Opioid use and COVID-19: a secondary analysis of the impact of relaxation of methadone take-home dosing guidelines on use of illicit opioids.

Background: An exemption to existing U.S. regulation of methadone maintenance therapy after the onset of the COVID-19 pandemic permitted increased take-home doses beginning March 2020.Objectives: We assessed the impact of this exemption on opioid use.Methods: A pre/post study of 187 clients recruited from an OTP who completed a survey and consented to share their urine drug testing (UDT) data. Use of fentanyl, morphine, hydromorphone, codeine, and heroin was assessed via UDT. Receipt of take-home methadone doses was assessed from clinic records for 142 working days pre- and post-COVID exemption. Analysis was conducted using a linear regression model to assess the association between increased take-home doses and use of illicit opioids.Results: In the pre- vs. post-COVID-19 SAMHSA exemption periods, 26.2% vs. 36.3% of UDTs were positive for 6-acetylmorphine respectively, 32.6% vs. 40.6% positive for codeine, 34.2% vs 44.2% positive for hydromorphone, 39.5% vs. 48.1% positive for morphine, 8.0% vs. 14.4% positive for fentanyl (p-value < .001). However, in the unadjusted descriptive data, when grouped by change in substance use, those clients who experienced a decrease in the use of morphine, codeine, and heroin post-COVID-19 were given significantly more take-home doses than the groups that had no change or an increase in the use of these substances. In the adjusted model, there was no significant relationship between change in opioid use and increased receipt of take-home methadone doses.Conclusions: Although take-home doses post-COVID-19 nearly doubled, this increase was not associated with a significant change in use of illicit opioids.

The impact of relaxation of methadone take-home protocols on treatment outcomes in the COVID-19 era.

BACKGROUND: Background: In response to the COVID-19 pandemic, the US Substance Abuse and Mental Health Services Administration (SAMHSA) allowed for an increase in methadone take-home doses for the treatment of Opioid Use Disorder (OUD) in March 2020. OBJECTIVE: To evaluate the effects of the SAMSHA exemption on methadone adherence and OUD-related outcomes. METHODS: A convenience sample of 183 clients (58% female) were recruited from a methadone clinic in the fall of 2019 for a cross-sectional survey. Survey data was linked to clinical records, including urine drug testing (UDT) results for methadone and emergency department (ED) visits at the local hospital. Participants were on stable methadone dosing for 9 months prior to and following March 2020. Methadone adherence was assessed by UDTs; OUD-related outcomes were assessed by overdose events and ED visits. Logistic regression was used to assess the association between change in take-home methadone doses and outcomes. RESULTS: Mean take-home doses increased nearly 200% (11.4 doses/30 days pre-COVID-19 vs. 22.3 post-SAMHSA exemption). ED visits dropped from 74 (40.4%) pre-COVID-19 to 56 (30.6%) post-SAMHSA exemption (p = <0.001). No significant changes were observed in either the number of clients experiencing overdose or those who experienced one or more methadone negative UDTs in the post-SAMHSA exemption period. Adjusted models did not show a significant association between changes in take-home doses and associated outcomes. CONCLUSIONS: Despite a near-doubling of take-home methadone doses during the COVID-19 exemption period, the increase in take-home doses was not associated with negative treatment outcomes in methadone-adherent clients.

Sport-Specific Increased Risk of Anterior Cruciate Ligament Injury Following a Concussion in Collegiate Female Lacrosse.

ABSTRACT: Poor neurocognitive performance has been associated with a greater risk of musculoskeletal injury, and anterior cruciate ligament (ACL) injury prevention protocols include exercises to improve neuromuscular control. Research shows that a concussion elevates the risk for subsequent lower-extremity injury, because concussions lead to lower neurocognitive performance. Studies have been conducted using data within individual male sports, such as football and rugby, or across collegiate sports in aggregate; no study has focused on women's sports. Using 7 years of data collected by athletic training staff at Davidson College, this paper evaluates preconcussive versus postconcussive lower-extremity injury risk across five collegiate women's sports: field hockey, soccer, basketball, volleyball, and lacrosse. Using incidence rate ratios, lacrosse athletes had a five-fold increase in ACL injury risk within 365 d following a concussion. Recognizing that postconcussive ACL tear risk varies across different women's sports is important in informing sport-specific concussion return to play protocols.

