Informing evidence-based medicine for opioid use disorder using pharmacoeconomic studies.

INTRODUCTION: The health and economic consequences of inadequately treated opioid use disorder (OUD) are substantial. Healthcare systems in the United States (US) and other countries are facing a growing healthcare crisis due to opioids. Although effective medications for OUD exist, relying solely on clinical information is insufficient for addressing the opioid crisis. AREAS COVERED: In this review, the role of pharmacoeconomic studies in informing evidence-based medication treatment for OUD is discussed, with a particular emphasis on the US healthcare system, where the economic burden is significantly higher than the global average. The scope/objective of pharmacoeconomics as a distinct scientific research program is briefly defined, followed by a discussion of existing evidence informed by data from systematic reviews, in addition to a convenience sample of recently published pharmacoeconomic studies and protocols. The review also explores the need for methodological advancements in the field. EXPERT OPINION: Despite the potential of pharmacoeconomic research in shaping evidence-based medicine for OUD, significant challenges limiting its real-world application remain. How to address these challenges are explored, including how to combine cost-effectiveness and budget impact analyses to address the needs of the healthcare system as a whole and specific stakeholders interested in adopting new OUD treatment strategies.

Impact of jail-based methadone or buprenorphine treatment on non-fatal opioid overdose after incarceration.

BACKGROUND: Non-fatal overdose is a leading predictor of subsequent fatal overdose. For individuals who are incarcerated, the risk of experiencing an overdose is highest when transitioning from a correctional setting to the community. We assessed if enrollment in jail-based medications for opioid use disorder (MOUD) is associated with lower risk of non-fatal opioid overdoses after jail release among individuals with opioid use disorder (OUD). METHODS: This was a retrospective, observational cohort study of adults with OUD who were incarcerated in New York City jails and received MOUD or did not receive any MOUD (out-of-treatment) within the last three days before release to the community in 2011-2017. The outcome was the first non-fatal opioid overdose emergency department (ED) visit within 1 year of jail release during 2011-2017. Covariates included demographic, clinical, incarceration-related, and other characteristics. We performed multivariable cause-specific Cox proportional hazards regression analysis to compare the risk of non-fatal opioid overdose ED visits within 1 year after jail release between groups. RESULTS: MOUD group included 8660 individuals with 17,119 incarcerations; out-of-treatment group included 10,163 individuals with 14,263 incarcerations. Controlling for covariates and accounting for competing risks, in-jail MOUD was associated with lower non-fatal opioid overdose risk within 14 days after jail release (adjusted HR=0.49, 95% confidence interval=0.33-0.74). We found no significant differences 15-28, 29-56, or 57-365 days post-release. CONCLUSION: MOUD group had lower risk of non-fatal opioid overdose immediately after jail release. Wider implementation of MOUD in US jails could potentially reduce post-release overdoses, ED utilization, and associated healthcare costs.

The association between naloxone claims and proportion of independent vs. chain pharmacies: A longitudinal analysis of naloxone claims in the US.

BACKGROUND: Expanding access to naloxone through pharmacies is an important policy goal. Our objective was to characterize national county-level naloxone dispensing of chain versus independent pharmacies. METHODS: The primary exposure in our longitudinal analysis was the proportion of chain pharmacies in a county, identified through the US Department of Homeland Security 2010 Infrastructure Foundation-Level Data. We defined counties as having "higher proportion" of chain pharmacies if at least 50% of pharmacies were large national chains. The primary outcome was quarter-year (2016Q1-2019Q2) rate of pharmacy naloxone claims per 100,000 persons from Symphony Health at the county-level. We compared the naloxone dispensing rate between county types using two-sample t-tests. We estimated the association between county-level chain pharmacy proportion and rate of naloxone claims using a linear model with year-quarter fixed effects. RESULTS: Nearly one third of counties (n=946) were higher proportion. Higher proportion counties had a significantly higher rate of naloxone claims across the study period, in 4 of 6 urban-rural classifications, and in counties with and without naloxone access laws. The linear model confirmed that higher proportion counties had a significantly higher rate of naloxone claims, adjusting for urban/rural designation, income, population characteristics, opioid mortality rate, co-prescribing laws and naloxone access laws. CONCLUSION: In this national study, we found an association between naloxone dispensing rates and the county-level proportion of chain (versus independent) pharmacies. Incentivizing naloxone dispensing through educational, regulatory, or legal efforts may improve naloxone availability and dispensing rates - particularly in counties with proportionately high numbers of independent pharmacies.

