycle effects, are unknown. METHODS: Ex vivo whole-cell patch clamp electrophysiology was conducted to investigate the effects of cocaine exposure, sex, and estrous cycle fluctuations on two properties that can influence spontaneous activity of BLA pyramidal neurons: (1) frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) and (2) intrinsic excitability. Recordings of BLA pyramidal neurons were conducted in adult male and female rats and across the estrous cycle following 2-4 weeks of withdrawal from extended-access cocaine self-administration (6 h/day for 10 days) or drug-naïve conditions. RESULTS: In both sexes, cocaine exposure increased the frequency, but not amplitude, of sEPSCs and neuronal intrinsic excitability. Across the estrous cycle, sEPSC frequency and intrinsic excitability were significantly elevated only in cocaine-exposed females in the estrus stage of the cycle, a stage when cocaine-seeking behavior is known to be enhanced. CONCLUSIONS: Here, we identify potential mechanisms underlying cocaine-induced alterations in the spontaneous activity of BLA pyramidal neurons in both sexes along with changes in these properties across the estrous cycle.

mGlu5 inhibition in the basolateral amygdala prevents estrous cycle-dependent changes in cue-induced cocaine seeking.

Drug associated cues are a common relapse trigger for individuals recovering from cocaine use disorder. Sex and ovarian hormones influence patterns of cocaine use and relapse vulnerability, with studies indicating that females show increased cue-induced craving and relapse vulnerability compared to males. In a rodent model of cocaine craving and relapse vulnerability, cue-induced cocaine seeking behavior following weeks of withdrawal from extended-access cocaine self-administration is higher in females in the estrus stage of the reproductive (estrous) cycle (Estrus Females) compared to both Males and females in all other stages (Non-Estrus Females). However, the neuronal substrates and cellular mechanisms underlying these sex differences is not fully understood. One region that contributes to both sex differences in behavioral responding and cue-induced cocaine seeking is the basolateral amygdala (BLA), while one receptor known to play a critical role in mediating cocaine seeking behavior is metabotropic glutamate receptor 5 (mGlu5). Here we assessed the effects of BLA mGlu5 inhibition following prolonged withdrawal from cocaine self-administration on observed estrous cycle-dependent changes in cue-induced cocaine seeking behavior. We found that BLA microinjections of the mGlu5 antagonist MTEP selectively reduced the enhanced cue-induced cocaine seeking normally observed in Estrus Females while having no effect on cocaine seeking in Males and Non-Estrus Females. These findings identify a unique interaction between cocaine-exposure, estrous cycle fluctuations and BLA mGlu5-dependent transmission on cue-induced cocaine seeking behavior.

GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models.

For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.

The GPR171 pathway suppresses T cell activation and limits antitumor immunity.

The recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.

Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy.

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.

Alcohol-control public service announcements (PSAs) and drunk-driving fatal accidents in the United States, 1996-2010.

Widespread concern regarding the detrimental effects of excessive alcohol consumption (especially by minors) and associated social problems (particularly drunk driving) continues to exist among policymakers, law enforcement officers, and the general public. Alcohol consumption is a leading contributor to death from injuries, which itself is one of the main causes of death for people under 21years of age in the United States. This study examines the relationship between the volume and timing of alcohol-control public service announcements (PSAs) and rates of drunk-driving fatal accidents in the U.S. We estimate ordinary least squares (OLS) regression models to predict rates of drunk-driving fatal accidents by state and month as a function of the volume of alcohol-control PSAs aired during the previous 8months. Models include controls for state anti-drunk-driving laws and regulations, state demographic characteristics, state taxes on alcohol, calendar year, and seasonality. Results indicate that higher volumes of anti-drunk driving PSAs airing in the preceding 2 to 3months are associated, albeit modest in magnitude, with reduced rates of drunk-driving fatal accidents. The regression coefficients are largest for adults (relative to underage drunk drivers) and when the PSAs air during prime time (relative to daytime or nighttime). We conclude that PSAs could play an important contributing role in reducing drunk-driving fatal accidents, although levels of exposure and potential effects likely remain modest due to reliance on donated air time. Well-funded anti-drunk driving campaigns could achieve higher levels of exposure and have a larger impact.

Microsphere lithography on hydrophobic surfaces for generating gold films that exhibit infrared localized surface plasmon resonances.

Evaporation induced self-assembly is an established method for producing close-packed two-dimensional sphere masks on hydrophilic surfaces such as glass. In sphere lithography, gold or silver is deposited over sphere masks to generate a film-over-nanospheres or a nanoprism array that can be used as a sensing surface in localized surface plasmon extinction and surface enhanced Raman spectroscopy experiments. Sphere lithography is less commonly used to prepare sphere masks on hydrophobic surfaces associated with infrared window materials, in part because it is challenging to find solvents with wetting and evaporation characteristics that are appropriate for such surfaces. This wetting challenge can be overcome with appropriate surfactants. However, surfactant residues are then left behind on the sensing surface. We report methods for depositing monolayer crystalline sphere masks onto CaF2 windows that minimize surfactant residue by either using ethanol as a volatile cosolvent that enhances wetting, or by increasing the concentration of colloid to compensate for the reduced attractions between spheres and surface. The rate of evaporation of solvents from the colloid drop is controlled by fixing the headspace partial pressure of ethanol and/or water.