The Association Between Obesity, Socio-Economic Status, and Neighborhood Environment: A Multi-Level Analysis of Spokane Public Schools.

Socio economic inequities in obesity have been attributed to individuals' psychosocial and behavioral characteristics. School environment, where children spend a large part of their day, may play an important role in shaping their health. This study aims to assess whether prevalence of overweight and obesity among elementary school students was associated with the school's social and built environments. Analyses were based on 28 public elementary schools serving a total of 10,327 children in the city of Spokane, Washington. Schools were classified by percentage of students eligible for free and reduced meals (FRM). Crime rates, density of arterial roads, healthy food access, and walkability were computed in a one-mile walking catchment around schools to characterize their surrounding neighborhood. In the unadjusted multilevel logistic regression analyses, age, sex, percentage of students eligible for FRM, crime, walkability, and arterial road exposure were individually associated with the odds of being overweight or obese. In the adjusted model, the odds of being overweight or obese were higher with age, being male, and percentage of students eligible for FRM. The results call for policies and programs to improve the school environment, students' health, and safety conditions near schools.

Spatial access to opioid treatment program and alcohol and cannabis outlets: analysis of missed doses of methadone during the first, second, and third 90 days of treatment.

Background: The burden of access to opioid treatment programs (OTPs) may change as clients become eligible for take-home privileges. Our previous study showed clients who lived more than 10-miles away from an OTP were more likely to miss methadone doses during the first 30 days of treatment. Proximity to alcohol and cannabis outlets may also negatively influence treatment adherence.Objective: To examine the association between access to this OTP, alcohol and cannabis outlets, and the number of missed methadone doses during the first, second, and third 90 days of treatment.Methods: The number of missed methadone doses was calculated for 752, 689, and 584 clients who remained in treatment, respectively, for at least 3, 6, and 9 months (50% female). Distance between client's home and the OTP, alcohol, and cannabis outlets was measured. Generalized linear models were employed.Results: Shorter distance from a client's residence to the OTP was associated with a decreased number of missed methadone doses during the first 90 days of treatment. Shorter distance to the closest cannabis retail outlet was associated with an increased number of missed methadone doses during the first and second 90 days of treatment. Shorter distance to the closest off-premise alcohol outlet was associated with an increased number of missed methadone doses during the third 90 days of treatment.Conclusions: Improving spatial accessibility of OTPs are essential to ensure treatment opportunities are available for individuals so affected. Exploring to what extent residing in areas that facilitate alcohol and cannabis availability can influence treatment adherence is warranted.

A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies.

CD37 has gathered renewed interest as a therapeutic target in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, CD37-directed antibody-drug conjugates (ADCs) have not been explored. Here, we identified a novel anti-CD37 antibody, K7153A, with potent in vitro activity against B-cell lines through multiple mechanisms including apoptosis induction, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. The antibody was conjugated to the maytansinoid, DM1, a potent antimicrotubule agent, via the thioether linker, N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and the resulting ADC, IMGN529, retained the intrinsic antibody activities and showed enhanced cytotoxic activity from targeted payload delivery. In lymphoma cell lines, IMGN529 induced G2/M cell cycle arrest after internalization and lysosomal processing to lysine-N(ε)-SMCC-DM1 as the sole intracellular maytansinoid metabolite. IMGN529 was highly active against subcutaneous B-cell tumor xenografts in severe combined immunodeficient mice with comparable or better activity than rituximab, a combination of cyclophosphamide, vincristine, and prednisone, or bendamustine. In human blood cells, CD37 is expressed in B cells at similar levels as CD20, and IMGN529 resulted in potent and specific depletion of normal and CLL B cells. These results support evaluation of the CD37-targeted ADC, IMGN529, in clinical trials in patients with B-cell malignancies including NHL and CLL.

