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Abstract Aim Illicitly manufactured fentanyl and its analogs are the primary drivers of opioid overdose deaths in the United States (U.S.). People who use drugs may be exposed to fentanyl or its analogs intentionally or unintentionally. This study sought to identify strategies used by rural people who use drugs to reduce harms associated with unintentional fentanyl exposure. Methods This analysis focused on 349 semi-structured qualitative interviews across 10 states and 58 rural counties in the U.S conducted between 2018 and 2020. Interview guides were collaboratively standardized across sites and included questions about drug use history (including drugs currently used, frequency of use, mode of administration) and questions specific to fentanyl. Deductive coding was used to code all data, then inductive coding of overdose and fentanyl codes was conducted by an interdisciplinary writing team. Results Participants described being concerned that fentanyl had saturated the drug market, in both stimulant and opioid supplies. Participants utilized strategies including: (1) avoiding drugs that were perceived to contain fentanyl, (2) buying drugs from trusted sources, (3) using fentanyl test strips, 4) using small doses and non-injection routes, (5) using with other people, (6) tasting, smelling, and looking at drugs before use, and (7) carrying and using naloxone. Most people who used drugs used a combination of these strategies as there was an overwhelming fear of fatal overdose. Conclusion People who use drugs living in rural areas of the U.S. are aware that fentanyl is in their drug supply and use several strategies to prevent associated harms, including fatal overdose. Increasing access to harm reduction tools (e.g., fentanyl test strips, naloxone) and services (e.g., community drug checking, syringe services programs, overdose prevention centers) should be prioritized to address the polysubstance-involved overdose crisis. These efforts should target persons who use opioids and other drugs that may contain fentanyl.

Abstract Background Pharmacies are critical healthcare partners in community efforts to eliminate bloodborne illnesses. Pharmacy sale of sterile syringes is central to this effort. Methods A mixed methods “secret shopper” syringe purchase study was conducted in the fall of 2022 with 38 community pharmacies in Maricopa and Pima Counties, Arizona. Pharmacies were geomapped to within 2 miles of areas identified as having a potentially high volume of illicit drug commerce. Daytime venue sampling was used whereby separate investigators with lived/living drug use experience attempted to purchase syringes without a prescription. Investigator response when prompted for purchase rationale was “to protect myself from HIV and hepatitis C.” A 24-item instrument measured sales outcome, pharmacy staff interaction (hostile/neutral/friendly), and the buyer’s subjective experience. Results Only 24.6% (n = 28) of 114 purchase attempts across the 38 pharmacies resulted in syringe sale. Less than one quarter (21.1%) of pharmacies always sold, while 44.7% never sold. Independent and food store pharmacies tended not to sell syringes. There emerged distinct pharmacy staff interactions characterized by body language, customer query, normalization or othering response, response to purchase request and closure. Pharmacy discretion and pharmacy policy not to sell syringes without a prescription limited sterile syringe access. Investigators reported frequent and adverse emotional impact due to pharmacy staff negative and stigmatizing interactions. Conclusions Pharmacies miss opportunities to advance efforts to eliminate bloodborne infections by stringent no-sale policy and discretion about syringe sale. State regulatory policy facilitating pharmacy syringe sales, limiting pharmacist discretion for syringe sales, and targeting pharmacy-staff level education may help advance the achievement of public health goals to eliminate bloodborne infections in Arizona.

Abstract Background Opioid withdrawal is a regular occurrence among many people who use illicit opioids (PWUIO) that has also been shown to increase their willingness to engage in risk-involved behavior. The proliferation of fentanyl in the illicit opioid market may have amplified this relationship, potentially putting PWUIO at greater risk of negative health outcomes. Understanding the relationship between withdrawal and risk-involved behavior may also have important implications for the ways that problematic drug use is conceptualized, particularly in disease models of addiction, which position risk behavior as evidence of pathology that helps to justify ontological distinctions between addicts and non-addicts. Examining withdrawal, and its role in PWUIO’s willingness to engage in risk, may aid in the development of alternative theories of risk involvement and create discursive spaces for de-medicalizing and de-othering people who use illegal drugs. Methods This article is based on 32 semi-structured interviews with PWUIO in the New York City area who also reported recent withdrawal experience. Interviews were conducted remotely between April and August 2022 and recorded for later transcription. Data were then coded and analyzed based on a combination of inductive and deductive coding strategies and informed by the literature. Results Participants described a strong relationship between withdrawal and their willingness to engage in risk-involved behavior that was exacerbated by the proliferation of fentanyl. Yet, their descriptions did not align with narratives of risk as a product of bad decisions made by individuals. Rather, data demonstrated the substantial role of social and structural context, particularly drug policies like prohibition and criminalization, in the kinds of risks that PWUIO faced and their ability to respond to them. Conclusions Withdrawal should be taken more seriously both from an ethical perspective and as an important catalyst of risk behavior. However, theories that position activities taken to avoid withdrawal as irrational and as evidence of pathology are poorly aligned with the complexity of PWUIO’s actual lives. We recommend the use of less deterministic and less medicalized theories of risk that better account for differences between how people view the world, and for the role of socio-structural forces in the production of risk.