Effect of nanocurcumin on fertility in murine model of polycystic ovary syndrome.

The precise pathophysiology of polycystic ovary syndrome (PCOS) is not well-founded. In an attempt to fill this gap, the current study was executed to probe the effect of nanocurcumin (NCC) on ovarian tissue, in vitro fertilization (IVF) and pre-implantation embryo development in a mouse model of PCOS. Fifty adult female mice were randomly categorized into five equal groups including non-treated control and PCOS (receiving 0.20 mg estradiol valerate (EV) intra-peritoneally once a day for 21 days) as well as NCC12.50 + PCOS, NCC25 + PCOS and NCC50 + PCOS (receiving respectively 12.50, 25.00 and 50.00 mg kg-1 NCC daily along with EV injection through oral gavages for 21 days) groups. Subsequently, ovarian histo-architecture and total anti-oxidant capacity, and malonaldehyde and catalase levels as well as in vitro fertilizing potential, early embryonic development and serum testosterone concentration were analyzed. Results showed that NCC in a dose-dependent manner improved ovarian cyto-architectural organization and oxidant/anti-oxidant balance along with IVF rate and pre-implantation embryo development in PCOS mice. These findings revealed that NCC at the doses of 25.00 and 50.00 mg kg-1 could alleviate PCOS-linked reproductive disruptions in female mice.

Jail-based medication for opioid use disorder and patterns of reincarceration and acute care use after release: A sequence analysis.

BACKGROUND: Treatment with methadone and buprenorphine medications for opioid use disorder (MOUD) during incarceration may lead to better community re-entry, but evidence on these relationships have been mixed. We aimed to identify community re-entry patterns and examine the association between in-jail MOUD and a pattern of successful reentry defined by rare occurrence of reincarceration and preventable healthcare utilization. METHODS: Data came from a retrospective, observational cohort study of 6066 adults with opioid use disorder who were incarcerated in New York City jails and released to the community during 2011-14. An outcome was community re-entry patterns identified by sequence analysis of 3-year post-release reincarceration, emergency department visits, and hospitalizations. An exposure was receipt of in-jail MOUD versus out-of-treatment (42 % vs. 58 %) for the last 3 days before discharge. The study accounted for differences in baseline demographic, clinical, behavioral, housing, and criminal legal characteristics between in-jail MOUD and out-of-treatment groups via propensity score matching. RESULTS: This study identified five re-entry patterns: stability (64 %), hospitalization (23 %), delayed reincarceration (7 %), immediate reincarceration (4 %), and continuous incarceration (2 %). After addressing confounding, 64 % and 57 % followed the stability pattern among MOUD and out-of-treatment groups who were released from jail in 2011, respectively. In 2012-14, the prevalence of following the stability pattern increased year-by-year while a consistently higher prevalence was observed among those with in-jail MOUD. CONCLUSIONS: Sequence analysis helped define post-release stability based on health and criminal legal system involvement. Receipt of in-jail MOUD was associated with a marker of successful community re-entry.

Resistive switching transparent SnO2 thin film sensitive to light and humidity.

