Trends in recurrent overdose and treatment initiation following emergency department visits for opioid overdose between 2016 and 2021.

BACKGROUND: Overdose remains a pressing public health concern in the United States, particularly with the emergence of fentanyl and other potent synthetic opioids in the drug supply. We evaluated trends in recurrent overdose and opioid use disorder (OUD) treatment initiation following emergency department (ED) visits for opioid overdose to inform response efforts. METHODS: This retrospective cohort study used electronic health record and statewide administrative data from Rhode Island residents who visited EDs for opioid overdose between July 1, 2016, and June 30, 2021, a period with fentanyl predominance in the local drug supply. The primary outcome was recurrent overdose in the 365 days following the initial ED visit. OUD treatment initiation within 180 days following the initial ED visit was considered as a secondary outcome. Trends in study outcomes were summarized by year of the initial ED visit. RESULTS: Among 1745 patients attending EDs for opioid overdose, 20 % (n=352) experienced a recurrent overdose within 365 days, and this percentage was similar by year (p=0.12). Among patients who experienced any recurrent overdose, the median time to first recurrent overdose was 88 days (interquartile range=23-208), with 85 % (n=299/352) being non-fatal. Among patients not engaged in OUD treatment at their initial ED visit, 33 % (n=448/1370) initiated treatment within 180 days; this was similar by year (p=0.98). CONCLUSIONS: Following ED visits for opioid overdose in Rhode Island from 2016-2021, the one-year risk of recurrent overdose and six-month treatment initiation rate remained stable over time. Innovative prevention strategies and improved treatment access are needed.

Diversity and evolution of nitric oxide reduction in bacteria and archaea.

Nitrous oxide is a potent greenhouse gas whose production is catalyzed by nitric oxide reductase (NOR) members of the heme-copper oxidoreductase (HCO) enzyme superfamily. We identified several previously uncharacterized HCO families, four of which (eNOR, sNOR, gNOR, and nNOR) appear to perform NO reduction. These families have novel active-site structures and several have conserved proton channels, suggesting that they might be able to couple NO reduction to energy conservation. We isolated and biochemically characterized a member of the eNOR family from the bacterium Rhodothermus marinus and found that it performs NO reduction. These recently identified NORs exhibited broad phylogenetic and environmental distributions, greatly expanding the diversity of microbes in nature capable of NO reduction. Phylogenetic analyses further demonstrated that NORs evolved multiple times independently from oxygen reductases, supporting the view that complete denitrification evolved after aerobic respiration.

Distraction Osteogenesis for Frontosphenoidal Craniosynostosis: a Novel Surgical Treatment Modality of a Rare Suture Fusion.

Frontosphenoidal craniosynostosis (FSC) is a rare premature fusion of the frontosphenoidal suture that results in anterior plagiocephaly. When associated with severe cranial deformity, surgical treatment is beneficial. All previously reported cases of FSC correction have utilized fronto-orbital remodeling and advancement to achieve improved anatomy and increased intracranial volume. For patients with isolated synostosis deformities, we believe that distraction osteogenesis can be a viable option, with the additional benefit of quicker operating time, shorter hospital stays, and less irregularity in final head contour. This case illustrates the feasibility of using distraction osteogenesis in the management of FSC.

Epidemiology of Injuries Among National Basketball Association Players: 2013-2014 Through 2018-2019.

BACKGROUND: Understanding the epidemiology of injuries to athletes is essential to informing injury prevention efforts. HYPOTHESIS: The incidence and impact of basketball-related injuries among National Basketball Association (NBA) players from 2013-2014 through 2018-2019 is relatively stable over time. STUDY DESIGN: Descriptive epidemiology study. LEVEL OF EVIDENCE: Level 3. METHODS: Injuries from 2013-2014 through 2018-2019 were analyzed using the NBA Injury and Illness Database from an electronic medical record system. Descriptive statistics were calculated for injuries by season, game-loss, and onset. Incidence rates were estimated using Poisson models and linear trend tests. RESULTS: Between 552 and 606 players participated in ≥1 game per season during the study. Annual injury incidence ranged from 1550 to 1892, with 33.6% to 38.5% resulting in a missed NBA game. Game-loss injury rates ranged from 5.6 to 7.0 injuries per 10,000 player-minutes from 2014-2015 through 2018-2019 (P = 0.19); the rate was lower in 2013-2014 (5.0 injuries per 10,000 player-minutes), partly due to increased preseason injury rates and transition of reporting processes. The 6-year game-loss injury rate in preseason and regular season games was 6.9 (95% CI 6.0, 8.0) and 6.2 (95% CI 6.0, 6.5) injuries per 10,000 player-minutes; the rate in playoff games was lower (P < 0.01) at 2.8 (95% CI 2.2, 3.6). Most (73%) game-loss injuries had acute onset; 44.4% to 52.5% of these involved contact with another player. CONCLUSION: From 2013-2014 through 2018-2019, over one-third of injuries resulted in missed NBA games, with highest rates of game-loss injuries in preseason games and lowest rates in playoff games. Most game-loss injuries had acute onset, and half of those involved contact with another player. CLINICAL RELEVANCE: These findings - through reliable data reporting by team medical staff in an audited system - can guide evidence-based injury reduction strategies and inform player health priorities.

