Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. METHODS: We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. FINDINGS: The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study. INTERPRETATION: NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. FUNDING: D&D Pharmatech-Neuraly.

Deaths of profound despair: A retrospective cohort study of mortality among people experiencing homelessness.

INTRODUCTION: The number of people dying while unhoused is increasing nationally. In Santa Clara County (SCC), deaths of unhoused people have almost tripled in 9 years. This is a retrospective cohort study examining mortality trends among unhoused people in SCC. The objective of the study is to characterize mortality outcomes in the unhoused population, and compare these to the SCC general population. MATERIALS AND METHODS: We obtained data from the SCC Medical Examiner-Coroner's Office on unhoused people's deaths that occurred between 2011-2019. We analyzed demographic trends and cause of death, compared to mortality data on the SCC general population obtained from CDC databases. We also compared rates of deaths of despair. RESULTS: There were a total of 974 unhoused deaths in the SCC cohort. The unadjusted mortality rate among unhoused people is higher than the general population, and unhoused mortality has increased over time. The standardized mortality ratio for unhoused people is 3.8, compared to the general population in SCC. The most frequent age of death among unhoused people was between 55-64 years old (31.3%), followed by 45-54 (27.5%), compared to 85+ in the general population (38.3%). Over ninety percent of deaths in the general population were due to illness. In contrast, 38.2% of unhoused deaths were due to substance use, 32.0% illness, 19.0% injury, 4.2% homicide, and 4.1% suicide. The proportion of deaths of despair was 9-fold higher in the unhoused cohort compared to the housed cohort. DISCUSSION: Homelessness has profound impacts on health, as people who are unhoused are dying 20 years younger, with higher rates of injurious, treatable, and preventable causes, than people in the general population. System-level, inter-agency interventions are needed. Local governments need to systematically collect housing status at death to monitor mortality patterns among unhoused people, and adapt public health systems to prevent rising unhoused deaths.

Systemic Bioavailability of Sublingual Atropine Ophthalmic Solution: a Phase I Study in Healthy Volunteers with Implications for Use as a Contingency Medical Countermeasure.

INTRODUCTION: Atropine sulfate is an FDA-approved medical countermeasure (MCM) for the treatment of organophosphorus nerve agent and organophosphate pesticide toxicity. Sufficient MCM supplies must be available in an incident involving a mass human exposure either from an accidental chemical release or a terrorist attack. METHODS: We performed a randomized, 3-sequence, 3-period phase I crossover study to assess the bioavailability and pharmacokinetics (PK) of a single dose (0.5 mg and 1.0 mg) of 1% ophthalmic atropine sulfate solution administered sublingually to 15 healthy adult volunteers. The primary endpoint was evaluation of the bioavailability of each of the two sublingual doses against a 1.0 mg reference intravenous (IV) atropine dose. Secondary endpoints included the safety and tolerability (xerostomia scale) of atropine sulfate administered sublingually. RESULTS: Sublingual atropine was safe (no severe AEs or SAEs were reported with either dose) and well tolerated, with a single subject reaching maximum xerostomia on a single dosing day. The geometric mean AUC∞ was 286.40, 493.81, and 816.47 min*ng/mL for the 0.5 mg and 1.0 mg sublingual doses, and the 1.0 mg IV dose, respectively. Compared to IV administration, the 1.0 mg sublingual dose produced 0.60 (90% CI: 0.55-0.66) of the overall concentration of atropine over time (AUC∞). CONCLUSION: Sublingual atropine sulfate 1% ophthalmic solution may be an alternative formulation and route of administration combination which expands the capacity and dosing options of atropine as a nerve agent MCM.

Invisibility as a structural determinant: Mortality outcomes of Asians and Pacific Islanders experiencing homelessness.