Designing and manufacturing memristor devices with simple and less complicated methods is highly promising for their future development. Here, an Ag/SnO2/FTO(F-SnO2) structure is used through the deposition of the SnO2 layer attained by its sol via the air-brush method on an FTO substrate. This structure was investigated in terms of the memristive characteristics. The negative differential resistance (NDR) effect was observed in environment humidity conditions. In this structure, valance change memory and electrometalization change memory mechanisms cause the current peak in the NDR region by forming an OH- conductive filament. In addition, the photoconductivity effect was found under light illumination and this structure shows the positive photoconductance effect by increasing the conductivity. Memristivity was examined for up to 100 cycles and significant stability was observed as a valuable advantage for neuromorphic computing. Our study conveys a growth mechanism of an optical memristor that is sensitive to light and humidity suitable for sensing applications.

Cost-Effectiveness of Annual Prostate MRI and Potential MRI-Guided Biopsy After Prostate-Specific Antigen Test Results.

Importance: Magnetic resonance imaging (MRI) and potential MRI-guided biopsy enable enhanced identification of clinically significant prostate cancer. Despite proven efficacy, MRI and potential MRI-guided biopsy remain costly, and there is limited evidence regarding the cost-effectiveness of this approach in general and for different prostate-specific antigen (PSA) strata. Objective: To examine the cost-effectiveness of integrating annual MRI and potential MRI-guided biopsy as part of clinical decision-making for men after being screened for prostate cancer compared with standard biopsy. Design, Setting, and Participants: Using a decision analytic Markov cohort model, an economic evaluation was conducted projecting outcomes over 10 years for a hypothetical cohort of 65-year-old men in the US with 4 different PSA strata (<2.5 ng/mL, 2.5-4.0 ng/mL, 4.1-10.0 ng/mL, >10 ng/mL) identified by screening through Monte Carlo microsimulation with 10 000 trials. Model inputs for probabilities, costs in 2020 US dollars, and quality-adjusted life-years (QALYs) were from the literature and expert consultation. The model was specifically designed to reflect the US health care system, adopting a federal payer perspective (ie, Medicare). Exposures: Magnetic resonance imaging with potential MRI-guided biopsy and standard biopsy. Main Outcomes and Measures: Incremental cost-effectiveness ratios (ICERs) using a willingness-to-pay threshold of $100 000 per QALY was estimated. One-way and probabilistic sensitivity analyses were performed. Results: For the 3 PSA strata of 2.5 ng/mL or greater, the MRI and potential MRI-guided biopsy strategy was cost-effective compared with standard biopsy (PSA 2.5-4.0 ng/mL: base-case ICER, $21 131/QALY; PSA 4.1-10.0 ng/mL: base-case ICER, $12 336/QALY; PSA >10.0 ng/mL: base-case ICER, $6000/QALY). Results varied depending on the diagnostic accuracy of MRI and potential MRI-guided biopsy. Results of probabilistic sensitivity analyses showed that the MRI and potential MRI-guided biopsy strategy was cost-effective at the willingness-to-pay threshold of $100 000 per QALY in a range between 76% and 81% of simulations for each of the 3 PSA strata of 2.5 ng/mL or more. Conclusions and Relevance: This economic evaluation of a hypothetical cohort suggests that an annual MRI and potential MRI-guided biopsy was a cost-effective option from a US federal payer perspective compared with standard biopsy for newly eligible male Medicare beneficiaries with a serum PSA level of 2.5 ng/mL or more.

Racial/ethnic differences in receipt of naloxone distributed by opioid overdose prevention programs in New York City.