Regulator of G protein signaling 6 (RGS6) in dopamine neurons promotes EtOH seeking, behavioral reward, and susceptibility to relapse.

Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). The neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, and abstinence remains the only effective way to prevent alcohol use disorders (AUDs). Here, we developed novel RGS6fl/fl; DAT-iCreER mice to determine the role of RGS6 in DA neurons on EtOH consumption, reward, and relapse behaviors. We found that RGS6 is expressed in DA neurons in both human and mouse ventral tegmental area (VTA), and that RGS6 loss in mice upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals. Remarkably, loss of RGS6 in DA neurons significantly reduced EtOH consumption, preference, and reward in a manner indistinguishable from that seen in RGS6-/- mice. Strikingly, RGS6 loss from DA neurons before or after EtOH behavioral reward is established significantly reduced (~ 50%) re-instatement of reward following extinguishment, demonstrating distinct roles of RGS6 in promoting reward and relapse susceptibility to EtOH. These studies identify DA neurons as the locus of RGS6 action in promoting EtOH consumption, preference, reward, and relapse. RGS6 is unique among R7 RGS proteins in promoting rather than suppressing behavioral responses to drugs of abuse and to modulate EtOH behavioral reward. This is a result of RGS6's pre-synaptic actions that we hypothesize promote VTA DA transmission by suppressing GPCR-Gαi/o-DAT signaling in VTA DA neurons. These studies identify RGS6 as a potential therapeutic target for behavioral reward and relapse to EtOH.

Association Between Emergency Department Operational Metrics and Substance Use Disorder Treatment Interest in Two Rhode Island Hospitals.

OBJECTIVE: This study examined if emergency department (ED) operational metrics, such as wait time or length of stay, are associated with interest in substance use disorder (SUD) treatment referral among patients at high risk of opioid overdose. METHODS: In this observational study, 648 ED patients at high risk of opioid overdose completed a baseline questionnaire. Operational metrics were summarized using electronic health record data. The association between operational metrics and treatment interest was estimated with multivariable logistic regression. RESULTS: Longer time to room (adjusted odds ratio [AOR]=1.12, 95% confidence interval [CI]=1.01-1.25) and length of stay (AOR=1.02, 95% CI=1.00-1.05) were associated with treatment referral interest. Time to provider and number of treating providers showed no significant association. CONCLUSION: Longer rooming wait times and longer ED visits were associated with increased SUD treatment referral interest. This suggests patients who wait for longer periods may be motivated for treatment and warrant further resource investment.

Distal Tibiofibular Syndesmosis Injuries in the National Football League (NFL): A Spectrum of Pathology That Correlates With Time to Return to Full Participation.