Design of Coltuximab Ravtansine, a CD19-Targeting Antibody-Drug Conjugate (ADC) for the Treatment of B-Cell Malignancies: Structure-Activity Relationships and Preclinical Evaluation.

Coltuximab ravtansine (SAR3419) is an antibody-drug conjugate (ADC) targeting CD19 created by conjugating a derivative of the potent microtubule-acting cytotoxic agent, maytansine, to a version of the anti-CD19 antibody, anti-B4, that was humanized as an IgG1 by variable domain resurfacing. Four different linker-maytansinoid constructs were synthesized (average ∼3.5 maytansinoids/antibody for each) to evaluate the impact of linker-payload design on the activity of the maytansinoid-ADCs targeting CD19. The ADC composed of DM4 (N(2')-deacetyl-N(2')-[4-mercapto-4-methyl-1-oxopentyl]maytansine) conjugated to antibody via the N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB) linker was selected for development as SAR3419. A molar ratio for DM4/antibody of between 3 and 5 was selected for the final design of SAR3419. Evaluation of SAR3419 in Ramos tumor xenograft models showed that the minimal effective single dose was about 50 µg/kg conjugated DM4 (∼2.5 mg/kg conjugated antibody), while twice this dose gave complete regressions in 100% of the mice. SAR3419 arrests cells in the G2/M phase of the cell cycle, ultimately leading to apoptosis after about 24 h. The results of in vitro and in vivo studies with SAR3419 made with DM4 that was [(3)H]-labeled at the C20 methoxy group of the maytansinoid suggest a mechanism of internalization and intracellular trafficking of SAR3419, ultimately to lysosomes, in which the antibody is fully degraded, releasing lysine-N(ε)-SPDB-DM4 as the initial metabolite. Subsequent intracellular reduction of the disulfide bond between linker and DM4 generates the free thiol species, which is then converted to S-methyl DM4 by cellular methyl transferase activity. We provide evidence to suggest that generation of S-methyl DM4 in tumor cells may contribute to in vivo tumor eradication via bystander killing of neighboring tumor cells. Furthermore, we show that S-methyl DM4 is converted to the sulfoxide and sulfone derivatives in the liver, suggesting that hepatic catabolism of the payload to less cytotoxic maytansinoid species contributes to the overall therapeutic window of SAR3419. This compound is currently in phase II clinical evaluation for the treatment of diffuse large B cell lymphoma.

Fulminant pulmonary tuberculosis in a previously healthy young woman from the Marshall Islands: Potential risk factors.

A 19-year-old woman originally from the Republic of the Marshall Islands presented with diffuse pneumonia and acute hypoxemic respiratory failure. She dies one month into her hospitalization but the diagnosis of pulmonary tuberculosis (TB) was not made until one day before her demise. A contact investigation screened a total of 155 persons with 36 (23%) found to have latent TB infection and seven (4.5%) with active pulmonary TB. This unfortunate case provided the opportunity to analyze the epidemiology of TB in the state of Washington in the context of those who emigrated from the Marshall Islands. The development of fulminant pulmonary TB in this previously healthy young woman also provides a segue to discuss potential risk factors for TB in the index case that include: (i) foreign-born in a TB-endemic country; (ii) race and genetic factors; (iii) age; (iv) body habitus; (v) pregnancy; and (vi) use of glucocorticoids.

Changes in methadone take-home dosing before and after COVID-19.