INTRODUCTION: We evaluated racial/ethnic differences in the receipt of naloxone distributed by opioid overdose prevention programs (OOPPs) in New York City (NYC). METHODS: We used naloxone recipient racial/ethnic data collected by OOPPs from April 2018 to March 2019. We aggregated quarterly neighborhood-specific rates of naloxone receipt and other covariates to 42 NYC neighborhoods. We used a multilevel negative binomial regression model to assess the relationship between neighborhood-specific naloxone receipt rates and race/ethnicity. Race/ethnicity was stratified into four mutually exclusive groups: Latino, non-Latino Black, non-Latino White, and non-Latino Other. We also conducted racial/ethnic-specific geospatial analyses to assess whether there was within-group geographic variation in naloxone receipt rates for each racial/ethnic group. RESULTS: Non-Latino Black residents had the highest median quarterly naloxone receipt rate of 41.8 per 100,000 residents, followed by Latino residents (22.0 per 100,000), non-Latino White (13.6 per 100,000) and non-Latino Other residents (13.3 per 100,000). In our multivariable analysis, compared with non-Latino White residents, non-Latino Black residents had a significantly higher receipt rate, and non-Latino Other residents had a significantly lower receipt rate. In the geospatial analyses, both Latino and non-Latino Black residents had the most within-group geographic variation in naloxone receipt rates compared to non-Latino White and Other residents. CONCLUSIONS: This study found significant racial/ethnic differences in naloxone receipt from NYC OOPPs. We observed substantial variation in naloxone receipt for non-Latino Black and Latino residents across neighborhoods, indicating relatively poorer access in some neighborhoods and opportunities for new approaches to address geographic and structural barriers in these locations.

Prevalence of pathogenic germline variants in adult-type diffuse glioma.

Background: No consensus germline testing guidelines currently exist for glioma patients, so the prevalence of germline pathogenic variants remains unknown. This study aims to determine the prevalence and type of pathogenic germline variants in adult glioma. Methods: A retrospective review at a single institution with paired tumor/normal sequencing from August 2018-April 2022 was performed and corresponding clinical data were collected. Results: We identified 152 glioma patients of which 15 (9.8%) had pathogenic germline variants. Pathogenic germline variants were seen in 11/84 (13.1%) of Glioblastoma, IDH wild type; 3/42 (7.1%) of Astrocytoma, IDH mutant; and 1/26 (3.8%) of Oligodendroglioma, IDH mutant, and 1p/19q co-deleted patients. Pathogenic variants in BRCA2, MUTYH, and CHEK2 were most common (3/15, 20% each). BRCA1 variants occurred in 2/15 (13%) patients, with variants in NF1, ATM, MSH2, and MSH3 occurring in one patient (7%) each. Prior cancer diagnosis was found in 5/15 patients (33%). Second-hit somatic variants were seen in 3/15 patients (20%) in NF1, MUTYH, and MSH2. Referral to genetics was performed in 6/15 (40%) patients with pathogenic germline variants. 14/15 (93%) of patients discovered their pathogenic variant as a result of their paired glioma sequencing. Conclusions: These findings suggest a possible overlooked opportunity for determination of hereditary cancer syndromes with impact on surveillance as well as potential broader treatment options. Further studies that can determine the role of variants in gliomagenesis and confirm the occurrence and types of pathogenic germline variants in patients with IDH wild type compared to IDH mutant tumors are necessary.

Comparison of a national commercial pharmacy naloxone data source to state and city pharmacy naloxone data sources-Rhode Island, Massachusetts, and New York City, 2013-2019.

