National Institute on Drug Abuse Clinical Trials Network Meeting Report: Managing Patients Exposed to Xylazine-Adulterated Opioids in Emergency, Hospital and Addiction Care Settings.

Used as a veterinary sedative and not approved for human use, xylazine has been increasingly linked with opioid overdose deaths in the United States. A growing number of people have been exposed to xylazine in the illicit opioid supply (especially fentanyl) or in other drugs, particularly in some areas of the Northeast. Xylazine is an α-2 adrenergic agonist that decreases sympathetic nervous system activity. When combined with fentanyl or heroin, it is purported to extend the duration of the opioid's sedative effect and to cause dependence and an associated withdrawal syndrome; however, data to support these concerns are limited. Despite the escalating frequency of detection of xylazine in people with nonfatal and fatal opioid overdose, direct links to these outcomes have not been identified. Because the strongest causal link is to fentanyl coexposure, ventilatory support and naloxone remain the cornerstones of overdose management. Xylazine is also associated with severe tissue injury, including skin ulcers and tissue loss, but little is known about the underlying mechanisms. Nonetheless, strategies for prevention and treatment are emerging. The significance and clinical effects of xylazine as an adulterant is focused on 4 domains that merit further evaluation: fentanyl-xylazine overdose, xylazine dependence and withdrawal, xylazine-associated dermal manifestations, and xylazine surveillance and detection in clinical and nonclinical settings. This report reflects the Proceedings of the National Institute on Drug Abuse Center for the Clinical Trials Network convening of clinical and scientific experts, federal staff, and other stakeholders to describe emerging best practices for treating people exposed to xylazine-adulterated opioids. Participants identified scientific gaps and opportunities for research to inform clinical practice in emergency departments, hospitals, and addiction medicine settings.

Media framing xylazine as a "zombie drug" is amplifying stigma onto people who use drugs.

Amid increasing efforts to understand xylazine-associated harms, examining the potentially catastrophic role of stigma resulting from media outlets framing xylazine as the "zombie drug" is imperative. Zombies are cinematically depicted as soulless, dangerous, and required to be killed off entirely for public safety, making the "zombie" analogy especially grave amid the fatal overdose crisis. Xylazine is called the "zombie drug" due to its heavy sedative effect and associated-severely infected skin ulcers. We surmise that wide-scale media framing of xylazine as the "zombie drug" has increased stigmas onto people who use drugs as their likening to zombies reifies subhuman status. The present commentary highlights many media headlines and quotes that use "zombie" terminology when writing about xylazine, and examine how this expansive media framing amplifies stigmas. Xylazine's proliferation in the illicit drug market will likely increase infected ulcers needing medical attention. People who use drugs are often reluctant to seek medical care due to experiences of medically-institutionalized stigma. Based on the media's extensive depiction of xylazine as the "zombie drug," it is plausible that medical practitioners have been exposed to this stigmatizing framing, which could unknowingly detrimentally impact provision of medical care. Strategies to offset harms of xylazine-associated stigmas are proposed, including that medical practitioners undergo evidence-based training to reduce stigmatizing responses to severe xylazine-associated ulcers as any indication of enacted stigma can be internalized by the person seeking treatment, which in turn can perpetuate harms like sepsis or overdose. Author ethnographic observations of xylazine presence are included, which encompass three distinct urban settings that span North America. Finally, we suggest approaches media outlets could adopt to reflect on how referring to xylazine as the "zombie" drug amplifies stigmas onto people already surviving under structural conditions heightening physical and mental trauma, and use language instead that could aid in lessening these harms.

"Once I take that one bite": the consideration of harm reduction as a strategy to support dietary change for patients with diabetes.

