In vivo CAR T-cell generation in nonhuman primates using lentiviral vectors displaying a multidomain fusion ligand.

ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformative efficacy in treating B-cell malignancies. However, high costs and manufacturing complexities hinder their widespread use. To overcome these hurdles, we have developed the VivoVec platform, a lentiviral vector capable of generating CAR T cells in vivo. Here, we describe the incorporation of T-cell activation and costimulatory signals onto the surface of VivoVec particles (VVPs) in the form of a multidomain fusion protein and show enhanced in vivo transduction and improved CAR T-cell antitumor functionality. Furthermore, in the absence of lymphodepleting chemotherapy, administration of VVPs into nonhuman primates resulted in the robust generation of anti-CD20 CAR T cells and the complete depletion of B cells for >10 weeks. These data validate the VivoVec platform in a translationally relevant model and support its transition into human clinical testing, offering a paradigm shift in the field of CAR T-cell therapies.

Associations of Local Cannabis Control Policies With Harmful Cannabis Exposures Reported to the California Poison Control System.

BACKGROUND: Cannabis exposures reported to the California Poison Control System increased following the initiation of recreational cannabis sales on 1 January 2018 (i.e., "commercialization"). We evaluated whether local cannabis control policies adopted by 2021 were associated with shifts in harmful cannabis exposures. METHODS: Using cannabis control policies collected for all 539 California cities and counties in 2020-2021, we applied a differences-in-differences design with negative binomial regression to test the association of policies with harmful cannabis exposures reported to California Poison Control System (2011-2020), before and after commercialization. We considered three policy categories: bans on storefront recreational retail cannabis businesses, overall restrictiveness, and specific recommended provisions (restricting product types or potency, packaging and labeling restrictions, and server training requirements). RESULTS: Localities that ultimately banned storefront recreational retail cannabis businesses had fewer harmful cannabis exposures for children aged <13 years (rate ratio = 0.82; 95% confidence interval = 0.65, 1.02), but not for people aged >13 years (rate ratio = 0.97; 95% confidence interval = 0.85, 1.11). Of 167 localities ultimately permitting recreational cannabis sales, overall restrictiveness was not associated with harmful cannabis exposures among children aged <13 years, but for people aged >13 years, a 1-standard deviation increase in ultimate restrictiveness was associated with fewer harmful cannabis exposures (rate ratio = 0.93; 95% confidence interval = 0.86, 1.01). For recommended provisions, estimates were generally too imprecise to detect associations with harmful cannabis exposures. CONCLUSION: Bans on storefront retail and other restrictive approaches to regulating recreational cannabis may be associated with fewer harmful cannabis exposures for some age groups following statewide commercialization.

Dataset on density functional theory investigation of ternary Heusler alloys.

This paper contains data and results from Density Functional Theory (DFT) investigation of 423 distinct X2YZ ternary full Heusler alloys, where X and Y represent elements from the D-block of the periodic table and Z signifies element from main group. The study encompasses both "regular" and "inverse" Heusler phases of these alloys for a total of 846 potential materials. For each specific alloy and each phase, a range of information is provided including total energy, formation energy, lattice constant, total and site-specific magnetic moments, spin polarization as well as total and projected density of electronic states. The aim of creating this dataset is to provide fundamental theoretical insights into ternary X2YZ Heusler alloys for further theoretical and experimental analysis.

Reported exposures to derived cannabis products in California before and after the 2018 federal reclassification of hemp.

BACKGROUND: As of June 2023, a majority of states had legalized the sale of cannabis, which past research has found to be associated with increased exposures. In 2018, a change in federal policy increased access to cannabidiol (CBD) and derived psychoactive cannabis products, but there has been limited study of reported exposures following this change. METHODS: This observational retrospective study analyzed exposures involving synthetic cannabinoid receptor agonists (SCRAs) and derived cannabis products, including CBD, reported to the California Poison Control System (CPCS) from 2010 to 2022. We focused primarily on potential shifts in reported exposures before and after the implementation of the 2018 Farm Bill, which removed products derived from hemp from the Controlled Substances Act. We reviewed and hand-coded individual call records to assess reported exposures over time and their characteristics, and conducted interrupted time series analysis to assess whether exposure counts changed after policy interventions. RESULTS: Reported CBD exposures significantly increased following the federal reclassification of hemp products. Exposure reports were most common among young children and for edibles. Exposure reports provided limited information about derived psychoactive cannabis products. CONCLUSIONS: Our findings suggest a need for improved data collection regarding derived psychoactive cannabis products, as well as potential public health value in modifying packaging regulations and in providing additional guidance to parents to help prevent CBD exposures.