Introduction: Asians and Pacific Islanders (APIs) who are experiencing homelessness are situated in a social intersection that has rendered them unrecognized and therefore vulnerable. There has been increasing attention to racial disparities in homelessness, but research into API homelessness is exceedingly rare, despite rapidly growing populations. The purpose of this study is to examine the causes of death among APIs who died while homeless in Santa Clara County (SCC) and compare these causes to other racial groups. Materials and methods: We report on data obtained from the SCC Medical Examiner-Coroner's Office on unhoused people's deaths that occurred between 2011 and 2021 (n = 1,394), including data on deaths of APIs experiencing homelessness (n = 87). Results: APIs comprised 6.2% of total deaths of unhoused people. APIs died less often of causes related to drug/alcohol use than all other racial groups (24.1, compared to 39.3%), and there was a trend toward more API deaths from injuries or illnesses. When APIs were disaggregated into sub-groups (East/Southeast Asian, South Asian, Pacific Islander), there were notable mortality differences in cause of death, age, and sex. Discussion: We argue that invisibility is a structural determinant of health that homeless APIs face. Though relatively small in numbers, APIs who are invisible may experience increased social isolation and, subsequently, specific increased mortality risks. To understand the health outcomes of unhoused APIs, it is essential that researchers and policymakers recognize API homelessness and gather and report disaggregated races and ethnicities.

Diagnostic Performance of an Antigen Test with RT-PCR for the Detection of SARS-CoV-2 in a Hospital Setting - Los Angeles County, California, June-August 2020.

Prompt and accurate detection of SARS-CoV-2, the virus that causes COVID-19, has been important during public health responses for containing the spread of COVID-19, including in hospital settings (1-3). In vitro diagnostic nucleic acid amplification tests (NAAT), such as real-time reverse transcription-polymerase chain reaction (RT-PCR) can be expensive, have relatively long turnaround times, and require experienced laboratory personnel.* Antigen detection tests can be rapidly and more easily performed and are less expensive. The performance† of antigen detection tests, compared with that of NAATs, is an area of interest for the rapid diagnosis of SARS-CoV-2 infection. The Quidel Sofia 2 SARS Antigen Fluorescent Immunoassay (FIA) (Quidel Corporation) received Food and Drug Administration Emergency Use Authorization for use in symptomatic patients within 5 days of symptom onset (4). The reported test positive percentage agreement§ between this test and an RT-PCR test result is 96.7% (95% confidence interval [CI] = 83.3%-99.4%), and the negative percentage agreement is 100.0% (95% CI = 97.9%-100.0%) in symptomatic patients.¶ However, performance in asymptomatic persons in a university setting has shown lower sensitivity (5); assessment of performance in a clinical setting is ongoing. Data collected during June 30-August 31, 2020, were analyzed to compare antigen test performance with that of RT-PCR in a hospital setting. Among 1,732 paired samples from asymptomatic patients, the antigen test sensitivity was 60.5%, and specificity was 99.5% when compared with RT-PCR. Among 307 symptomatic persons, sensitivity and specificity were 72.1% and 98.7%, respectively. Health care providers must remain aware of the lower sensitivity of this test among asymptomatic and symptomatic persons and consider confirmatory NAAT testing in high-prevalence settings because a false-negative result might lead to failures in infection control and prevention practices and cause delays in diagnosis, isolation, and treatment.

Narratives of people who inject drugs on factors contributing to opioid overdose.

BACKGROUND: In recent years, there has been increasing national and global attention to opioid overdoses. In San Francisco, it is estimated that the population of people who inject drugs (PWID) has more than doubled in the past ten years. The risk factors for opioid overdose have been examined closely, but firsthand accounts of PWID who have experienced overdoses are less documented. In this paper, we use two theories - lay expertise and structural vulnerabilities - as frameworks to frame and qualitatively examine the narratives of PWID surrounding their recent overdose experiences. METHODS: Audio-recorded semi-structured open-ended motivational interviewing counseling sessions were conducted with PWID in San Francisco who have experienced at least one non-fatal overdose event (N = 40). Participants discussed the context of recent opioid overdoses, either witnessed or personally experienced, focusing on their perceptions of unique contributing factors. Interview data were coded and analysed using ATLAS.ti. We used a thematic content analysis approach to qualitatively analyze data queries and generate themes. We used theories of structural vulnerability and lay expertise to frame the analysis. RESULTS: Using quotes from the participants, we report four central themes that contributed to participants' overdose experiences: 1) Social Dynamics and Opioid Expertise; 2) Uncertain Supply, Composition, Source; 3) Balancing Polysubstance Use, and 4) Emotional Pain. CONCLUSION: As PWID described their overdose experiences, many factors that contributed to their overdoses were situated at the structural level. The everyday, lived experiences of PWID often competed or conflicted with public health messages and approaches. The accumulated expertise of PWID about everyday risk factors can be leveraged by public health practitioners to inform and improve overdose prevention interventions and messages.