INTRODUCTION: In response to the COVID-19 pandemic, a federal exemption allowed stable and less stable patients greater take-home doses of methadone. We assessed the adoption of increased take-home medication during COVID-19 and whether increased take-home doses is associated with clients' characteristics. METHODOLOGY: We completed a pre-post study of adults receiving methadone for OUD from an OTP in Spokane, Washington. Our outcome was the change in the number of take-home methadone doses three months before and three months after the March 2020 take-home medication exemption. Clients' characteristics included age, gender, ethnicity, education level, homelessness, spatial access to the clinic, and methamphetamine use. RESULTS: The study included 194 clients in treatment for a median of three years. All study participants experienced an average increase in take-home medication of 41.4 in the three-month period after the COVID-19 exemption. In the final adjusted models, clients who reported using methamphetamine in the last 30 days experienced a significantly larger increase in take-home dosage (55.6 days) compare to clients who did not use methamphetamine (p ≤0.001). Most of the clients who reported using methamphetamine were also likely to be homeless. All other variables were not associated with a change in take-home doses. CONCLUSION: These results suggest that the Spokane OTP quickly expanded take-home medication dosing in response to the COVID-19 exemption and broadly expanded take-home dosing among established clients. Clients with concurrent methamphetamine use were allowed fewer take-home doses prior to COVID-19, but after the exemption the clinic provided them the same number of take-home doses as clients who had not used methamphetamine.

Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage.

In this report, we describe the synthesis of a panel of disulfide-linked huC242 (anti-CanAg) antibody maytansinoid conjugates (AMCs), which have varying levels of steric hindrance around the disulfide bond, in order to investigate the relationship between stability to reduction of the disulfide linker and antitumor activity of the conjugate in vivo. The conjugates were first tested for stability to reduction by dithiothreitol in vitro and for plasma stability in CD1 mice. It was found that the conjugates having the more sterically hindered disulfide linkages were more stable to reductive cleavage of the maytansinoid in both settings. When the panel of conjugates was tested for in vivo efficacy in two human colon cancer xenograft models in SCID mice, it was found that the conjugate with intermediate disulfide bond stability having two methyl groups on the maytansinoid side of the disulfide bond and no methyl groups on the linker side of the disulfide bond (huC242-SPDB-DM4) displayed the best efficacy. The ranking of in vivo efficacies of the conjugates was not predicted by their in vitro potencies, since all conjugates were highly active in vitro, including a huC242-SMCC-DM1 conjugate with a noncleavable linkage which showed only marginal activity in vivo. These data suggest that factors in addition to intrinsic conjugate potency and conjugate half-life in plasma influence the magnitude of antitumor activity observed for an AMC in vivo. We provide evidence that bystander killing of neighboring nontargeted tumor cells by diffusible cytotoxic metabolites produced from target cell processing of disulfide-linked antibody-maytansinoid conjugates may be one additional factor contributing to the activity of these conjugates in vivo.

Transient Quadriplegia: A Case-Based Approach to Cervical Trauma.

INTRODUCTION: Spinal cord injuries are a common reason for presentation to the emergency department (ED). Sports-related spinal injuries are one of the least common spinal injuries, falling behind vehicular accidents, acts of violence, and falls. CASE REPORT: This case report describes a case of transient quadriplegia in a 17-year-old male who presented to the ED after a helmet-to-helmet collision while participating in football. CONCLUSION: Emergency physicians should be cognizant of potential spinal cord injury using clinical decision tools and radiologic imaging to properly disposition a patient presenting with cervical spine injury.

The Warrior Model for Human Performance Optimization.

Special Operations Combat Personnel (SOCP) face significant challenges and occupational demands that put them at significant risk for musculoskeletal injury. Musculoskeletal injury leads to lost-duty days, medical disqualification, and compromises operational readiness and mission success. Optimizing human performance and developing injury prevention strategies can position SOCP for success, but human performance optimization is a complex process that demands the integration of multiple disciplines to address a broad range of capabilities necessary for this success. The Warrior Model for Human Performance Optimization outlines a step-by-step approach to human performance optimization embedded within a scientific, evidenced-based approach to injury prevention and performance optimization that includes a step to ensure specificity of training and interventions. This evidence-based approach can insure that SOCP capabilities match the demands of occupation enabling them to successfully execute their occupation tasks without risk of injury. While the focus of this review is on military personnel, the same principles have application to nonmilitary high-performance athletes.