BACKGROUND: Despite well-established guidelines to treat diabetes, many people with diabetes struggle to manage their disease. For many, this struggle is related to challenges achieving nutrition-related lifestyle changes. We examined how people with diabetes describe barriers to maintaining a healthy diet and considered the benefits of using a harm reduction approach to assist patients to achieve nutrition-related goals. METHODS: This is a secondary analysis of 89 interviews conducted with adults who had type 1 or type 2 diabetes. Interviews were analyzed using a content analysis approach. Themes regarding food or diet were initially captured in a "food" node. Data in the food node were then sub-coded for this analysis, again using a content analysis approach. RESULTS: Participants frequently used addiction language to talk about their relationship with food, at times referring to themselves as "an addict" and describing food as "their drug." Participants perceived their unhealthy food choices either as a sign of weakness or as "cheating." They also identified food's ability to comfort them and an unwillingness to change as particular challenges to sustaining a healthier diet. CONCLUSION: Participants often described their relationship with food through an addiction lens. A harm reduction approach has been associated with positive outcomes among those with substance abuse disorder. Patient-centered communication incorporating the harm reduction model may improve the patient-clinician relationship and thus improve patient outcomes and quality-of-life while reducing health-related stigma in diabetes care. Future work should explore the effectiveness of this approach in patients with diabetes. TRIAL REGISTRATION: Registered on ClinicalTrials.gov, NCT02792777. Registration information submitted 02/06/2016, with the registration first posted on the ClinicalTrials.gov website 08/06/2016. Data collection began on 29/04/2016.

Recommendations from people who use drugs in Philadelphia, PA about structuring point-of-care drug checking.

BACKGROUND: Adulterants, such as fentanyl and xylazine, among others, are present in a high percentage of the illicit drug supply, increasing the risk for overdose and other adverse health events among people who use drugs (PWUD). Point-of-care drug checking identifies components of a drug sample and delivers results consumers. To successfully meet the diverse needs of PWUD, more information is needed about the utility of drug checking, motivations for using services contextualized in broader comments on the drug supply, hypothesized actions to be taken after receiving drug checking results, and the ideal structure of a program. METHODS: In December 2021, semi-structured interviews were conducted with 40 PWUD who were accessing harm reduction services in Philadelphia, PA. Participants were asked about opinions and preferences for a future drug checking program. Interviews were audio recorded, transcribed and coded using content analysis to identify themes. RESULTS: Participants were primarily White (52.5%) and male (60%). Heroin/fentanyl was the most frequently reported drug used (72.5%, n = 29), followed by crack cocaine (60.0%, n = 24) and powder cocaine (47.5%, n = 19). Emerging themes from potential drug checking consumers included universal interest in using a drug checking program, intentions to change drug use actions based on drug checking results, deep concern about the unpredictability of the drug supply, engaging in multiple harm reduction practices, and concerns about privacy while accessing a service. CONCLUSIONS: We offer recommendations for sites considering point-of-care drug checking regarding staffing, safety, logistics, and cultural competency. Programs should leverage pre-existing relationships with organizations serving PWUD and hire people with lived experiences of drug use. They should work with local or state government to issue protections to people accessing drug checking programs and ensure the service is anonymous and that data collection is minimized to keep the program low-threshold. Programs will ideally operate in multiple locations and span "atmosphere" (e.g., from clinical to a drop-in culture), offer in-depth education to participants about results, engage with a community advisory board, and not partner with law enforcement.

Making Harm Reduction More Accessible: Fentanyl Test Strip Awareness and Attitudes among Emergency Department Patients Who Use Drugs.

BACKGROUND: Fentanyl test strips (FTS) are a harm reduction method for people to test their drugs for fentanyl. Ideal points for FTS distribution have not been identified. Many people who use drugs have frequent contact with the Emergency Department (ED). We piloted FTS distribution in two urban hospital EDs. METHODS: Between June-December 2021 in Philadelphia, PA, patients with past 30-day drug use completed a survey about drug use, fentanyl attitudes, and FTS; then offered FTS and a brief training. Survey data were analyzed using SPSS for bivariate statistics. RESULTS: Patients (n = 135) were primarily White (68.1%) and male (72.6%). Participants regularly interacted with substance use (57.8%) and benefits coordination (49.6%) services. The most common drugs used were heroin/fentanyl (68.9%), crack cocaine (45.2%) and cannabis (40.0%). Most (98.5%) had heard of fentanyl though few (18.5%) had ever used FTS. Across most drug types, participants were concerned about fentanyl. All accepted FTS training and distribution. Few (9.6%) were somewhat or very concerned about having FTS if stopped by police and this number varied by race (7.6% of White people were somewhat or very concerned, compared to 12.8% of Black people). Most participants were already engaged in risk reduction practices. DISCUSSION: FTS are a widely desired harm reduction tool to facilitate informed decision-making, and non-harm reduction locations are potentially feasible and acceptable distribution sites. Given regular contact with EDs and social services across the sample, FTS should be offered at non-harm reduction locations that come into frequent contact with people who use drugs.