A ten-year retrospective California Poison Control System experience with possible amatoxin mushroom calls.

INTRODUCTION: Mushrooms containing amatoxin are found worldwide and represent a challenging poisoning for the clinician and consulting poison center. This study evaluates the experience of a large poison system with possible amatoxin-containing mushroom ingestion calls. METHODS: A 10-year retrospective review of the California Poison Control System database was performed for amatoxin mushroom ingestion calls resulting in hospitalization. Cases found were abstracted and data statistically analyzed for association with a composite endpoint of death, liver transplant, and/or the need for dialysis. RESULTS: Amatoxin-containing mushroom calls are infrequent with the vast majority (98.4 percent) coming from Northern California during the rainier first and fourth quarters (October through March) of the year. Elevated initial aminotransferase activities and international normalized ratios were predictive of the composite negative outcome. The mortality plus liver transplant and hemodialysis composite rate was 8.2 percent, consistent with current literature. CONCLUSION: The California Poison Control System has relatively few amatoxin-containing mushroom ingestion calls that result in hospitalization but those that are reported mostly occur in Northern California. Treatment bias towards the sickest patients may explain the association of intravenous fluid use or treatment with acetylcysteine or silibinin with meeting the composite outcome. The initial presence of elevated hepatic aminotransferase activity and international normalized ratios are poor prognostic indicators and are likely reflective of late presentation, an advanced toxic phase of amatoxin poisoning, and/or delays in time to obtain poison center consultation.

The prevalence and impact of polypharmacy in rheumatology.

Polypharmacy is increasingly common in rheumatology due to the complex nature of managing chronic autoimmune diseases. To date there has been limited research into the impact of polypharmacy on rheumatology patients. In this article we reviewed the literature to characterize the prevalence of polypharmacy and its effect on patients. In addition, we have highlighted some key drug-drug interactions to consider involving DMARDs as well as complementary and alternative medicines. There is emerging evidence demonstrating that polypharmacy contributes to adverse outcomes and alters treatment response. This association is best described in RA and is less clear in other patient cohorts. It is also unclear whether polypharmacy is directly harmful or just a surrogate marker for other factors affecting outcomes. Rheumatologists should be aware of the risk of polypharmacy as well as specific drug-drug interactions that can occur in managing chronic autoimmune disease.

Trends in concomitant and single opioid and benzodiazepine exposures reported to the California Poison Control System following the Centers for Disease Control and Prevention release of opioid guidelines in 2016.

INTRODUCTION: In March 2016, the Centers for Disease Control and Prevention released the Guideline for Prescribing Opioids for Chronic Pain, intended for primary care clinicians. One recommendation advised against concurrent prescription of opioids and benzodiazepines. Although existing research suggests a reduction in co-prescribing of these drug classes by clinicians after guideline release, there are limited data assessing its possible effect on patient medical outcomes, such as overdoses. METHODS: This retrospective observational study analyzed opioid and benzodiazepine exposures, alone or in combination, reported to the California Poison Control System from January 2012 to June 2021. Interrupted time series analyses identified the difference in monthly call volume between pre- and post-guideline release. For exposures resulting in serious medical outcomes, additional analyses assessed trends and identified associated variables. RESULTS: There was no significant change in concomitant opioid and benzodiazepine exposures reported to California Poison Control System between pre- and post-guideline release. Compared to pre-guideline release, exposures to a single opioid or to a single benzodiazepine significantly decreased by 1.07 (95% CI: -1.62, -0.51) and 1.82 (95% CI: -2.33, -1.31) calls per month, respectively, after the guideline release. For exposure calls associated with serious medical outcomes, there was a significant increase of 0.11 (95% CI: 0.04, 0.18) and 0.2 (95% CI: 0.05, 0.34) calls per month for concomitant opioid and benzodiazepine and single opioid exposures, respectively, following guideline release. DISCUSSION: The guideline release appeared to have a variable association with exposures to single opioid, single benzodiazepines, and concomitant opioid and benzodiazepine cases reported to California Poison Control System. Although exposures to opioids or benzodiazepines alone significantly decreased after guideline release, there was no significant change in concomitant exposures. Additionally, for exposures associated with serious medical outcomes, concomitant exposures, and single opioid exposures significantly increased following guideline release. CONCLUSION: Our results suggest that the guideline was not associated with a corresponding decrease in the number of concomitant poisoning exposures reported to California Poison Control System. Additional interventions may be needed to reduce concomitant exposures to opioids and benzodiazepines.

An Unusual Case of Primary Gastric Balloon Cell Melanoma.