OBJECTIVE: Accurate naloxone distribution data are critical for planning and prevention purposes, yet sources of naloxone dispensing data vary by location, and completeness of local datasets is unknown. We sought to compare available datasets in Massachusetts, Rhode Island, and New York City (NYC) to a commercially available pharmacy national claims dataset (Symphony Health Solutions). DATA SOURCES AND STUDY SETTING: We utilized retail pharmacy naloxone dispensing data from NYC (2018-2019), Rhode Island (2013-2019), and Massachusetts (2014-2018), and pharmaceutical claims data from Symphony Health Solutions (2013-2019). STUDY DESIGN: We conducted a descriptive, retrospective, and secondary analysis comparing naloxone dispensing events (NDEs) captured via Symphony to NDEs captured by local datasets from the three jurisdictions between 2013 and 2019, when data were available from both sources, using descriptive statistics, regressions, and heat maps. DATA COLLECTION/EXTRACTION METHODS: We defined an NDE as a dispensing event documented by the pharmacy and assumed that each dispensing event represented one naloxone kit (i.e., two doses). We extracted NDEs from local datasets and the Symphony claims dataset. The unit of analysis was the ZIP Code annual quarter. PRINCIPAL FINDINGS: NDEs captured by Symphony exceeded those in local datasets for each time period and location, except in RI following legislation requiring NDEs to be reported to the PDMP. In regression analysis, absolute differences in NDEs between datasets increased substantially over time, except in RI before the PDMP. Heat maps of NDEs by ZIP code quarter showed important variations reflecting where pharmacies may not be reporting NDEs to Symphony or local datasets. CONCLUSIONS: Policymakers must be able to monitor the quantity and location of NDEs in order to combat the opioid crisis. In regions where NDEs are not required to be reported to PDMPs, proprietary pharmaceutical claims datasets may be useful alternatives, with a need for local expertise to assess dataset-specific variability.

Racial/Ethnic differences in receipt of naloxone distributed by opioid overdose prevention programs in New York City.

Introduction: We evaluated racial/ethnic differences in the receipt of naloxone distributed by opioid overdose prevention programs (OOPPs) in New York City (NYC). Methods: We used naloxone recipient racial/ethnic data collected by OOPPs from April 2018 to March 2019. We aggregated quarterly neighborhood-specific rates of naloxone receipt and other covariates to 42 NYC neighborhoods. We used a multilevel negative binomial regression model to assess the relationship between neighborhood-specific naloxone receipt rates and race/ethnicity. Race/ethnicity was stratified into four mutually exclusive groups: Latino, non-Latino Black, non-Latino White and non-Latino Other. We also conducted racial/ethnic-specific geospatial analyses to assess whether there was within-group geographic variation in naloxone receipt rates for each racial/ethnic group. Results: Non-Latino Black residents had the highest median quarterly naloxone receipt rate of 41.8 per 100,000 residents, followed by Latino residents (22.0 per 100,000), non-Latino White (13.6 per 100,000) and non-Latino Other residents (13.3 per 100,000). In our multivariable analysis, compared with non-Latino White residents, non-Latino Black residents had a significantly higher receipt rate and non-Latino Other residents had a significantly lower receipt rate. In the geospatial analyses, both Latino and non-Latino Black residents had the most within-group geographic variation in naloxone receipt rates compared to non-Latino White and Other residents. Conclusions: This study found significant racial/ethnic differences in naloxone receipt from NYC OOPPs. We observed substantial variation in naloxone receipt for non-Latino Black and Latino residents across neighborhoods, indicating relatively poorer access in some neighborhoods and opportunities for new approaches to address geographic and structural barriers in these locations.

Impact of Medication-Based Treatment on Health Care Utilization Among Individuals With Opioid Use Disorder.

OBJECTIVE: This study evaluated the association between medication for opioid use disorder (MOUD) and health care utilization over time among a sample of treatment-seeking individuals with opioid use disorder. In contrast to previous studies, this study used a novel measure of MOUD adherence, more comprehensive utilization data, and analyses that controlled for detailed individual and social determinants of health. METHODS: This study was a secondary analysis of a comparative effectiveness trial (N=570) of extended-release naltrexone versus buprenorphine-naloxone. The outcome of interest was usage of nonstudy acute care, inpatient and outpatient addiction services, and other outpatient services across 36 weeks of assessment. Adherence (percentage of days taking MOUD) was defined as low (<20%), medium (≥20% but <80%), or high (≥80%). A two-part model evaluated the probability of utilizing a resource and the quantity (utilization days) of the resource consumed. A time-varying approach was used to examine the effect of adherence in a given month on utilization in the same month, with analyses controlling for a wide range of person-level characteristics. RESULTS: Participants with high adherence (vs. low) were significantly less likely to use inpatient addiction (p<0.001) and acute care (p<0.001) services and significantly more likely to engage in outpatient addiction (p=0.045) and other outpatient (p=0.042) services. CONCLUSIONS: These findings reinforce the understanding that greater MOUD adherence is associated with reduced usage of high-cost health services and increased usage of outpatient care. The results further suggest the need for enhanced access to MOUD and for interventions that improve adherence.