The Facilitators and Barriers to Digital Health for Managing Nutrition in People With Parkinson's Disease and Their Caregivers: A Formative, Qualitative Study.

OBJECTIVE: Identify techniques to assist in designing digital health platforms for nutrition services for people with Parkinson's disease and caregivers to improve their quality of life. DESIGN: Semistructured, dyadic interviews with 20 dyads (20 people with Parkinson's disease and 20 caregivers). SETTING: Home visits were conducted in the northeast US. PARTICIPANTS: People with Parkinson's disease and their caregivers were recruited via email, flyers, news articles and announcements at support groups. PHENOMENON OF INTEREST: Identification of facilitators and barriers to using digital health platforms to inform future digital nutrition services. ANALYSIS: Interviews were recorded, transcribed and double-coded using a framework analysis method. RESULTS: Reported digital health platforms utilization facilitators were: knowledge acquisition, convenience, intention to use, socializing, enjoyment, and forced adoption. Barriers included: negative feelings toward technology, lack of access or knowledge, disinterest, product design, frustration and functional reliability, and applying health information. CONCLUSIONS AND IMPLICATIONS: Although dyads often lack knowledge on both how to use technology and nutrition, they are willing to use digital health platforms to increase their nutrition knowledge if platforms are convenient. Based on the identified facilitators and barriers, the added benefits of access and training nutrition digital health platforms must be clearly communicated to end-users to improve their quality of life.

A Qualitative Analysis of Hospitalist Perceptions of Self-Directed Discharge Among Inpatients with Opioid Use Disorder.

Background: People with opioid use disorder (OUD) have high rates of hospital admissions and high rates of patient-directed discharge, leading to significant morbidity and mortality. In this study, we aimed to understand hospitalist attitudes toward patients with OUD leaving before treatment completion and their willingness to collaborate with patients in future initiatives focused on improving the experience of hospital-based care for patients with OUD. Methods: We conducted semi-structured interviews with hospitalists at two hospitals in Philadelphia, PA to explore their perspectives on social and structural factors that contribute to patients with OUD leaving the hospital before treatment completion. Interviews were recorded, transcribed, and coded with NVivo using conventional content analysis. Results: Twenty-two hospitalists (64% female, 72.7% White, mean age 37) were interviewed between February and April 2021. Hospitalists listed the following as reasons for patients with OUD leaving before treatment completion: untimely and inadequate pain/withdrawal treatment, limited prescribing options in medications for OUD, restrictive visitor and smoking policies, and patient social and other obligations. Twenty out of 22 hospitalists were willing to engage in collaborative patient-centered care but noted institutional barriers. Conclusion: Hospitalists stated willingness to collaborate with patients on identifying and developing systems-level solutions that would allow for patient-centered care. In-hospital access to addiction consult service, staff with lived experience, and other culturally competent resources are key to reducing self-directed discharge, as is training to address stigma and reframe perceptions of appropriate dosing for pain and withdrawal. Hospitalists note a need for transitions to outpatient care after hospital discharge.

The interaction of race and age in methadone treatment retention outcomes: A single-center analysis.

OBJECTIVES: Early treatment drop-out is due to the unique interplay of the individual and their context, and is associated with overdose death. The objective of this project was to determine if age or race is associated with 6-month treatment retention outcome differences at a single-center opioid treatment program. METHODS: The study team performed a retrospective administrative database study from January 2014 to January 2017 using admission data with age and race as predictors of 6-month treatment retention outcomes. RESULTS: Of the 457 admissions, 114 were under the age of 30; however, only 4 % of these young adults were Black, Indigenous, and/or People of Color (BIPOC). While retention for BIPOC patients (62 %) was slightly higher than for White patients (57 %), this difference did not reach traditional levels of significance. CONCLUSIONS: Once BIPOC enter treatment, their treatment retention is similar to their White counterparts. Young adult BIPOC were less represented in the admission data, but treatment retention across racial groups was similar. An urgent need exists to determine the barriers and facilitators to treatment access among BIPOC young adults.