Loss of the histone demethylase KDM5D (lysine‐specific demethylase 5D) leads to in vitro resistance of prostate cancer cells to androgen deprivation therapy (ADT) with and without docetaxel. We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP‐seq) of the LNCaP cell line (androgen‐sensitive human prostate adenocarcinoma) with and without silenced KDM5D, MYBL2‐binding sites were analyzed. Associations between MYBL2 mRNA expression and clinical outcomes were assessed in cohorts of men with localized and metastatic hormone‐sensitive prostate cancer. In vitro assays with silencing and overexpression of MYBL2 and KDM5D in androgen receptor (AR)‐positive hormone‐sensitive prostate cancer cell lines, LNCaP and LAPC4, were used to assess their influence on cellular proliferation, apoptosis, and cell cycle distribution, as well as sensitivity to androgen deprivation, docetaxel, and cabazitaxel. We found that silencing KDM5D increased histone H3 lysine K4 (H3K4) trimethylation and increased MYBL2 expression. KDM5D and MYBL2 were negatively correlated with some but not all clinical samples. Higher MYBL2 expression was associated with a higher rate of relapse in localized disease and poorer overall survival in men with metastatic disease in the CHAARTED trial. Lower MYBL2 levels enhanced LNCaP and LAPC4 sensitivity to androgen deprivation and taxanes. In vitro, modifications of KDM5D and MYBL2 altered cell cycle distribution and apoptosis in a cell line‐specific manner. These results show that the transcription factor MYBL2 impacts in vitro hormone‐sensitive prostate cancer sensitivity to androgen deprivation and taxanes, and lower levels are associated with better clinical outcomes in men with hormone‐sensitive prostate cancer.

IntroductionRates of illicit opioid use are particularly high among young adults, yet research on overdose experience and factors associated with overdose in this population remains limited. This study examines the experiences and correlates of non-fatal overdose among young adults using illicit opioids in New York City (NYC).Methods539 participants were recruited via Respondent-Driven Sampling in 2014-2016. Eligibility criteria included: aged 18–29 years old; current residence in NYC; and nonmedical prescription opioid (PO) use and/or heroin use in the past 30 days. Participants completed structured interviews to assess their socio-demographics, drug use trajectories, current substance use and lifetime and most recent overdose experiences, and were tested on-site for hepatitis C virus (HCV) antibodies.Results43.9% of participants reported lifetime overdose experience; of these, 58.8% had experienced two or more overdose events. The majority of participants’ most recent overdoses (63.5%) were due to polysubstance use. In bivariable analyses, after RDS adjustment, having ever overdosed was correlated with: household income of >$100,00 growing up (vs. $51,000-100,000); lifetime homelessness; HCV antibody-positive status; lifetime engagement in regular nonmedical benzodiazepine use, regular heroin injection and regular PO injection; and using a non-sterile syringe in the past 12 months. Multivariable logistic regression identified childhood household income >$100,00 (AOR=1.88), HCV-positive status (AOR=2.64), benzodiazepine use (AOR=2.15), PO injection (AOR=1.96) and non-sterile syringe use (AOR=1.70) as significant independent correlates of lifetime overdose. A multivariable model with multiple overdoses (vs. one) found only lifetime regular heroin use and PO injection to be strong correlates.DiscussionResults indicate a high prevalence of lifetime and repeated overdose among opioid-using young adults in NYC, highlighting a need for intensified overdose prevention efforts for this population. The strong associations of HCV and indices of polydrug use with overdose suggest that prevention efforts should address the complex risk environment in which overdose occurs, attending to the overlapping nature of disease-related risk behavior and overdose risk behavior among young people who inject opioids. Overdose prevention efforts tailored for this group may find it useful to adopt a syndemic conception of overdose that understands such events as resulting from multiple, and often interrelated, risk factors.