Frequently asked questions about dabbing concentrates in online cannabis community discussion forums.

BACKGROUND: "Dabbing" involves vaporizing a "dab" of cannabis concentrate on a heated "nail," passing the vapour through a water-pipe rig or portable pen device, and inhaling the vapour. While some cannabis industry media claims that this process is cleaner, safer, and more effective for getting high, medical and public health sources raise concerns about residual solvents and pesticides, unexpectedly intense effects, and rapid increases in tolerance. The aim of this study is to characterize the content of questions about dabbing posed in cannabis and dabbing-specific forums on the Reddit social media platform, as well as comment responses to these questions. METHODS: We conducted a content analysis of one year (2017) of information-seeking user-generated posts to three Reddit online cannabis community discussion forums ("subreddits") that contained the terms "dab" and "question." We also examined post engagement and the types and sentiment of information exchanged in the comment responses. RESULTS: Across 193 dabbing question posts, the most frequently asked question content was about types and logistical use of devices and related equipment (38%) and comparisons of cannabis products (32%), followed by questions about the step-by-step process of getting high (18%), legal issues (17%), and health concerns (13%). Nearly every post had a response (98%), with a median 5 comments per post and few negative (i.e. hostile, condescending, or trolling) comments (4%). Source of advice or information was stated in about a quarter (26%) of comment responses, with the overwhelming majority of this information (89%) coming from disclosures of personal experience vs. web or commercial sources. CONCLUSION: People seeking advice online about dabbing inquired most often about logistics of use, but less often about health, tolerance, and legal risks. These findings may be used to inform public health efforts and health practitioner education as cannabis becomes increasingly legal and accessible.

Perceived Causes of Personal versus Witnessed Overdoses among People who Inject Opioids.

Background: Studies show that people who inject drugs (PWID) underestimate their overdose risk. We sought to explore this phenomenon by comparing how PWID perceive causes of personal overdoses compared to witnessed overdoses. Methods: We analyzed 40 interviews from participants enrolled in a randomized-controlled behavioral intervention to reduce overdose among at-risk PWID in San Francisco from 2014 to 2016. Subjects were current illicit opioid injectors with opioid use disorder, had received take-home naloxone, and had overdosed within five years. Interviews were audio-recorded and transcribed verbatim. Using thematic content analysis, three analysts coded the interviews and measured interrater reliability. The analysts developed a codebook of a priori and inductively generated codes, and applied it to all interviews. Coding discrepancies were discussed. Results: We used two theoretical frameworks - actor observer bias (AOB) and intragroup stigma - to analyze participants' descriptions of personal and witnessed overdoses. AOB suggests individuals may assign responsibility of their actions to external factors, while assigning responsibility for others' actions to internal mechanisms. Intragroup stigma describes the process whereby people perpetuate stigma within their own group. Related to these concepts, two principal themes were used to describe personal overdose: (1) drug volatility and (2) ascribing blame to others, and witnessed overdoses: (1) greed and (2) inexperience/foolishness. Conclusion/Importance: The differences in perceived causes of personal versus witnessed overdose align with AOB and intragroup stigma. Understanding how these theories shape overdose experiences may improve behavioral interventions by introducing peer based supports and encouraging PWIDs to employ evidence-based safety precautions when using opioids.

Sources and Impact of Time Pressure on Opioid Management in the Safety-Net.