Alphav integrin-targeted immunoconjugates regress established human tumors in xenograft models.

PURPOSE: Targeted delivery of cytotoxic agents to solid tumors through cell surface antigens can potentially reduce systemic toxicity and increase the efficacy of the targeted compounds. The purpose of this study was to show the feasibility of treating solid tumors by targeting alpha(v) integrins with antibody-maytansinoid conjugates and to test the relative in vivo activities of several linker-maytansinoid chemistries. EXPERIMENTAL DESIGN: CNTO 364, CNTO 365, and CNTO 366 are targeted cytotoxic agents created by conjugating the CNTO 95 anti-alpha(v) integrin antibody with three distinct maytansinoid-linker structures. These structures were designed to have varying degrees of chemical substitution surrounding the disulfide bond linking the cytotoxic agent to the antibody. A model conjugate was shown to be specifically cytotoxic in vitro and highly active against established human tumor xenografts in immunocompromised rats. The in vivo antitumor activities of CNTO 364, CNTO 365, and CNTO 366 were compared in rat xenograft models. RESULTS: CNTO 365, with a linker chemistry of expected intermediate stability, was shown to be substantially more active than the other two conjugates with lesser or greater substitution around the disulfide linkage. CONCLUSION: CNTO 95-maytansinoid immunoconjugates are potent antitumor agents against alpha(v) integrin-expressing human carcinomas. These studies show for the first time the feasibility of targeting alpha(v) integrins on solid tumors with tumor-activated prodrugs. The DM4 linker-maytansinoid configuration of CNTO 365 was substantially more active in the models tested here when compared with alternative configurations with greater or lesser chemical substitution surrounding the linker.

Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing.

Antibody-drug conjugates are targeted anticancer agents consisting of a cytotoxic drug covalently linked to a monoclonal antibody for tumor antigen-specific activity. Once bound to the target cell-surface antigen, the conjugate must be processed to release an active form of the drug, which can reach its intracellular target. Here, we used both biological and biochemical methods to better define this process for antibody-maytansinoid conjugates. In particular, we examined the metabolic fate in cells of huC242-maytansinoid conjugates containing either a disulfide linker (huC242-SPDB-DM4) or a thioether linker (huC242-SMCC-DM1). Using cell cycle analysis combined with lysosomal inhibitors, we showed that lysosomal processing is required for the activity of antibody-maytansinoid conjugates, irrespective of the linker. We also identified and characterized the released maytansinoid molecules from these conjugates, and measured their rate of release compared with the kinetics of cell cycle arrest. Both conjugates are efficiently degraded in lysosomes to yield metabolites consisting of the intact maytansinoid drug and linker attached to lysine. The lysine adduct is the sole metabolite from the thioether-linked conjugate. However, the lysine metabolite generated from the disulfide-linked conjugate is reduced and S-methylated to yield the lipophilic and potently cytotoxic metabolite, S-methyl-DM4. These findings provide insight into the mechanism of action of antibody-maytansinoid conjugates in general, and more specifically, identify a biochemical mechanism that may account for the significantly enhanced antitumor efficacy observed with disulfide-linked conjugates.

Increased distance was associated with lower daily attendance to an opioid treatment program in Spokane County Washington.