Abstract Background Methadone Maintenance Treatment (MMT) is widely recognized as one of the most effective ways of reducing risk of overdose, arrest, and transmission of blood-borne viruses like HIV and HCV among people that use opioids. Yet, MMT’s use of restrictive take-home dose policies that force most patients to attend their clinic on a daily, or near-daily, basis may be unpopular with many patients and lead to low rates of treatment uptake and retention. In response, this article examines how clinics’ take-home dosing policies have affected patients’ experiences of treatment and lives in general. Methods This article is based on semi-structured, qualitative interviews with a variety of stakeholders in MMT. Interviews explored: reasons for engaging with, or not engaging with MMT; how MMT is conceptualized by patients and treatment providers (e.g., as harm reduction or route to abstinence and/or recovery); experiences with MMT; perception of barriers to MMT (e.g., organizational/regulatory, social) and how MMT might be improved to support peoples’ substance use treatment needs and goals. Results Nearly all of the patients with past or present MMT use were highly critical of the limited access to take-home doses and consequent need for daily or near daily clinic attendance. Participants described how the use of restrictive take-home dose policies negatively impacted their ability to meet day-to-day responsibilities and also cited the need for daily attendance as a reason for quitting or avoiding OAT. Responses also demonstrate how such policies contribute to an environment of cruelty and stigma within many clinics that exposes this already-stigmatized population to additional trauma. Conclusions Take-home dose policies in MMT are not working for a substantial number of patients and are reasonably seen by participants as degrading and dehumanizing. Revision of MMT regulations and policies regarding take home doses are essential to improve patient satisfaction and the quality and effectiveness of MMT as a key evidence-based treatment and harm reduction strategy.

BackgroundThe COVID-19 pandemic has transformed how people seeking to reduce opioid use access treatment services and navigate efforts to abstain from using opioids. Social distancing policies have drastically reduced access to many forms of social support, but they may have also upended some perceived barriers to reducing or abstaining from opioid use. ObjectiveThis qualitative study aims to identify informal coping strategies for reducing and abstaining from opioid use among Reddit users who have posted in opioid-related subreddits at the beginning of the COVID-19 pandemic. MethodsWe extracted data from 2 major opioid-related subreddits. Thematic data analysis was used to evaluate subreddit posts dated from March 5 to May 13, 2020, that referenced COVID-19 and opioid use, resulting in a final sample of 300 posts that were coded and analyzed. ResultsOf the 300 subreddit posts, 100 (33.3%) discussed at least 1 type of informal coping strategy. Those strategies included psychological and behavioral coping skills, adoption of healthy habits, and use of substances to manage withdrawal symptoms. In addition, 12 (4%) subreddit posts explicitly mentioned using social distancing as an opportunity for cessation of or reduction in opioid use. ConclusionsReddit discussion forums have provided a community for people to share strategies for reducing opioid use and support others during the COVID-19 pandemic. Future research needs to assess the impact of COVID-19 on opioid use behaviors, especially during periods of limited treatment access and isolation, as these can inform future efforts in curbing the opioid epidemic and other substance-related harms.

Background: Often people assume that entry into drug treatment is a voluntary action for persons who use drugs (PWUD). This narrative informs the organizational and regulatory structure of most treatment programs and consequently affects patients’ ability to exert agency over their own treatment. Yet, this view ignores the complex interplay between individual and structural factors in peoples’ decision-making processes, particularly among people who use drugs who are stigmatized and criminalized. Treatment programs that assume voluntary entry may lack appropriate services for the populations of treatment seekers that they serve.Methods: This paper uses semi-structured interviews with 42 participants in Opioid Substitution Treatment (OST) (including patients, clinic doctors and staff, and advocates) informed by one of the author’s own lived experience in OST, to examine patients’ treatment decisions, and in particular, if and how, the structural context of drugs’ illegality/criminalization affected their willingness to pursue treatment. A Critical Discourse Analysis was used to identify key themes.Results: Interview data demonstrates that most people who use drugs enter treatment under constrained conditions related to drugs’ illegality. Themes that emerged included: 1. A feeling of limited choices due to drugs’ illegality; 2. Peer and family pressure; 3. Fear of losing children; and 4. Internalized stigma (i.e. feeling they are dirty or bad for using).Conclusion: Narratives that frame PWUD’s treatment decisions as volitional provide political cover to policies that criminalize PWUD by obscuring their effect on PWUD’s treatment decisions. Treatment models, particularly those that serve highly criminalized populations, should be re-conceptualized outside of normative narratives of individual choice, and be broadened to understand how larger structures constrain choices. By looking at macro-level factors, including the interplay of criminalization and drug treatment, programs can begin to understand the complexity of PWUD motivations to enter drug treatment. Recognizing the role of the War on Drugs as a force of oppression for people who use drugs, and that their treatment decisions are made within that setting, may enable people in treatment, and providers, to develop more productive ways of interacting with one another. Additionally, this may lead to better retention in treatment programs.