PURPOSE: This study sought to understand clinicians' and patients' experience managing chronic noncancer pain (CNCP) and opioids in safety-net primary care settings. This article explores the time requirements of safer opioid prescribing for medically and socially complex patients in the context of safety-net primary care. METHODS: We qualitatively interviewed 23 primary care clinicians and 46 of their patients with concurrent CNCP and substance use disorder (past or current). We also conducted observations of clinical interactions between the clinicians and patients. We transcribed, coded, and analyzed interview and clinical observation recordings using grounded theory methodology. RESULTS: Clinicians reported not having enough time to assess patients' CNCP, functional status, and risks for opioid misuse. Inadequate assessment of CNCP contributed to tension and conflicts during visits. Clinicians described pain conversations consuming a substantial portion of primary care visits despite patients' other serious health concerns. System-level constraints (eg, changing insurance policies, limited access to specialty and integrative care) added to the perceived time burden of CNCP management. Clinicians described repeated visits with little progress in patients' pain or functional status due to these barriers. Patients acknowledged clinical time constraints and reported devoting significant time to following new opioid management protocols for CNCP. CONCLUSIONS: Time pressure was identified as a major barrier to safer opioid prescribing. Efforts, including changes to reimbursement structures, are needed to relieve time stress on primary care clinicians treating medically and socially complex patients with CNCP in safety-net settings.

Long-term clinical and visual outcomes after surgical resection of pediatric pilocytic/pilomyxoid optic pathway gliomas.

OBJECTIVE: The choice of treatment modality for optic pathway gliomas (OPGs) is controversial. Chemotherapy is widely regarded as first-line therapy; however, subtotal resections have been reported for decompression or salvage therapy as first- and second-line treatment. The goal of this study was to further investigate the role and efficacy of resection for OPGs. METHODS: A retrospective chart review was performed on 83 children who underwent surgical treatment for OPGs between 1986 and 2014. Pathology was reviewed by a neuropathologist. Clinical outcomes, including progression-free survival (PFS), overall survival (OS), and complications, were analyzed. RESULTS: The 5- and 10-year PFS rates were 55% and 46%, respectively. The 5- and 10-year OS rates were 87% and 78%, respectively. The median extent of resection was 80% (range 30%-98%). Age less than 2 years at surgery and pilomyxoid features of the tumor were found to be associated with significantly lower 5-year OS. No difference was seen in PFS or OS of children treated with surgery as a first-line treatment compared with children with surgery as a second- or third-line treatment. Severe complications included new disabling visual deficit in 5%, focal neurological deficit in 8%, and infection in 2%. New hormone deficiency occurred in 22% of the children. CONCLUSIONS: Approximately half of all children experience a long-term benefit from resection both as primary treatment and as a second-line therapy after failure of primary treatment. Primary surgery does not appear to have a significant benefit for children younger than 2 years or tumors with pilomyxoid features. Given the risks associated with surgery, an interdisciplinary approach is needed to tailor the treatment plan to the individual characteristics of each child.

Patient Experiences With Integrated Pain Care: A Qualitative Evaluation of One VA's Biopsychosocial Approach to Chronic Pain Treatment and Opioid Safety.

BACKGROUND: Mounting concern about the risks and limited effectiveness of opioid therapy for chronic pain has spurred the implementation of novel integrated biopsychosocial pain care models in health-care systems like the Department of Veterans Affairs (VA). However, little is known about patient experiences with these new care models. OBJECTIVE: We conducted a qualitative study to examine patient experiences with a pain care model currently being disseminated at the VA: interdisciplinary, integrated pain teams (IPTs) embedded in primary care. METHOD: We interviewed 41 veterans who received care from VA's first IPT to learn how working with the team impacted their pain care and quality of life. We asked about their overall experience with IPT, what worked and did not work for them, and what changes they would recommend to improve IPT care. RESULTS: The interviews revealed a wide spectrum of patient experiences and varying perspectives on the extent to which the new model improved their pain and quality of life. Thematic analysis shed light on factors impacting patients' experiences, including pretreatment goals and expectations as well as attitudes toward opioids and nonpharmacological treatments. CONCLUSION: We discuss the implications of our findings for national efforts to implement biopsychosocial pain care, and we offer recommendations to promote patient-centered implementation.