Most cases of melanoma found in the gastrointestinal tract are the result of metastasis. Although uncommon and only described in isolated case reports, primary gastric melanoma should be considered when patients present with vague gastrointestinal symptoms and a mass is identified on esophagogastroduodenoscopy or imaging. We describe a case of primary gastric balloon cell melanoma in a 73-year-old man who presented with melena. Given the high morbidity and mortality of gastric mucosal melanoma, early diagnosis and initiation of treatment can lead to improved outcomes and survival.

The pharmacotherapeutic options in patients with catecholamine-resistant vasodilatory shock.

INTRODUCTION: Septic and vasoplegic shock are common types of vasodilatory shock (VS) with high mortality. After fluid resuscitation and the use of catecholamine-mediated vasopressors (CMV), vasopressin, angiotensin II, methylene blue (MB), and hydroxocobalamin can be added to maintain blood pressure. AREAS COVERED: VS treatment utilizes a phased approach with secondary vasopressors added to vasopressor agents to maintain an acceptable mean arterial pressure (MAP). This review covers additional vasopressors and adjunctive therapies used when fluid and catecholamine-mediated vasopressors fail to maintain target MAP. EXPERT OPINION: Evidence supporting additional vasopressor agents in catecholamine-resistant VS is limited to case reports, series, and a few randomized control trials (RCTs) to guide recommendations. Vasopressin is the most common agent added next when MAPs are not adequately supported with CMV. VS patients failing fluids and vasopressors with cardiomyopathy may have cardiotonic agents such as dobutamine or milrinone added before or after vasopressin. Angiotensin II, another class of vasopressor, is used in VS to maintain adequate MAP. MB and/or hydroxocobalamin, vitamin C, thiamine, and corticosteroids are adjunctive therapies used in refractory VS. More RCTs are needed to confirm the utility of these drugs, at what doses, which combinations and in what order they should be given.

STING Is Required in Conventional Dendritic Cells for DNA Vaccine Induction of Type I T Helper Cell- Dependent Antibody Responses.

DNA vaccines elicit antibody, T helper cell responses and CD8+ T cell responses. Currently, little is known about the mechanism that DNA vaccines employ to induce adaptive immune responses. Prior studies have demonstrated that stimulator of interferon genes (STING) and conventional dendritic cells (cDCs) play critical roles in DNA vaccine induced antibody and T cell responses. STING activation by double stranded (dsDNA) sensing proteins initiate the production of type I interferon (IFN),but the DC-intrinsic effect of STING signaling is still unclear. Here, we investigated the role of STING within cDCs on DNA vaccine induction of antibody and T cell responses. STING knockout (STING-/- ) and conditional knockout mice that lack STING in cDCs (cDC STING cKO), were immunized intramuscularly with a DNA vaccine that expressed influenza A nucleoprotein (pNP). Both STING-/- and cDC STING cKO mice had significantly lower type I T helper (Th1) type antibody (anti-NP IgG2C) responses and lower frequencies of Th1 associated T cells (NP-specific IFN-γ+CD4+ T cells) post-immunization than wild type (WT) and cDC STING littermate control mice. In contrast, all mice had similar Th2-type NP-specific (IgG1) antibody titers. STING-/- mice developed significantly lower polyfunctional CD8+ T cells than WT, cDC STING cKO and cDC STING littermate control mice. These findings suggest that STING within cDCs mediates DNA vaccine induction of type I T helper responses including IFN-γ+CD4+ T cells, and Th1-type IgG2C antibody responses. The induction of CD8+ effector cell responses also require STING, but not within cDCs. These findings are the first to show that STING is required within cDCs to mediate DNA vaccine induced Th1 immune responses and provide new insight into the mechanism whereby DNA vaccines induce Th1 responses.

Changes in California cannabis exposures following recreational legalization and the COVID-19 pandemic.