CAR-T Therapies in Solid Tumors: Opportunities and Challenges.

PURPOSE OF REVIEW: This review will discuss the challenges facing chimeric antigen receptor (CAR)-T cell application for solid tumors and opportunities to overcome these obstacles. In addition, this review will examine therapies that are in development for pediatric solid tumors. RECENT FINDINGS: The similar success of CAR-T cell treatment for hematological malignancies has not been observed in solid tumors because of the hostile tumor microenvironment and tumor heterogeneity. Most strategies developed to combat these limitations emphasize combinatorial techniques that still require further testing. Preliminary results of multiple clinical trials, including GD2- and HER2-CAR-T cells, are encouraging but must be reproduced and validated on a larger scale. CAR-T cell application in solid tumors remains challenging, and most research is in development. Several clinical trials are ongoing for pediatric solid tumors. Early results are promising but demonstrate the need for CAR-T cell modification to prevent tumor recurrence.

CAR T-cells to treat brain tumors.

Tremendous success using CAR T therapy in hematological malignancies has garnered significant interest in developing such treatments for solid tumors, including brain tumors. This success, however, has yet to be mirrored in solid organ neoplasms. CAR T function has shown limited efficacy against brain tumors due to several factors including the immunosuppressive tumor microenvironment, blood-brain barrier, and tumor-antigen heterogeneity. Despite these considerations, CAR T-cell therapy has the potential to be implemented as a treatment modality for brain tumors. Here, we review adult and pediatric brain tumors, including glioblastoma, diffuse midline gliomas, and medulloblastomas that continue to portend a grim prognosis. We describe insights gained from different preclinical models using CAR T therapy against various brain tumors and results gathered from ongoing clinical trials. Furthermore, we outline the challenges limiting CAR T therapy success against brain tumors and summarize advancements made to overcome these obstacles.

Sorting through life: evaluating patient-important measures of success in a medication for opioid use disorder (MOUD) treatment program.

BACKGROUND: Medication for opioid use disorder (MOUD) is the gold standard treatment for opioid use disorder. Traditionally, "success" in MOUD treatment is measured in terms of program retention, adherence to MOUD, and abstinence from opioid and other drug use. While clinically meaningful, these metrics may overlook other aspects of the lives of people with opioid use disorder (OUD) and surprisingly do not reflect the diagnostic criteria for OUD. METHODS: Authors identified items for a pilesorting task to identify participant-driven measures of MOUD treatment success through semi-structured interviews. Interviews were transcribed verbatim and coded in Nvivo using directed and conventional content analysis to identify measures related to treatment success and quality of life goals. Participants of a low-threshold MOUD program were recruited and asked to rank identified measures in order of importance to their own lives. Multidimensional scaling (MDS) compared the similarity of items while non-metric MDS in R specified a two-dimensional solution. Descriptive statistics of participant demographics were generated in SPSS. RESULTS: Sixteen semi-structured interviews were conducted between June and August 2020 in Philadelphia, PA, USA, and 23 measures were identified for a pilesorting activity. These were combined with 6 traditional measures for a total list of 29 items. Data from 28 people were included in pilesorting analysis. Participants identified a combination of traditional and stakeholder-defined recovery goals as highly important, however, we identified discrepancies between the most frequent and highest ranked items within the importance categories. Measures of success for participants in MOUD programs were complex, multi-dimensional, and varied by the individual. However, some key domains such as emotional well-being, decreased drug use, and attendance to basic functioning may have universal importance. The following clusters of importance were identified: emotional well-being, decreased drug use, and human functioning. CONCLUSIONS: Outcomes from this research have practical applications for those working to provide services in MOUD programs. Programs can use aspects of these domains to both provide patient-centered care and to evaluate success. Specifics from the pilesorting results may also inform approaches to collaborative goal setting during treatment.

Genetic Encoding of a Photocaged Histidine for Light-Control of Protein Activity.