We open with the question of subjectivity as it is presented in Hamlet; the focus then moves to the breakdown of subjectivity as experienced in extreme situations and clinical psychosis. Gabel’s idea of continuity from psychosis to ideology (false consciousness) is used to show that William S. Burroughs is in fact a theorist of global ideological pathology. The concept of reification allows us to combine the voices of Gabel and Burroughs. This is not a study of what has been said about Burroughs or Shakespeare, our concern is with the future of the City, not the nature of the finger that points towards it. The cycle of “William & William” refers to the birth and destruction of subjectivity as defined by “conditions such as these”.

Methadone Maintenance Treatment (MMT) in the United States has recently adopted an approach based on the principles of the Recovery movement — a view of treatment informed by addiction-as-disease models but also incorporating social, psychological, and spiritual components. Although organizations that administer drug treatment services claim that the shift represents a more client-centered, individualistic approach, it may not meet the needs of the many individuals who use MMT to reduce the harms of drug use, like overdose, rather than as a way to become abstinent. In this article, I use interview data from treatment providers to argue against institutional claims of Recovery as an individualistic model. My research demonstrates how — despite the wide variety of treatment goals among people on MMT — the Recovery discourse positions and organizes treatment strictly as abstinence-based, self-help. Moreover, I show how the Recovery model serves as the justification for an expansion of clinics’ ability to surveil and intervene in aspects of people’s lives which had previously been seen as outside of MMT’s purview, including nutrition, public service, and spirituality. In conclusion, I argue that Recovery restricts MMT’s ability to reduce harms, like overdose, in the lives of people who use drugs, and recommend that MMT adopt a more open-ended, low-threshold approach to treatment.

ABSTRACT Mice lacking expression of the homologous phosphatases Sts-1 and Sts-2 (Sts−/− mice) are resistant to disseminated candidiasis caused by the fungal pathogen Candida albicans. To better understand the immunological mechanisms underlying the enhanced resistance of Sts−/− mice, we examined the kinetics of fungal clearance at early time points. In contrast to the rapid C. albicans growth seen in normal kidneys during the first 24 h postinfection, we observed a reduction in kidney fungal CFU within Sts−/− mice beginning at 12 to 18 h postinfection. This corresponds to the time period when large numbers of innate leukocytes enter the renal environment to counter the infection. Because phagocytes of the innate immune system are important for host protection against pathogenic fungi, we evaluated responses of bone marrow leukocytes. Relative to wild-type cells, Sts−/− marrow monocytes and bone marrow-derived dendritic cells (BMDCs) displayed a heightened ability to inhibit C. albicans growth ex vivo. This correlated with significantly enhanced production of reactive oxygen species (ROS) by Sts−/− BMDCs downstream of Dectin-1, a C-type lectin receptor that plays a critical role in stimulating host responses to fungi. We observed no visible differences in the responses of other antifungal effector pathways, including cytokine production and inflammasome activation, despite enhanced activation of the Syk tyrosine kinase downstream of Dectin-1 in Sts−/− cells. Our results highlight a novel mechanism regulating the immune response to fungal infections. Further understanding of this regulatory pathway could aid the development of therapeutic approaches to enhance protection against invasive candidiasis. IMPORTANCE Systemic candidiasis caused by fungal Candida species is becoming an increasingly serious medical problem for which current treatment is inadequate. Recently, the Sts phosphatases were established as key regulators of the host antifungal immune response. In particular, genetic inactivation of Sts significantly enhanced survival of mice infected intravenously with Candida albicans. The Sts−/− in vivo resistance phenotype is associated with reduced fungal burden and an absence of inflammatory lesions. To understand the underlying mechanisms, we studied phagocyte responses. Here, we demonstrate that Sts−/− phagocytes have heightened responsiveness to C. albicans challenge relative to wild-type cells. Our data indicate the Sts proteins negatively regulate phagocyte activation via regulating selective elements of the Dectin-1–Syk tyrosine kinase signaling axis. These results suggest that phagocytes lacking Sts respond to fungal challenge more effectively and that this enhanced responsiveness partially underlies the profound resistance of Sts−/− mice to systemic fungal challenge.