INTRODUCTION: Since 2012, eighteen states and the District of Columbia have legalized recreational cannabis. Past research suggests this policy change is associated with increased cannabis exposures however this has not yet been studied in California, despite its status as the world's largest legal cannabis market. METHODS: This observational, retrospective study analyzed trends in cannabis exposures reported to the California Poison Control System (CPCS) from 2010 to 2020. We assessed shifts in exposures before and after the legalization of recreational cannabis in November 2016, the establishment of recreational retail sales in January 2018, and the institution of a statewide shelter-in-place order due to the COVID-19 pandemic in March 2020 using interrupted time-series analysis and reviewed all records to identify specific products associated with exposures. RESULTS: Between 2010 and 2020 edible exposures increased from near zero to 79% of exposures in 2020. Cannabis exposures significantly increased following recreational legalization in 2016 (by an estimated 2.07 exposures per month [CI: 0.60, 3.55]; p < 0.01) and initiation of retail sales in 2018 (0.85 [CI: 0.12, 1.58]; p < 0.05). There was no significant change in cannabis exposures following the first shelter-in-place order of the COVID-19 pandemic (1.59 [CI: -1.61, 3.68]; p = 0.43). Cannabis exposures for those thirteen and under increased significantly both after recreational legalization (1.04 [CI: 0.38, 1.70]) and after the opening of the retail sales market (0.73 [CI: 0.34, 1.12]), but not following the shelter-in-place order (1.59 [CI: -1.61, 3.68]), nor was there a significant change for those older than thirteen. CONCLUSIONS: Our findings suggest that cannabis legalization is linked to increased exposures, particularly for products such as gummies and candy edibles among children under the age of thirteen. Clinicians should be aware of these risks and communicate them to patients, and policymakers should consider stronger regulations on packaging to reduce these exposures.Key pointsQuestion: How have cannabis exposures changed following legalization of recreational use, the opening of the recreational retail sales market, and the institution of shelter-in-place orders during the COVID-19 pandemic?Findings: In this retrospective review of 10,757 cases reported to the California Poison Control System (CPCS) between 2010 and 2020, exposures increased significantly after the legalization of recreational cannabis use and the opening of the recreational retail sales market, particularly among children, who primarily consumed candies and gummies.Meaning: Stronger regulation of cannabis edibles that mimic other products is warranted to decrease exposures among children.

Trends in hydrocodone combination product exposures reported to California Poison Control System (CPCS) following DEA rescheduling.

CONTEXT: On October 6, 2014, the United States Drug Enforcement Administration (DEA) implemented a regulatory change for hydrocodone combination products (HCPs), moving them from Schedule III to II, in an effort to decrease drug overdoses. Existing research suggests this regulatory action reduced HCP prescribing and dispensing; however, there is limited research assessing its possible effects on overdoses and accidental exposures. OBJECTIVE: To analyze the changes in opioid exposures reported to the California Poison Control System (CPCS) before and after DEA rescheduling of HCPs. METHODS: We collected monthly exposure data reported to CPCS from 2012 to 2019 and conducted interrupted time series analyses to assess changes in exposures after rescheduling for HCPs, tramadol, oxycodone, morphine, codeine, fentanyl, and heroin. Additional analyses were done to assess any changes in exposures resulting in severe outcomes (moderate or major health effects). For HCPs, we also conducted logistic regressions to identify characteristics of exposures resulting in severe outcomes before and after rescheduling. RESULTS: Overall monthly opioid exposures reported to CPCS decreased after DEA rescheduling of HCPs. These decreases were significant for HCP, tramadol, and morphine (p < 0.001). Exposures significantly increased for heroin and fentanyl (p < 0.001). There were no significant changes in the share of severe outcomes attributed to HCP exposures after rescheduling. DISCUSSION: The DEA rescheduling of HCPs was associated with a significant decrease in HCP exposures and prescription opioid exposures overall, but was associated with increased fentanyl and heroin exposures. While other initiatives may have contributed to this decrease, our findings suggest that rescheduling may be a useful regulatory strategy to reduce drug exposures. CONCLUSION: DEA rescheduling of HCPs was associated with a significant reduction in prescription opioid exposures, suggesting that rescheduling high-risk drugs may be an effective strategy to improve public health.

Association between Tunneled Pleural Catheter Use and Infection in Patients Immunosuppressed from Antineoplastic Therapy. A Multicenter Study.

