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.

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.

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 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.

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.

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.

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.

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.

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.

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.

Maytansinoid immunoconjugate IMGN901 is cytotoxic in a three-dimensional culture model of multiple myeloma.

Environmental-mediated drug-resistance (EM-DR) presents a major challenge for therapeutic development. Tissue microenvironment in the form of extracellular matrix, soluble factors, and stroma contribute to EM-DR. In multiple myeloma (MM), drug-resistance has hindered treatment success with 5-year survival rates remaining <50%. Here we evaluated IMGN901, a maytansinoid immunoconjugate, for its ability to overcome EM-DR alone or in combination with lenalidomide or dexamethasone. We show that while adhesion of MM cells to the extracellular matrix reduces potency of IMGN901, it remains cytotoxic with an average LC50=43 nM. However, only a combination of IMGN901, lenalidomide, and dexamethasone was able to overcome drug-resistance arising from the direct contact between MM and stromal cells. We demonstrate that multi-drug resistance protein-1 (MDR-1) was upregulated in MM cells grown in contact with stroma, likely responsible for the observed resistance. This study emphasizes the importance of incorporating the elements of tumor microenvironment during preclinical testing of novel therapeutics.

The effects of combat-related mild traumatic brain injury (mTBI): Does blast mTBI history matter?

BACKGROUND: The effects of mild traumatic brain injury (mTBI) have received significant attention since the beginning of the conflicts in Afghanistan and Iraq. Surprisingly, little is known about the temporal nature of neurocognitive impairment, mTBI, and posttraumatic stress (PTS) symptoms following combat-related mTBI. It is also unclear as to the role that blast exposure history has on mTBI and PTS impairments and symptoms. The purposes of this study were to examine prospectively the effects of mTBI on neurocognitive performance as well as mTBI and PTS symptoms among US Army Special Operations Command personnel and to study the influence of history of blast mTBI on these effects. METHODS: Eighty US Army Special Operations Command personnel with (n = 19) and without (n = 61) a history of blast-related mTBI completed the military version of the Immediate Post-concussion Assessment Cognitive Test (ImPACT), Post Concussion Symptom Scale (PCSS), and the PTSD Checklist (PCL) at baseline as well as 1 day to 7 days and 8 days to 20 days following a combat-related mTBI. RESULTS: Results indicated that verbal memory (p = 0.002) and processing speed (p = 0.003) scores were significantly lower and mTBI symptoms (p = 0.001) were significantly higher at 1 day to 7 days after injury compared with both baseline and 8 days to 20 days after injury. PTS remained stable across the three periods. Participants with a history of blast mTBI demonstrated lower verbal memory at 1 day to 7 days after mTBI compared with participants without a history of blast mTBI (p = 0.02). CONCLUSION: Decreases in neurocognitive performance and increased mTBI symptoms are evident in the first 1 day to 7 days following combat-related mTBI, and a history of blast-related mTBI may influence these effects. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level II.

IMGN853, a Folate Receptor-α (FRα)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors.

A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor α (FRα). Here, we report the development of an anti-FRα antibody-drug conjugate (ADC), consisting of a FRα-binding antibody attached to a highly potent maytansinoid that induces cell-cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FRα monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoid payload into FRα-positive cells. We compared M9346A conjugates with various linker/maytansinoid combinations, and found that a conjugate, now denoted as IMGN853, with the N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) linker and N(2')-deacetyl-N(2')-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) exhibited the most potent antitumor activity in several FRα-expressing xenograft tumor models. The level of expression of FRα on the surface of cells was a major determinant in the sensitivity of tumor cells to the cytotoxic effect of the conjugate. Efficacy studies of IMGN853 in xenografts of ovarian cancer and non-small cell lung cancer cell lines and of a patient tumor-derived xenograft model demonstrated that the ADC was highly active against tumors that expressed FRα at levels similar to those found on a large fraction of ovarian and non-small cell lung cancer patient tumors, as assessed by immunohistochemistry. IMGN853 displayed cytotoxic activity against FRα-negative cells situated near FRα-positive cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FRα. Together, these findings support the clinical development of IMGN853 as a novel targeted therapy for patients with FRα-expressing tumors.

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.

Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models.

Lorvotuzumab mertansine (LM) is an antibody-drug conjugate composed of a humanized anti-CD56 antibody, lorvotuzumab, linked via a cleavable disulfide linker to the tubulin-binding maytansinoid DM1. CD56 is expressed on most small cell lung cancers (SCLC), providing a promising therapeutic target for treatment of this aggressive cancer, which has a poor five-year survival rate of only 5-10%. We performed immunohistochemical staining on SCLC tumor microarrays, which confirmed that CD56 is expressed at high levels on most (~74%) SCLC tumors. Conjugation of lorvotuzumab with DM1 did not alter its specific binding to cells and LM demonstrated potent target-dependent cytotoxicity against CD56-positive SCLC cells in vitro. The anti-tumor activity of LM was evaluated against SCLC xenograft models in mice, both as monotherapy and in combination with platinum/etoposide and paclitaxel/carboplatin. Dose-dependent and antigen-specific anti-tumor activity of LM monotherapy was demonstrated at doses as low as 3 mg/kg. LM was highly active in combination with standard-of-care platinum/etoposide therapies, even in relatively resistant xenograft models. LM demonstrated outstanding anti-tumor activity in combination with carboplatin/etoposide, with superior activity over chemotherapy alone when LM was used in combinations at significantly reduced doses (6-fold below the minimally efficacious dose for LM monotherapy). The combination of LM with carboplatin/paclitaxel was also highly active. This study provides the rationale for clinical evaluation of LM as a promising novel targeted therapy for SCLC, both as monotherapy and in combination with chemotherapy.