Remote neuronal activity drives glioma progression through SEMA4F.

The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.

Determinants of health-related quality of life among individuals with opioid use disorder, recently released from incarceration.

BACKGROUND\OBJECTIVES: Concomitant with low rates of pharmacotherapy for incarcerated individuals with OUD, there is a high rate of opioid overdose following re-entry into the community. Our research objective was to develop a better understanding of the factors that influence health-related quality-of-life (HRQoL) among this population during the high-risk transition period from incarceration to community. Few studies have assessed health-related quality-of-life (HRQoL) among individuals with OUD who are involved with the criminal-legal system, let alone over the period directly surrounding release from incarceration. METHODS: Secondary longitudinal analysis of data from a clinical trial where participants were randomized 1:1 to pre-release extended-release naltrexone (XR-NTX) + referral to community XR-NTX, vs. referral only. We conducted individual, multivariable regressions of EQ-5D domains (mobility, pain/discomfort, anxiety/depression; usual activities and self-care were excluded due to insufficient variation in scores), and the overall preference/utility score. HRQoL data were subset to timepoints immediately before release (baseline) and 12 weeks post-release; treatment groups were collapsed across condition. Multiple imputation by chained equations was conducted to handle missing 3-month data in the dependent variables and covariates, ad hoc. RESULTS: Greater severity in the psychiatric composite score was associated with substantially lower HRQoL, across all measures, following release from incarceration. Greater severity in the medical composite score was associated with lower pain/discomfort-related HRQoL. CONCLUSIONS: Our findings highlight the importance of ensuring individuals with OUD are linked not only to MOUD, but also treatment for their comorbid conditions upon release from incarceration.

Effect of Lactobacillus sp. and yeast supplementation on performance and some blood attributes in deoxynivalenol-challenged broiler chickens.

An experiment was conducted to evaluate the effect of different concentrations of probiotic (Lactobacillus sp.) and yeast (Saccharomycese cerevisiae) on performance, organ attributes and blood traits in broiler chickens. A total of 360 one-day-old female broiler chickens (Hubbard)® were allocated to 9 treatments and four replicates (10 birds per replication). The trail was performed in a completely randomized design (3 × 3 factorial arrangement) to examine the interaction effect of three concentrations of Lactobacillus sp. (0, 0.2 and 0.4 g/kg) and yeast (0, 0.75 and 1.5 g/kg) in deoxynivalenol (DON)-contaminated diets. The results showed that consumption of Lactobacillus sp. and yeast in DON-contaminated diets did not have a significant effect on broiler performance except for feed intake during starter period which was enhanced by yeast administration (P < 0.05). Increasing the Lactobacillus sp. content also reduced (P = 0.05) the proportional liver weight. Administration of Lactobacillus sp. to DON diets increased total protein, albumin and globulin concentrations (P < 0.05). Calcium and creatinine were influenced by yeast and Lactobacillus sp., respectively. Yeast (1.5 g/kg) and Lactobacillus sp. (0.2 g/kg) and combination of two additives (1.5 × 0.2) led to lower triglyceride concentration compared to DON group (P < 0.05). The DON diet increased aspartate amino transferase (AST) and lactate dehydrogenase (LDH) enzymes concentrations; while, inclusion of 0.4 g/kg Lactobacillus sp. to DON diet decreased AST and LDH enzymes concentrations (P < 0.05). In conclusion, administration of Lactobacillus sp. and yeast could not influence the performance of DON-fed birds; but these additives could reduce negative effects of DON on enzyme activities and some blood attributes.