BACKGROUND: Studies routinely evaluate high ankle sprains in isolation, but recent data suggest that these injuries are often associated with concomitant pathology, potentially influencing return to full participation. HYPOTHESIS: In National Football League (NFL) players, isolated high ankle sprains are rare and syndesmosis injuries with concomitant pathology will result in increased time to return to full participation. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: Distal tibiofibular syndesmosis injuries sustained by NFL players between 2017 and 2019 were identified through NFL Injury Surveillance Database queries and verified with video analysis. Each injury underwent a comprehensive magnetic resonance imaging (MRI) review. Regression modeling was utilized to explore the influence of numerous imaging findings on time to return to full participation. RESULTS: There were 83 external rotation ankle injuries involving the syndesmosis. Isolated distal tibiofibular syndesmosis injuries were rare (n = 11; 13%) and more often associated with other ligamentous injury (deltoid ligament and lateral ligamentous complex) and/or fractures. Regression modeling resulted in clustering of 3 injury pattern groups for time to return to full participation across numerous imaging findings: syndesmosis injury-fracture combinations (250 days [interquartile range [IQR,] 142-266 days]), syndesmosis injury with complete deep deltoid tear or acute diastasis (175 days [IQR, 20-248 days]), and all other syndesmosis injuries (27 days [IQR, 18-46 days]). CONCLUSION: In NFL athletes with external rotation ankle injuries, isolated distal tibiofibular syndesmosis injuries were rare and more often associated with concomitant pathology. Time to return to full participation was affected by an associated fracture and complete deep deltoid ligament tear or diastasis but no other relevant MRI variables such as lateral ligament complex involvement or the presence of osteochondral lesions or bone contusions.

Endogenous CD28 drives CAR T cell responses in multiple myeloma.

Recent FDA approvals of chimeric antigen receptor (CAR) T cell therapy for multiple myeloma (MM) have reshaped the therapeutic landscape for this incurable cancer. In pivotal clinical trials B cell maturation antigen (BCMA) targeted, 4-1BB co-stimulated (BBζ) CAR T cells dramatically outperformed standard-of-care chemotherapy, yet most patients experienced MM relapse within two years of therapy, underscoring the need to improve CAR T cell efficacy in MM. We set out to determine if inhibition of MM bone marrow microenvironment (BME) survival signaling could increase sensitivity to CAR T cells. In contrast to expectations, blocking the CD28 MM survival signal with abatacept (CTLA4-Ig) accelerated disease relapse following CAR T therapy in preclinical models, potentially due to blocking CD28 signaling in CAR T cells. Knockout studies confirmed that endogenous CD28 expressed on BBζ CAR T cells drove in vivo anti-MM activity. Mechanistically, CD28 reprogrammed mitochondrial metabolism to maintain redox balance and CAR T cell proliferation in the MM BME. Transient CD28 inhibition with abatacept restrained rapid BBζ CAR T cell expansion and limited inflammatory cytokines in the MM BME without significantly affecting long-term survival of treated mice. Overall, data directly demonstrate a need for CD28 signaling for sustained in vivo function of CAR T cells and indicate that transient CD28 blockade could reduce cytokine release and associated toxicities.

The true complexities of "standard" family practice visits unmasked: an observational cross-sectional study in Regina.

BACKGROUND: Many patients present to their family medicine clinic with more than one health concern, placing an increased demand on family physicians. Research into the average number of concerns per regular family medicine visit is limited. Recognition of the frequency that family physicians address more than one concern per visit and adapting practices accordingly is important for improving patient care. OBJECTIVE: To examine whether family physicians routinely address multiple different patient concerns during a single visit and if this is influenced by patient demographics. METHODS: This study was conducted at a multi-physician family medicine clinic in Regina, Saskatchewan, Canada. Five physicians contributed their 500 most recent charts, extending retrospectively from 1 June 2023, from in-person visits by patients over 18 years of age and billed as regular appointments without billed procedures. Each chart was reviewed for the number of concerns addressed in the visit. RESULTS: Fifty percent of visits addressed more than 1 concern (range = 1-8). A generalized linear mixed model using Poisson distribution showed certain physicians (incident rate ratio [IRR]: 1.192, 95% CI: 1.087-1.307, P < 0.001) and adults older than 65 years compared to adults less than 40 years (IRR 1.151, 95% CI: 1.069-1.239, P < 0.001) were more likely to present with multiple concerns, but patient sex was not a significant predictor. CONCLUSIONS: Family physicians routinely address more than one concern per visit. Standard visit length and billing practices should be adapted to reflect this complexity.

Conditionally replicative adenovirus as a therapy for malignant peripheral nerve sheath tumors.