The use of light to control protein function is a critical tool in chemical biology. Here we describe the addition of a photocaged histidine to the genetic code. This unnatural amino acid becomes histidine upon exposure to light and allows for the optical control of enzymes that utilize active-site histidine residues. We demonstrate light-induced activation of a blue fluorescent protein and a chloramphenicol transferase. Further, we genetically encoded photocaged histidine in mammalian cells. We then used this approach in live cells for optical control of firefly luciferase and, Renilla luciferase. This tool should have utility in manipulating and controlling a wide range of biological processes.

Pilot testing fentanyl test strip distribution in an emergency department setting: Experiences, lessons learned, and suggestions from staff.

OBJECTIVES: Fentanyl test strips (FTSs) are increasingly used to address fentanyl contamination of the illicit drug supply by testing a drug for the presence of fentanyl, allowing people who use drugs (PWUD) to engage in overdose prevention. While emergency departments (EDs) have implemented various harm reduction strategies for PWUD, to date distribution of FTSs in EDs is limited and not evaluated. Thus, we sought to explore ED staff experiences distributing FTSs. METHODS: Twenty-one staff serving different roles (e.g., physician, nurse, technician, social worker, certified recovery specialist) within two urban EDs in a major metropolitan area were enrolled in a pilot study to distribute FTS to patients who use drugs. Participants were interviewed about their experience at 3 weeks and again at 3 months. Interviews were recorded, transcribed verbatim, and coded using a conventional content analysis approach. RESULTS: All participants endorsed the utility of FTS distribution in the ED. Across 42 interviews, participants discussed evolving strategies to approach patients about FTS, primarily favorable patient reactions to FTSs, improved dynamics between participants and patients, mixed intervention support from other staff, and named challenges of FTS distribution and recommendations to make FTS distribution in the ED widespread. Recommendations included medical records prompts to offer FTS, offering via different types of staff, and offering FTS during triage. CONCLUSIONS: Implementing FTS distribution may improve patient rapport while providing patients with tools to avoid a fentanyl overdose. Participants generally reported positive experiences distributing FTSs within the ED but the barriers they identified limited opportunities to make distribution more integrated into their workflow. EDs considering this intervention should train staff on FTSs and how to identify and train patients and explore mechanisms to routinize distribution in the ED environment.

Communication with Kin in the Wake of the COVID-19 Pandemic.

This study investigates patterns of communication among non-coresident kin in the aftermath of the COVID-19 pandemic using data from the New York City Robin Hood Poverty Tracker. Over half of New Yorkers spoke to their non-coresident family members several times a week during the pandemic and nearly half increased their communication with non-coresident kin since March 2020. Siblings and extended kin proved to be especially important ties activated during the pandemic. New Yorkers were most likely to report increased communication with siblings. A quarter of respondents reported that they increased communication with at least one aunt, uncle, cousin, or other extended family member. While non-Hispanic White respondents reported the highest frequency of communication with kin, it was those groups most impacted by COVID-19 - foreign-born, Black, and Hispanic New Yorkers - who were most likely to report that they increased communication with kin in the wake of the pandemic.

Perspectives on the origin of language: Infants vocalize most during independent vocal play but produce their most speech-like vocalizations during turn taking.

A growing body of research emphasizes both endogenous and social motivations in human vocal development. Our own efforts seek to establish an evolutionary and developmental perspective on the existence and usage of speech-like vocalizations ("protophones") in the first year of life. We evaluated the relative occurrence of protophones in 40 typically developing infants across the second-half year based on longitudinal all-day recordings. Infants showed strong endogenous motivation to vocalize, producing vastly more protophones during independent vocal exploration and play than during vocal turn taking. Both periods of vocal play and periods of turn-taking corresponded to elevated levels of the most advanced protophones (canonical babbling) relative to periods without vocal play or without turn-taking. Notably, periods of turn taking showed even more canonical babbling than periods of vocal play. We conclude that endogenous motivation drives infants' tendencies to explore and display a great number of speech-like vocalizations, but that social interaction drives the production of the most speech-like forms. The results inform our previously published proposal that the human infant has been naturally selected to explore protophone production and that the exploratory inclination in our hominin ancestors formed a foundation for language.

Anti-glioblastoma activity of monensin and its analogs in an organoid model of cancer.