Tree rings dominate millennium-long temperature reconstructions and many records originate from Scandinavia, an area for which the relative roles of external forcing and internal variation on climatic changes are, however, not yet fully understood. Here we compile 1,179 series of maximum latewood density measurements from 25 conifer sites in northern Scandinavia, establish a suite of 36 subset chronologies, and analyse their climate signal. A new reconstruction for the 1483-2006 period correlates at 0.80 with June-August temperatures back to 1860. Summer cooling during the early 17th century and peak warming in the 1930s translate into a decadal amplitude of 2.9°C, which agrees with existing Scandinavian tree-ring proxies. Climate model simulations reveal similar amounts of mid to low frequency variability, suggesting that internal ocean-atmosphere feedbacks likely influenced Scandinavian temperatures more than external forcing. Projected 21st century warming under the SRES A2 scenario would, however, exceed the reconstructed temperature envelope of the past 1,500 years.

Clinical responses achieved with FLT3 kinase inhibitors in acute myeloid leukemia (AML) are typically transient and partial. Thus, there is a need for identification of molecular mechanisms of clinical resistance to these drugs. In response, we characterized MOLM13 AML cell lines made resistant to two structurally-independent FLT3 inhibitors.MOLM13 cells were made drug resistant via prolonged exposure to midostaurin and HG-7-85-01, respectively. Cell proliferation was determined by Trypan blue exclusion. Protein expression was assessed by immunoblotting, immunoprecipitation, and flow cytometry. Cycloheximide was used to determine protein half-life. RT-PCR was performed to determine FLT3 mRNA levels, and FISH analysis was performed to determine FLT3 gene expression.We found that MOLM13 cells readily developed cross-resistance when exposed to either midostaurin or HG-7-85-01. Resistance in both lines was associated with dramatically elevated levels of cell surface FLT3 and elevated levels of phosphor-MAPK, but not phospho-STAT5. The increase in FLT3-ITD expression was at least in part due to reduced turnover of the receptor, with prolonged half-life. Importantly, the drug-resistant phenotype could be rapidly reversed upon withdrawal of either inhibitor. Consistent with this phenotype, no significant evidence of FLT3 gene amplification, kinase domain mutations, or elevated levels of mRNA was observed, suggesting that protein turnover may be part of an auto-regulatory pathway initiated by FLT3 kinase activity. Interestingly, FLT3 inhibitor resistance also correlated with resistance to cytosine arabinoside. Over-expression of FLT3 protein in response to kinase inhibitors may be part of a novel mechanism that could contribute to clinical resistance.

Investigations of climate–growth interactions can shed light on the response of forest growth to climate change and the dendroclimatic reconstructions. However, most existing studies in the climatically important Tibetan Plateau (TP) and surrouding regions focus on linear growth responses to environmental variation. Herein we investigated both the linear and the nonlinear climate–growth interactions for 152 tree-ring chronologies in the TP and vicinity. We introduced the boosted regression tree (BRT) technique to study the nonlinear climate–growth relationships by pooling several sites with similar climate–growth relationships to mitigate potential biases due to the shortness of the instrumental records. Across most of the TP and surroundings, tree growth is stressed by drought. The warming induced drought has been evidenced by the strong interactions between temperature and precipitation in the BRT analyses. The drought stress on forest growth is particularly conspicuous for a hydrological year over much of the Northern TP and surroundings. The BRT analyses indicate the compensation effect of moisture prior to the growing season for the moisture deficit in the early growing season in May to July, when most of the ring-width formation occurs.

Climatic extreme events strongly affect forest growth and thus significantly influence the inter-annual terrestrial carbon balance. As we are facing an increase in frequency and intensity of climate extremes, extensive empirical archives are required to assess continental scale impacts of temperature and precipitation anomalies. Here we divide a tree-ring network of approximately 1000 sites into fifteen groups of similar high-frequency growth variability to reconstruct regional positive and negative extreme events in different parts of Europe between 1500 and 2008. Synchronized growth maxima or minima within and among regions indicate eighteen years in the pre-instrumental period and two events in the 20th century (1948, 1976) with extensive radial growth fluctuations. Comparisons with instrumental data showed that the European tree-ring network mirrors the spatial extent of temperature and precipitation extremes, but the interpretation of pre-instrumental events is challenged by lagged responses to off-growing season climate extremes. We were able to attribute growth minima in subsequent years to unfavourable August–October conditions and to mild climate during winter months associated with respiratory carbon losses. Our results emphasize the importance of carry-over effects and species-specific growth characteristics for forest productivity. Furthermore, they promote the use of regional tree-ring chronologies in research related to climate variability and terrestrial carbon sink dynamics.