Oncolytic adenoviruses (Ads) stand out as a promising strategy for the targeted infection and lysis of tumor cells, with well-established clinical utility across various malignancies. This study delves into the therapeutic potential of oncolytic Ads in the context of neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). Specifically, we evaluate conditionally replicative adenoviruses (CRAds) driven by the cyclooxygenase 2 (COX2) promoter, as selective agents against MPNSTs, demonstrating their preferential targeting of MPNST cells compared with non-malignant Schwann cell control. COX2-driven CRAds, particularly those with modified fiber-knobs exhibit superior binding affinity toward MPNST cells and demonstrate efficient and preferential replication and lysis of MPNST cells, with minimal impact on non-malignant control cells. In vivo experiments involving intratumoral CRAd injections in immunocompromised mice with human MPNST xenografts significantly extend survival and reduce tumor growth rate compared with controls. Moreover, in immunocompetent mouse models with MPNST-like allografts, CRAd injections induce a robust infiltration of CD8+ T cells into the tumor microenvironment (TME), indicating the potential to promote a pro-inflammatory response. These findings underscore oncolytic Ads as promising, selective, and minimally toxic agents for MPNST therapy, warranting further exploration.

Methylotrophic methanogenesis in the Archaeoglobi revealed by cultivation of Ca. Methanoglobus hypatiae from a Yellowstone hot spring.

Over the past decade, environmental metagenomics and polymerase chain reaction-based marker gene surveys have revealed that several lineages beyond just a few well-established groups within the Euryarchaeota superphylum harbor the genetic potential for methanogenesis. One of these groups are the Archaeoglobi, a class of thermophilic Euryarchaeota that have long been considered to live non-methanogenic lifestyles. Here, we enriched Candidatus Methanoglobus hypatiae, a methanogen affiliated with the family Archaeoglobaceae, from a hot spring in Yellowstone National Park. The enrichment is sediment-free, grows at 64-70°C and a pH of 7.8, and produces methane from mono-, di-, and tri-methylamine. Ca. M. hypatiae is represented by a 1.62 Mb metagenome-assembled genome with an estimated completeness of 100% and accounts for up to 67% of cells in the culture according to fluorescence in situ hybridization. Via genome-resolved metatranscriptomics and stable isotope tracing, we demonstrate that Ca. M. hypatiae expresses methylotrophic methanogenesis and energy-conserving pathways for reducing monomethylamine to methane. The detection of Archaeoglobi populations related to Ca. M. hypatiae in 36 geochemically diverse geothermal sites within Yellowstone National Park, as revealed through the examination of previously published gene amplicon datasets, implies a previously underestimated contribution to anaerobic carbon cycling in extreme ecosystems.

Alpha-Synuclein Pre-Formed Fibrils Injected into Prefrontal Cortex Primarily Spread to Cortical and Subcortical Structures.

BACKGROUND: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in DLB and PDD. OBJECTIVE: To investigate the long-term behavioral and cognitive consequences of α-syn pathology in the cortex and characterize pathological spread of α-syn. METHODS: We injected human α-syn pre-formed fibrils into the PFC of wild-type male mice. We then assessed the behavioral and cognitive effects between 12- and 21-months post-injection and characterized the spread of pathological α-syn in cortical, subcortical, and brainstem regions. RESULTS: We report that PFC PFFs: 1) induced α-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; and 3) increased open field exploration. CONCLUSIONS: This model of cortical-dominant pathology aids in our understanding of how local α-syn aggregation might impact some symptoms in PDD and DLB.

Epidemiology of Stingers in the National Football League, 2015-2019.

BACKGROUND: Transient traumatic neuropraxia of either the brachial plexus or cervical nerve root(s) is commonly described as a "stinger" or "burner" by the athlete. Stingers in American Football commonly occur acutely as isolated injuries; however, concomitant injuries, including cervical spine pathologies, have also been reported. HYPOTHESIS: Among National Football League (NFL) athletes, the incidence rate of stingers is higher during the regular season than during the preseason and among positions with high velocity impacts such as running backs, linebackers, defensive backs, and receivers. STUDY DESIGN: Retrospective epidemiology study. LEVEL OF EVIDENCE: Level 4. METHODS: Aggregation of all in-game injuries with a clinical impression of "neck brachial plexus stretch" or "neck brachial plexus compression" entered into the NFL injury surveillance database through the centralized league-wide electronic medical record system over 5 years (2015-2019 seasons). Incidence rates per player-play were calculated and reported. RESULTS: A total of 691 in-game stingers occurred during the study period, with a mean of 138.2 per year. Average single-season injury risk for incident stinger was 3.74% (95% CI, 3.46%-4.05%). The incidence rate was higher during regular season games than during preseason games (12.26 per 100,000 player-plays [11.30-13.31] vs 8.87 [7.31-10.76], P < 0.01, respectively). The highest reported stinger incidence rates were among running backs and linebackers (both >15 per 100,000 player-plays). Among stingers, 76.41% did not miss time. Of those that resulted in time lost from football activities, mean time missed due to injury was 4.79 days (range, 3.17-6.41 days). Concomitant injuries were relatively low (7.09%). CONCLUSION: In-game stinger incidence was stable across the study period and occurred most frequently in running backs and linebackers. Stingers were more common during the regular season, and most players did not miss time. Concomitant injuries were relatively rare. CLINICAL RELEVANCE: An improved understanding of the expected time loss due to stinger and concomitant injuries may provide insight for medical personnel in managing these injuries.

CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity.

Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.

Disparities in Surgical Treatment of Resectable Pancreatic Adenocarcinoma at Minority Serving Hospitals.

INTRODUCTION: Minority serving hospitals (MSH) are those serving a disproportionally high number of minority patients. Previous research has demonstrated that treatment at MSH is associated with worse outcomes. We hypothesize that patients treated at MSH are less likely to undergo surgical resection of pancreatic adenocarcinoma compared to patients treated at non-MSH. METHODS: Patients with resectable pancreatic cancer were identified using the National Cancer Database. Institutions treating Black and Hispanic patients in the top decile were categorized as an MSH. Factors associated with the primary outcome of definitive surgical resection were evaluated using multivariable logistic regression. Univariate and multivariable survival analysis was performed. RESULTS: Of the 75,513 patients included in this study, 7.2% were treated at MSH. Patients treated at MSH were younger, more likely to be uninsured, and higher stage compared to those treated at non-MSH (P < 0.001). Patients treated at MSH underwent surgical resection at lower rates (MSH 40% versus non-MSH 44.5%, P < 0.001). On multivariable logistic regression, treatment at MSH was associated with decreased likelihood of undergoing definitive surgery (odds ratio 0.91, P = 0.006). Of those who underwent surgical resection, multivariable survival analysis revealed that treatment at an MSH was associated with increased morality (hazard ratio 1.12, P < 0.001). CONCLUSIONS: Patients with resectable pancreatic adenocarcinoma treated at MSH are less likely to undergo surgical resection compared to those treated at non-MSH. Targeted interventions are needed to address the unique barriers facing MSH facilities in providing care to patients with pancreatic adenocarcinoma.

Impact of a Palatal Fistula After Cleft Palate Repair on Velopharyngeal Closure.

PURPOSE: A palatal fistula is an adverse outcome of cleft palate repair. It is unknown if a palatal fistula will influence velopharyngeal closure, even after repair of the fistula. This study determines the effect of a soft palate fistula on the risk of developing velopharyngeal insufficiency. METHODS: A retrospective chart review was conducted on patients who underwent primary cleft palate repair between 2000 and 2015, with complete records at 4 years of age. Fistulae involving the secondary palate following primary palatoplasty were classified as the soft or hard palate. A forced-entry multivariate logistic regression model was built to detect predictors of velopharyngeal dysfunction. RESULTS: Records of 329 patients were analyzed with a mean follow-up of 8.7 years. A palatal fistula was identified in 89/329 patients (27%) and 29/329 patients (9%) underwent an independent fistula repair. Of the patients with fistula, 44% were located in the hard palate only and 56% had soft palate involvement. Compared to patients without a fistula, rates of velopharyngeal dysfunction were significantly higher in patients with a fistula involving the soft palate (OR 3.875, CI: 1.964-7.648, P < .001) but not in patients with a hard palate fistula (OR 1.140, CI: 0.497-2.613, P = .757). Veau class, age at primary repair, and syndromic status were not significant predictors of VPI (0.128≤P ≤ .975). CONCLUSIONS: A palatal fistula involving the soft palate is a significant predictor for development of velopharyngeal dysfunction after primary palatoplasty. Surgical intervention, at the time of fistula repair, to add vascularized tissue may be indicated to prophylactically decrease the risk of velopharyngeal dysfunction.

Association between comorbid chronic pain or prior hospitalization for mental illness and substance use treatment among a cohort at high risk of opioid overdose.