Glioblastoma (GBM) remains the most frequently diagnosed primary malignant brain cancer in adults. Despite recent progress in understanding the biology of GBM, the clinical outcome for patients remains poor, with a median survival of approximately one year after diagnosis. One factor contributing to failure in clinical trials is the fact that traditional models used in GBM drug discovery poorly recapitulate patient tumors. Previous studies have shown that monensin (MON) analogs, namely esters and amides on C-26 were potent towards various types of cancer cell lines. In the present study we have investigated the activity of these molecules in GBM organoids, as well as in a host:tumor organoid model. Using a mini-ring cell viability assay we have identified seven analogs (IC50 = 91.5 ± 54.4-291.7 ± 68.8 nM) more potent than parent MON (IC50 = 612.6 ± 184.4 nM). Five of these compounds induced substantial DNA fragmentation in GBM organoids, suggestive of apoptotic cell death. The most active analog, compound 1, significantly reduced GBM cell migration, induced PARP degradation, diminished phosphorylation of STAT3, Akt and GSK3ß, increased É£H2AX signaling and upregulated expression of the autophagy associated marker LC3-II. To investigate the activity of MON and compound 1 in a tumor microenvironment, we developed human cerebral organoids (COs) from human induced pluripotent stem cells (iPSCs). The COs showed features of early developing brain such as multiple neural rosettes with a proliferative zone of neural stem cells (Nestin+), neurons (TUJ1 +), primitive ventricular system (SOX2 +/Ki67 +), intermediate zone (TBR2 +) and cortical plate (MAP2 +). In order to generate host:tumor organoids, we co-cultured RFP-labeled U87MG cells with fully formed COs. Compound 1 and MON reduced U87MG tumor size in the COs after four days of treatment and induced a significant reduction of PARP expression. These findings highlight the therapeutic potential of MON analogs towards GBM and support the application of organoid models in anti-cancer drug discovery.

A Qualitative Exploration of the Functional, Social, and Emotional Impacts of the COVID-19 Pandemic on People Who Use Drugs.

Since 2020, people who use drugs (PWUD) experienced heightened risks related to drug supply disruptions, contamination, overdose, social isolation, and increased stress. This study explored how the lives of PWUD changed in Philadelphia over a one-year period. Using semi-structured interviews with 20 participants in a Housing First, low-barrier medication for opioid use (MOUD) program in Philadelphia, the effects of the first year of the COVID-19 pandemic on the daily lives, resources, functioning, substance use, and treatment of PWUD were explored. Interviews were analyzed using a combination of directed and conventional content analysis. Six overarching themes emerged during data analysis: (1) response to the pandemic; (2) access to MOUD and support services; (3) substance use; (4) impacts on mental health, physical health, and daily functioning; (5) social network impacts; and (6) fulfillment of basic needs. Participants reported disruptions in every domain of life, challenges meeting their basic needs, and elevated risk for adverse events. MOUD service providers offset some risks and provided material supports, treatment, social interaction, and emotional support. These results highlight how there were significant disruptions to the lives of PWUD during the first year of the COVID-19 pandemic and identified critical areas for future intervention and policies.

"I'm Going to Be Good to Me": Exploring the Role of Shame and Guilt in Patients With Type 2 Diabetes.

Objective: People with type 2 diabetes are likely to experience shame or guilt as they navigate through their disease. Previous research has shown that feelings of shame and guilt often exist within the clinician-patient relationship, often as a result of the complex care regimen required to achieve treatment goals. The purpose of this qualitative study was to explore patients' experiences of shame and guilt in type 2 diabetes management and the impact their clinicians have on these experiences. Methods: Semistructured interviews were used to explore patients' experiences with shame and guilt. Interviews were audio-recorded, transcribed, and coded using directed content analysis. Demographic data were also obtained. Results: We completed 20 interviews with people with type 2 diabetes (65% Black, 70% female). Participants exhibited feelings more consistent with guilt than with shame. All participants discussed how their clinicians affected these feelings. Patients who expressed feelings of guilt were able to recognize opportunities for behavior change without experiencing global devaluation, in which they linked their actions to an unchangeable aspect of their identity or personality, often describing their guilt as motivating of change. Unlike guilt, when patients experienced shame, they often exhibited global devaluation, in which they blamed their personality, experienced hopelessness, and increased maladaptive behaviors. Conclusion: Our findings highlight a notable difference between shame and guilt in the context of type 2 diabetes management. We believe that incorporation of an understanding of these nuances, along with ideal responses to both shame and guilt, will enhance clinicians' ability to provide high-quality patient-centered care to people with diabetes.