OBJECTIVE: Adherence to opioid agonist therapy with methadone is associated with improved clinical and community outcomes such as reductions in drug use, criminal behavior, high-risk sexual behavior, and mortality. However, the need for daily attendance for witnessed ingestion may comprise adherence. METHODS: Data for this study were obtained from the Spokane Regional Health District's Treatment Services database. Generalized linear models with negative binomial log link function were used to assess the association between distance to the only state-funded opioid treatment program (OTP) in Spokane County, Washington and the number of missed methadone doses in the first month of treatment. RESULTS: In total, 892 individuals received methadone treatment at this OTP between February 2015 and December 2017. In the adjusted multivariable model, clients who lived more than 10 miles from the OTP were more likely to miss doses compared to individuals who lived within 5 miles of the clinic (IRR = 1.29, 95%CI = 1.03-1.61, p = 0.03). Clients who lived less than 5 miles and between 5 and 10 miles from the OTP were equally likely to miss treatment doses (IRR = 1.02, 95%CI = 0.84-1.23, p = 0.86). CONCLUSIONS: This study found significant positive associations between distance to an OTP and the number of missed doses in the first month of treatment. Findings suggest the need to improve the spatial availability of OTPs to optimize opioid use disorder treatment outcomes.

Three-year retention in methadone opioid agonist treatment: A survival analysis of clients by dose, area deprivation, and availability of alcohol and cannabis outlets.

OBJECTIVE: To determine the effect of clinical, socio-demographic, and contextual characteristics on treatment retention in an opioid treatment program (OTP). METHODS: A retrospective longitudinal review of 851 clients who received methadone at the only state-funded OTP in Spokane County, Washington between 2015 and 2017. A time variable (the number of days in treatment) and a status indicator (to distinguish between clients who dropped out or censored) worked together to define retention in treatment. Our hypothesized covariates included: area deprivation, distance to the OTP, availability of cannabis retail outlets, availability of on-premise and off-premise alcohol outlets, methadone dosage, age, gender, race, and years on treatment. Cox regression within the family of survival analysis was used to model time-to-event data in the presence of censored cases. RESULTS: The median duration of retention was 394 (95%CI = 324-464) days. In the multivariable Cox regression, factors predicting treatment retention were area deprivation (HR = 1.79, 95%CI = 1.02-3.15, p = 0.04), age (HR=0.99, 95%CI=0.98-.99, p = 0.008), dosage of methadone (HR=0.98, 95%CI=0.98-0.98, p < 0.001), and the number of years on treatment (HR=1.12, 95%CI=1.06-1.18, p < 0.001). CONCLUSIONS: The findings of this study showed age and methadone dosage were protective factors and area deprivation and years on treatment were risk factors for treatment retention. After dichotomizing methadone dosage, a unique finding of this study was that higher dosage of methadone did not lead to increasingly smaller HRs for dropping out of treatment. Considering that opioid use disorder is a chronic condition, efforts need to be made to target factors associated with retention.

Assessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: Sustained-release intravitreal drug implants for posterior segment diseases are associated with significant complications. As an alternative, subconjunctival infusions of drug to the episclera of the back of the eye have been performed, but results in clinical trials for macular diseases showed mixed RESULTS: To improve understanding of transscleral drug delivery to the posterior segment, the distribution and clearance of gadolinium-diethylene-triamino-penta-acetic acid (Gd-DTPA) infused in the subconjunctival or intrascleral space was investigated by means of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS: In anesthetized rabbits, catheters were placed anteriorly in the subconjunctival or intrascleral space and infused with Gd-DTPA at 1 and 10 muL/min. Distribution and clearance of Gd-DTPA were measured using DCE-MRI. Histologic examination was performed to assess ocular toxicity of the delivery system. results. Subconjunctival infusions failed to produce detectable levels of Gd-DTPA in the back of the eye. In contrast, intrascleral infusions expanded the suprachoroidal layer and delivered Gd-DTPA to the posterior segment. Suprachoroidal clearance of Gd-DTPA followed first-order kinetics with an average half-life of 5.4 and 11.8 minutes after intrascleral infusions at 1 and 10 muL/min, respectively. Histologic examination demonstrated expansion of the tissues in the suprachoroidal space that normalized after infusion termination. CONCLUSIONS: An intrascleral infusion was successful in transporting Gd-DTPA to the posterior segment from an anterior infusion site with limited anterior segment exposure. The suprachoroidal space appears to be an expandible conduit for drug transport to the posterior segment. Further studies are indicated to explore the feasibility of clinical applications.