Remote neuronal activity drives glioma infiltration via Sema4f.

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.

Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation.

Seizures are a frequent pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of brain hyperactivity and tumor progression; however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these genes, we identify IGSF3 as a mediator of glioma progression and dysregulated neural circuitry that manifests as spreading depolarization (SD). Mechanistically, we discover that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging reveals that dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirm in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.

Disruption of specific white matter tracts is associated with neurogenic lower urinary tract dysfunction in women with multiple sclerosis.

OBJECTIVE: To identify specific white matter tracts (WMTs) whose disruption is associated with the severity of neurogenic lower urinary tract dysfunction (NLUTD) in two independent cohorts of women with multiple sclerosis (MS) and NLUTD. METHODS: Cohort 1 consisted of twenty-eight women with MS and NLUTD. The validation cohort consisted of 10 women with MS and NLUTD. Eleven healthy women served as controls. Participants of both MS cohorts had the same inclusion and exclusion criteria. Both MS cohorts and the healthy controls underwent the same clinical assessment and functional MRI (fMRI) protocol, except that the validation MS cohort underwent 7-Tesla fMRI scan. Fifteen WMTs (six coursing to relevant brainstem areas) involved in bladder control were a priori regions of interest (ROI). Spearman's correlation test was performed between each the Fractional Anisotropy (FA) and mean diffusivity (MD) of each WMT and the clinical parameters. RESULTS: Overall, we found a very high degree of overlap (100% of a priori ROI) in the tracts identified by our correlation analysis as having the greatest contribution to NLUTD symptoms in MS women. The right inferior cerebellar peduncle, left posterior limb of internal capsule, and left superior cerebellar peduncle displayed significant associations to the greatest number of clinical parameters. CONCLUSIONS: Our correlation analysis supports the role of specific WMT disruptions in the contribution of symptoms in women with MS and NLUTD, as confirmed in two independent MS cohorts.

Association between jail-based methadone or buprenorphine treatment for opioid use disorder and overdose mortality after release from New York City jails 2011-17.

BACKGROUND AND AIMS: Opioid overdose is a leading cause of death during the immediate time after release from jail or prison. Most jails in the United States do not provide methadone and buprenorphine treatment for opioid use disorder (MOUD), and research in estimating its impact in jail settings is limited. We aimed to test the hypothesis that in-jail MOUD is associated with lower overdose mortality risk post-release. DESIGN, SETTING AND PARTICIPANTS: Retrospective, observational cohort study of 15 797 adults with opioid use disorder who were released from New York City jails to the community in 2011-2017. They experienced 31 382 incarcerations and were followed up to 1 year. MEASUREMENTS: The primary outcomes were death caused by accidental drug poisoning and all-cause death. The exposure was receipt of MOUD (17 119 events) versus out-of-treatment (14 263 events) during the last 3 days before community re-entry. Covariates included demographic, clinical, behavioral, housing, health-care utilization and legal characteristics variables. We performed a multivariable, mixed-effect Cox regression analysis to test association between in-jail MOUD and deaths. FINDINGS: The majority were male (82%) and their average age was 42 years. Receiving MOUD was associated with misdemeanor charges, being female, injection drug use and homelessness. During 1 year post-release, 111 overdose deaths occurred and crude death rates were 0.49 and 0.83 per 100 person-years for in-jail MOUD and out-of-treatment groups, respectively. Accounting for confounding and random effects, in-jail MOUD was associated with lower overdose mortality risk [adjusted hazard ratio (aHR) = 0.20, 95% confidence interval (CI) = 0.08-0.46] and all-cause mortality risk (aHR = 0.22, 95% CI = 0.11-0.42) for the first month post-release. CONCLUSIONS: Methadone and buprenorphine treatment for opioid use disorder during incarceration was associated with an 80% reduction in overdose mortality risk for the first month post-release.