Structural factors affecting Asians and Pacific Islanders in community-based substance use treatment: Treatment provider perspectives.

Asians and Pacific Islanders (API) have large disparities in utilization of substance use treatment compared to other racial groups. In this study, we analyzed factors that shape API experiences accessing and engaging in community-based treatment from the perspective of treatment providers. We conducted semi-structured interviews with 40 treatment providers who work with API clients in treatment programs in San Francisco and Los Angeles. We analyzed the transcribed interview data in ATLAS.ti using a content analysis approach. There were three main findings. First, treatment providers found the API category itself is too broad and heterogeneous to meaningfully explain substance use patterns. Second, beyond race/ethnicity, structural factors such as poverty, neighborhood, housing, and age had an impact on API substance use. Third, factors such as family, immigration status, religion, language, stigma played complex roles in API treatment experiences, contingent on how client, programs, and providers attended to differences in these categories.

Fair hearing outcomes of patients recommended discharge from methadone maintenance.

A system known as fair hearings is a due process opportunity for patients who are involuntarily discharged from methadone maintenance treatment to challenge the discharge recommendation. We know very little about the processes and outcomes of fair hearings. For this study, we used a mixed methods approach to retrospectively analyze 73 fair hearing reports that were documented from a California methadone maintenance treatment program between 2000 and 2014. The aims of the study were to identify the reasons for involuntary discharge recommendation from methadone maintenance, describe the factors involved when fair hearing outcomes decided in favor of the clinic, and describe the factors involved when fair hearing outcomes decided in favor of the patient. We found that patient attendance at the fair hearing meeting was significantly related to the outcome ruling in favor of the patient. We organized the reasons for discharge recommendations into five categories: 1) suspected diversion, 2) behavioral/interpersonal, 3) repeated, unexcused absences, 4) co-occurring substance use, and 5) multiple sources of opioids. For each category, we use excerpts from fair hearing reports to provide context to the circumstances involved in an outcome favoring the patient or the clinic.

Opioid pharmacovigilance: A clinical-social history of the changes in opioid prescribing for patients with co-occurring chronic non-cancer pain and substance use.

There is growing concern among US-based clinicians, patients, policy makers, and in the media about the personal and community health risks associated with opioids. Perceptions about the efficacy and appropriateness of opioids for the management of chronic non-cancer pain (CNCP) have dramatically transformed in recent decades. Yet, there is very little social scientific research identifying the factors that have informed this transformation from the perspectives of prescribing clinicians. As part of an on-going ethnographic study of CNCP management among clinicians and their patients with co-occurring substance use, we interviewed 23 primary care clinicians who practice in safety-net clinical settings. In this paper, we describe the clinical and social influences informing three historic periods: (1) the escalation of opioid prescriptions for CNCP; (2) an interim period in which the efficacy of and risks associated with opioids were re-assessed; and (3) the current period of "opioid pharmacovigilance," characterized by the increased surveillance of opioid prescriptions. Clinicians reported that interpretations of the evidence-base in favor of and opposing opioid prescribing for CNCP evolved within a larger clinical-social context. Historically, pharmaceutical marketing efforts and clinicians' concerns about racialized healthcare disparities in pain treatment influenced opioid prescription decision-making. Clinicians emphasized how patients' medical complexity (e.g. multiple chronic health conditions) and structural vulnerability (e.g. poverty, community violence) impacted access to opioids within resource-limited healthcare settings. This clinical-social history of opioid prescribing practices helps to elucidate the ongoing challenges of CNCP treatment in the US healthcare safety net and lends needed specificity to the broader, nationwide conversation about opioids.

Estimating the impact of adopting the revised United Kingdom acetaminophen treatment nomogram in the U.S. population.