INTRODUCTION: Chronic pain and serious mental illness increase risk of opioid use, and opioid use can exacerbate both conditions. Substance use disorder (SUD) treatment can be lifesaving, but chronic pain and serious mental illness may make recovery challenging. We evaluated the association between current chronic pain and prior hospitalization for mental illness and 90-day SUD treatment engagement, among emergency department (ED) patients at high risk of opioid overdose. METHODS: We conducted a cohort analysis of 648 ED patients enrolled in a randomized controlled trial in Rhode Island. We linked baseline study data on chronic pain and prior hospitalization for mental illness to statewide administrative data on state-licensed treatment programs (including methadone) and buprenorphine treatment via prescription. We defined treatment engagement as initiation of a state-licensed treatment program, transfer between state-licensed programs/providers, or a buprenorphine prescription (re-)fill. We used modified Poisson models to estimate the association between each baseline comorbidity and treatment engagement within 90 days following the ED visit, adjusted for a priori potential confounders. In an exploratory analysis, models were stratified by baseline treatment status. RESULTS: The mean age of participants was 37 years; 439 (68 %) were male, and 446 (69 %) had been recently unhoused. Overall, 278 participants (43 %) engaged in treatment within 90 days of the ED visit. Participants with prior hospitalization for mental illness were more likely to engage in treatment than those without (adjusted risk ratio [ARR] = 1.24, 95 % confidence interval [CI] = 1.01-1.53), although this association was only among those already accessing treatment at baseline (ARR = 1.58, 95 % CI = 1.10-2.27). Chronic pain was not associated with 90-day treatment engagement overall (ARR = 1.12, 95 % CI = 0.91-1.38) or within baseline treatment subgroups. CONCLUSIONS: Among ED patients at high risk of opioid overdose and accessing treatment at baseline, those with prior hospitalization for mental illness (but not chronic pain) were more likely to engage in treatment following the ED visit, which may reflect disproportionate initiation of additional treatment programs, transfer between programs/providers, or ongoing buprenorphine treatment. Touchpoints within the medical system should be leveraged to ensure that everyone, including those with serious mental illness, can access high-quality SUD treatment at the desired intensity level.

Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors.

The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against both solid and hematological malignancies. We have previously discovered potent dihydroisoquinolinone-based WDR5 WIN-site inhibitors with demonstrated efficacy and safety in animal models. In this study, we sought to optimize the bicyclic core to discover a novel series of WDR5 WIN-site inhibitors with improved potency and physicochemical properties. We identified the 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one core as an alternative scaffold for potent WDR5 inhibitors. Additionally, we used X-ray structural analysis to design partially saturated bicyclic P7 units. These benzoxazepinone-based inhibitors exhibited increased cellular potency and selectivity and favorable physicochemical properties compared to our best-in-class dihydroisoquinolinone-based counterparts. This study opens avenues to discover more advanced WDR5 WIN-site inhibitors and supports their development as novel anti-cancer therapeutics.

The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16176. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Regulator of G protein signaling 6 (RGS6) in ventral tegmental area (VTA) dopamine neurons promotes EtOH seeking, behavioral reward and susceptibility to relapse.

Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). EtOH is the most abused substance worldwide with chronic consumption often leading to the development of dependence and abuse. Unfortunately, the neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, and abstinence remains the only effective way to prevent alcohol use disorders (AUDs). Here, we developed novel RGS6 fl/fl ; DAT-iCreER mice to determine the role of RGS6 in VTA DA neurons on EtOH consumption and reward behaviors. We found that RGS6 is expressed in DA neurons in both human and mouse VTA, and that RGS6 loss in mice upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals. Remarkably, loss of RGS6 in VTA DA neurons significantly reduced EtOH consumption, preference, and reward in a manner indistinguishable from that seen in RGS6 -/- mice. Strikingly, RGS6 loss from VTA DA neurons before or after EtOH behavioral reward is established significantly reduced (∼50%) re-instatement of reward following extinguishment, demonstrating distinct roles of RGS6 in promoting reward and relapse susceptibility to EtOH. These studies illuminate a critical role of RGS6 in the mesolimbic circuit in promoting EtOH seeking, reward, and reinstatement. We propose that RGS6 functions to promote DA transmission through its function as a negative modulator of GPCR-Gα i/o -DAT signaling in VTA DA neurons. These studies identify RGS6 as a potential therapeutic target for behavioral reward and relapse to EtOH.