"If I had them, I would use them every time": Perspectives on fentanyl test strip use from people who use drugs.

INTRODUCTION: Fentanyl contamination in the illicit drug supply has contributed to a significant increase in overdose deaths in the United States. Fentanyl test strips (FTS), which can detect the presence of fentanyl in drugs, are increasingly given to people who use drugs (PWUD) as an overdose prevention intervention. No studies to date have described PWUD's perspectives from a real-world setting about ideal FTS program characteristics. These perspectives, specifically any identified facilitators, barriers, and suggestions for use, are crucial to informing scalability and implementation of FTS. METHODS: The study team conducted qualitative interviews between January and May 2021 with PWUD in Philadelphia, PA, who had used FTS on a variety of substances. The study recruited participants outside of a harm reduction agency and provided informed consent. The team conducted interviews utilizing a semi-structured interview guide, and audio-recorded and transcribed them. The research team analyzed interviews with a conventional content analysis approach. RESULTS: A total of 29 PWUD participated in an interview. Participants were predominantly cisgender male (n = 21, 72.4%) and White (n = 18, 62.1%). Participants reported previously using FTS on heroin (65.5%), crack cocaine (55.2%), powder cocaine (48.3%), synthetic cannabinoids (31.0%), and benzodiazepines (24.1%). Eighty-six percent of participants learned about FTS through harm reduction or other social service organizations. Most participants incorporated FTS into their daily lives and found them easy to use. Participants identified key barriers, including lack of necessary supplies needed to test, not having an ideal testing location, and confusion reading test results. Suggestions included adding supplies needed for using FTS to distribution packets, ensuring that each PWUD receives enough FTS per distribution, and expanding the types of programs distributing FTS. CONCLUSIONS: While most participants reported FTS as practical and easy to use, participants identified a few key barriers to use that should be addressed to optimize FTS use across a broader population. These barriers include expanding training materials and distributing additional testing materials (e.g., water, cookers) with FTS. Findings can inform sustainable and effective FTS distribution practices, such as distributing FTS in packs of 20 and distributing at other locations that regularly interact with PWUD (e.g., emergency departments, housing shelters, and food banks).

Primary acute lymphoblastic leukemia cells are susceptible to microtubule depolymerization in G1 and M phases through distinct cell death pathways.

Microtubule targeting agents (MTAs) are widely used cancer chemotherapeutics which conventionally exert their effects during mitosis, leading to mitotic or postmitotic death. However, accumulating evidence suggests that MTAs can also generate death signals during interphase, which may represent a key mechanism in the clinical setting. We reported previously that vincristine and other microtubule destabilizers induce death not only in M phase but also in G1 phase in primary acute lymphoblastic leukemia cells. Here, we sought to investigate and compare the pathways responsible for phase-specific cell death. Primary acute lymphoblastic leukemia cells were subjected to centrifugal elutriation, and cell populations enriched in G1 phase (97%) or G2/M phases (80%) were obtained and treated with vincristine. We found death of M phase cells was associated with established features of mitochondrial-mediated apoptosis, including Bax activation, loss of mitochondrial transmembrane potential, caspase-3 activation, and nucleosomal DNA fragmentation. In contrast, death of G1 phase cells was not associated with pronounced Bax or caspase-3 activation but was associated with loss of mitochondrial transmembrane potential, parylation, nuclear translocation of apoptosis-inducing factor and endonuclease G, and supra-nucleosomal DNA fragmentation, which was enhanced by inhibition of autophagy. The results indicate that microtubule depolymerization induces distinct cell death pathways depending on during which phase of the cell cycle microtubule perturbation occurs. The observation that a specific type of drug can enter a single cell type and induce two different modes of death is novel and intriguing. These findings provide a basis for advancing knowledge of clinical mechanisms of MTAs.