BACKGROUND: Acetaminophen toxicity is common in clinical practice. In recent years, several European countries have lowered the treatment threshold, which has resulted in increased number of patients being treated at a questionable clinical benefit. OBJECTIVE: The primary objective of this study is to estimate the cost and associated burden to the United States (U.S.) healthcare system, if such a change were adopted in the U.S. METHODS: This study is a retrospective review of all patients age 14 years or older who were admitted to one of eight different hospitals located throughout the U.S. with acetaminophen exposures during a five and a half year span, encompassing from 1 January 2008 to 30 June 2013. Those patients who would be treated with the revised nomogram, but not the current nomogram were included. The cost of such treatment was extrapolated to a national level. RESULTS: 139 subjects were identified who would be treated with the revised nomogram, but not the current nomogram. Extrapolating these numbers nationally, an additional 4507 (95%CI 3641-8751) Americans would be treated annually for acetaminophen toxicity. The cost of lowering the treatment threshold is estimated to be $45 million (95%CI 36,400,000-87,500,000) annually. CONCLUSIONS: Adopting the revised treatment threshold in the U.S. would result in a significant cost, yet provide an unclear clinical benefit.

The risks of opioid treatment: Perspectives of primary care practitioners and patients from safety-net clinics.

BACKGROUND: Patients with a history of substance use are more likely than those without substance use to experience chronic noncancer pain (CNCP), to be prescribed opioids, and to experience opioid misuse or overdose. Primary care practitioners (PCPs) in safety-net settings care for low-income patients with CNCP and substance use, usually without specialist consultation. To inform communication related to opioid risk, we explored PCPs' and patients' perceptions of the risks of chronic opioid therapy. METHODS: We conducted semistructured interviews with 23 PCPs and 46 of their patients, who had a history of CNCP and substance use. We recruited from 6 safety-net health care settings in the San Francisco Bay Area. We transcribed interviews verbatim and analyzed transcripts using grounded theory methodology. RESULTS: (1) PCPs feared harming patients and the community by opioid prescribing. PCPs emphasized fear of opioid overdose. (2) Patients did not highlight concerns about the adverse health consequences of opioids, except for addiction. (3) Both patients and PCPs were concerned about PCPs' medicolegal risks related to opioid prescribing. (4) Patients reported feeling stigmatized by policies aimed at reducing opioid misuse. CONCLUSION: We identified differences in how clinicians and patients perceive opioid risk. To improve the informed consent process for opioid therapy, patients and PCPs need to have a shared understanding of the risks of opioids and engage in discussions that promote patient autonomy and safety. As clinics implement opioid prescribing policies, clinicians must develop effective communication strategies in order to educate patients about opioid risks and decrease patients' experiences of stigma and discrimination.

Health in the Tenderloin: A resident-guided study of substance use, treatment, and housing.

Substance use researchers recognize that environments - our homes, streets, communities, and neighborhoods - set the stage for substance use and treatment experiences by framing interactions, health options, and decision-making. The role of environment is particularly salient in places deemed disadvantaged or risky, such as parts of the Tenderloin neighborhood of San Francisco. Since risk is historically, socially, and structurally situated, an individual's social position in a neighborhood shapes how risk environments are experienced. The purpose of this study was to explore how the environment shapes substance use and treatment experiences, described from the perspective of Tenderloin residents. I conducted docent method interviews with formerly homeless women living in supportive housing in San Francisco (N = 20). The docent method is a three-stage, participant-led, audiotaped, and photographed walking interview. As they guided me through target "sites of interest" (homes, streets, treatment programs, and safe spaces), participants discussed their experiences with substance use and treatment in the environment. First, they described that the risks of a broader drug market are concentrated in the Tenderloin, exposing residents to elevated and disproportionate risk. Second, for structural, economic, social, and physical reasons, participants described a sense of geographic or neighborhood stratification. Third, multiple levels of policing and surveillance were persistent, even in participants' homes. Fourth, despite all the challenges, participants found security and support in the Tenderloin, and considered it their home. In the discussion, I offer that the Tenderloin environment provided residents many advantages, but forms of structural and everyday violence largely defined their experiences in the neighborhood.