Rationale: Patients with malignant or paramalignant pleural effusions (MPEs or PMPEs) may have tunneled pleural catheter (TPC) management withheld because of infection concerns from immunosuppression associated with antineoplastic therapy.Objectives: To determine the rate of infections related to TPC use and to determine the relationship to antineoplastic therapy, immune system competency, and overall survival (OS).Methods: We performed an international, multiinstitutional study of patients with MPEs or PMPEs undergoing TPC management from 2008 to 2016. Patients were stratified by whether or not they underwent antineoplastic therapy and/or whether or not they were immunocompromised. Cumulative incidence functions and multivariable competing risk regression analyses were performed to identify independent predictors of TPC-related infection. Kaplan-Meier method and multivariable Cox proportional hazards modeling were performed to examine for independent effects on OS.Results: A total of 1,408 TPCs were placed in 1,318 patients. Patients had a high frequency of overlap between antineoplastic therapy and an immunocompromised state (75-83%). No difference in the overall (6-7%), deep pleural (3-5%), or superficial (3-4%) TPC-related infection rates between subsets of patients stratified by antineoplastic therapy or immune status was observed. The median time to infection was 41 (interquartile range, 19-87) days after TPC insertion. Multivariable competing risk analyses demonstrated that longer TPC duration was associated with a higher risk of TPC-related infection (subdistribution hazard ratio, 1.03; 95% confidence interval [CI], 1.00-1.06; P = 0.028). Cox proportional hazards analysis showed antineoplastic therapy was associated with better OS (hazard ratio, 0.84; 95% CI, 0.73-0.97; P = 0.015).Conclusions: The risk of TPC-related infection does not appear to be increased by antineoplastic therapy use or an immunocompromised state. The overall rates of infection are low and comparable with those of immunocompetent patients with no relevant antineoplastic therapy. These results support TPC palliation for MPE or PMPEs regardless of plans for antineoplastic therapy.

Subtle case of dapsone-induced methaemoglobinaemia.

Methaemoglobinaemia is a rare disease that is typically caused by a medication or other exogenous agent, with dapsone being the most common. It occurs when the concentration of methaemoglobin rises via ferrous haeme irons becoming oxidised to the ferric state, which shifts the oxygen dissociation curve to the left. The net result of an elevated methaemoglobin concentration is functional anaemia and impaired oxygen delivery to tissues. At lower blood levels, this can cause symptoms such as cyanosis, lethargy, headache and fatigue, whereas at higher levels it can be fatal. Here we discuss a subtle case of dapsone-induced methaemoglobinaemia presenting as subacute mental status changes and apparent hypoxia, thus highlighting the association between methaemoglobinaemia and dapsone. This case demonstrates the importance of thorough medication reconciliation and maintaining a broad differential diagnosis, while also recognising the significance of conflicting data and their implications for the workup.

Lupus-associated protein losing enteropathy (LUPLE) complicated by a hypercoagulable state and successfully treated with belimumab.

Protein-losing enteropathy (PLE) is a condition characterized by gut mucosal injury that typically manifests with edema and hypoalbuminemia due to protein loss in the GI tract. We present a rare case of lupus-associated PLE (LUPLE) manifested by profound edema, diarrhea, and thrombotic complications. Through our case report, we discuss the typical clinical presentation, diagnostic studies available, and treatment options for these patients. Our patient's clinical picture and laboratory markers improved with the initiation of corticosteroids and belimumab, which is a novel treatment regimen for LUPLE. Moreover, our patient was found to have a clinically significant hypercoagulable state that was ultimately attributed to PLE in the setting of systemic lupus erythematosus (SLE). We highlight the increased thrombotic risk in these patients and the subsequent management implications with regard to anticoagulation. Gastroenterologists are likely to be involved in the care of these patients, and may be the first to recognize the constellation of findings in PLE, leading to potentially very effective treatment.

Author Correction: Changes in Reef Fish Community Structure Following the Deepwater Horizon Oil Spill.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Severe Methemoglobinemia and Death From Intentional Sodium Nitrite Ingestions.

BACKGROUND: Sodium nitrite is known to induce methemoglobinemia and hypotension when ingested, but reports of intentional ingestion remain rare. CASE SERIES: We report five cases of severe methemoglobinemia secondary to large sodium nitrite ingestion that were reported to and managed by the California Poison Control System in 2019, resulting in three fatalities. The estimated doses ingested ranged from 15 grams to 113 grams, with one patient surviving after an ingestion of 60 grams. The highest documented methemoglobin level was 73%. The 2 patients who survived received methylene blue early in their clinical course. One patient required higher doses of methylene blue compared with other cases of nitrite-associated methemoglobinemia. In the patients who survived, all symptoms resolved within 24 h. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: These cases highlight the severe toxicity associated with intentional large sodium nitrite ingestion. In management, consideration should be given to administering higher initial or more frequent doses of methylene blue compared with standard practice. Given that sodium nitrite is readily accessible through online vendors, and is being circulated through various suicide forums, it has the potential to be more commonly encountered in the emergency department.

Acute Liver Failure in a Patient With Dengue Shock Syndrome.

Dengue is an arboviral disease of significant burden in tropical countries. It commonly affects the liver, ranging in presentation from asymptomatic transaminitis to acute liver failure. We present a young woman from India who developed acute liver failure because of dengue shock syndrome and improved without a liver transplant. We review the disease characteristics and management of dengue, with a focus on the natural history of illness and how to approach the possible need for liver transplant in these patients.