The Docent Method: A Grounded Theory Approach for Researching Place and Health.

To understand health, research needs to move outside of controlled research settings into the environments where health activities occur-homes, streets, and neighborhoods. I offer the docent method as a qualitative place-based approach for exploring health in a participant-driven, structured, and flexible way. The docent method is a participant-led, audiotaped, and photographed walking interview through broad "sites of interest" (SOIs). It is rooted in grounded theory and influenced by community-based participatory research and walking interviews. The three stages of the docent method involve: (a) a warm-up interview focusing on positionality, participant background, and mapping/planning SOIs; (b) a participant-led, photographed walking interview to and around the SOI; and (c) a wind-down interview in the community. I describe the methodological influences, development, and procedures of the docent method drawing from my own experiences conducting it with formerly homeless women living in permenant supportive housing in the Tenderloin neighborhood of San Francisco.

Provider Experiences With the Identification, Management, and Treatment of Co-occurring Chronic Noncancer Pain and Substance Use in the Safety Net.

BACKGROUND: In the United States and internationally, providers have adopted guidelines on the management of prescription opioids for chronic noncancer pain (CNCP). For "high-risk" patients with co-occurring CNCP and a history of substance use, guidelines advise that providers monitor patients using urine toxicology screening tests, develop opioid management plans, and refer patients to substance use treatment. OBJECTIVE: We report primary care provider experiences in the safety net interpreting and implementing prescription opioid guideline recommendations for patients with CNCP and substance use. METHODS: We interviewed primary care providers who work in safety net settings (N = 23) on their experiences managing CNCP and substance use. We analyzed interviews using a content analysis method. RESULTS: Providers found management plans and urine toxicology screening tests useful for informing patients about clinic expectations of opioid therapy and substance use. However, they described that guideline-based clinic policies had unintended consequences, such as raising barriers to open, honest dialogue about substance use and treatment. While substance use treatment was recommended for "high-risk" patients, providers described lack of integration with and availability of substance use treatment programs. CONCLUSIONS: Our findings indicate that clinicians in the safety net found guideline-based clinic policies helpful. However, effective implementation was challenged by barriers to open dialogue about substance use and limited linkages with treatment programs. Further research is needed to examine how the context of safety net settings shapes the management and treatment of co-occurring CNCP and substance use.

Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice.

BACKGROUND: Studies in vitro demonstrate that neuronal membrane/lipid rafts (MLRs) establish cell polarity by clustering progrowth receptors and tethering cytoskeletal machinery necessary for neuronal sprouting. However, the effect of MLR and MLR-associated proteins on neuronal aging is unknown. METHODS: Here, we assessed the impact of neuron-targeted overexpression of an MLR scaffold protein, caveolin-1 (Cav-1) (via a synapsin promoter, SynCav1), in the hippocampus in vivo in adult (6-month-old) and aged (20-month-old) mice on biochemical, morphologic, and behavioral changes. RESULTS: SynCav1 resulted in increased expression of Cav-1, MLRs, and MLR-localization of Cav-1 and tropomyosin-related kinase B receptor independent of age and time post gene transfer. Cav-1 overexpression in adult mice enhanced dendritic arborization within the apical dendrites of hippocampal cornu ammonis 1 and granule cell neurons, effects that were also observed in aged mice, albeit to a lesser extent, indicating preserved impact of Cav-1 on structural plasticity of hippocampal neurons with age. Cav-1 overexpression enhanced contextual fear memory in adult and aged mice demonstrating improved hippocampal function. CONCLUSIONS: Neuron-targeted overexpression of Cav-1 in the adult and aged hippocampus enhances functional MLRs with corresponding roles in cell signaling and protein trafficking. The resultant structural alterations in hippocampal neurons in vivo are associated with improvements in hippocampal-dependent learning and memory. Our findings suggest Cav-1 as a novel therapeutic strategy in disorders involving impaired hippocampal function.