Opioid initiation and injection transition in rural northern New England: A mixed-methods approach

BACKGROUND: In rural northern New England, located in the northeastern United States, the overdose epidemic has accelerated with the introduction of fentanyl. Opioid initiation and transition to opioid injection have been studied in urban settings. Little is known about opioid initiation and transition to injection drug use in rural northern New England. METHODS: This mixed-methods study characterized opioid use and drug injection in 11 rural counties in Massachusetts, Vermont, and New Hampshire between 2018 and 2019. People who use drugs completed audio computer-assisted self-interview surveys on substance use and risk behaviors (n = 589) and shared personal narratives through in-depth interviews (n = 22). The objective of the current study is to describe initiation of opioid use and drug injection in rural northern New England. RESULTS: Median age of first injection was 22 years (interquartile range 18-28 years). Key themes from in-depth interviews that led to initiating drug injection included normalization of drug use in families and communities, experiencing trauma, and abrupt discontinuation of an opioid prescription. Other factors that led to a transition to injecting included lower cost, increased effect/ rush, greater availability of heroin/ fentanyl, and faster relief of withdrawal symptoms with injection. CONCLUSIONS: Trauma, normalization of drug use, over-prescribing of opioids, and abrupt discontinuation challenge people who use drugs in rural northern New England communities. Inadequate opioid tapering may increase transition to non-prescribed drug use. The extent and severity of traumatic experiences described highlights the importance of enhancing trauma-informed care in rural areas

Pharmacy Participation in Non-Prescription Syringe Sales in Los Angeles and San Francisco Counties, 2007

Increasing sterile syringe access for injection drug users (IDUs) is one way to prevent HIV and hepatitis C virus (HCV) transmission in this population. In 2005, California Senate Bill 1159 allowed counties to adopt the Disease Prevention Demonstration Project (DPDP). Where enacted, the DPDP allows pharmacies that register with the county to sell up to ten syringes to adults without a prescription. In the current study, we describe pharmacy participation in nonprescription syringe sales (NPSS) in two counties in California and examine factors associated with NPSS. Telephone and in-person interviews were conducted in Los Angeles (LA) and San Francisco (SF) with 238 pharmacies in 2007 (n = 67 in SF; n = 171 in LA). Quantitative survey items captured pharmacy registration with the county, pharmacy policies/practices, episodes and conditions of NPSS and refusals to sell, potential negative consequences of NPSS, and staff attitudes regarding HIV and HCV prevention for IDUs. Overall, 42% of pharmacies reported NPSS (28% in LA and 81% in SF), although only 34% had registered with the county (17% in LA and 76% in SF). Many pharmacies required proof of a medical condition (80% in LA and 30% in SF) and refused NPSS if the customer was a suspected IDU (74% in LA, 33% in SF). Few negative consequences of NPSS were reported. In multivariate logistic regression analysis, we found that the odds of NPSS were significantly higher among pharmacists who thought syringe access was important for preventing HIV among IDUs [adjusted odds ratio (AOR) = 2.95; 95% confidence interval (CI) = 1.10–7.92], were chain pharmacies (AOR = 12.5; 95% CI = 4.55–33.33), and were located in SF (AOR = 4.88; 95% CI = 1.94–12.28). These results suggest that NPSS were influenced by pharmacists’ perception. NPSS might be increased through greater educational efforts directed at pharmacists, particularly those in non-chain pharmacies

Access to Sterile Syringes through San Francisco Pharmacies and the Association with HIV Risk Behavior among Injection Drug Users

Increased options for syringe acquisition and disposal have been associated with reductions in high-risk behaviors. This study determined the extent of pharmacy uptake in accessing syringes among injection drug users (IDUs) and estimated associations between pharmacy uptake and safer injection/disposal practices. Two years after the implementation of California’s Disease Prevention Demonstration Project, which removed restrictions to non-prescription syringe sales through pharmacies with local authorization, IDUs were recruited through street outreach in San Francisco and interviewed regarding recent syringe acquisition, use, and disposal. The sample of 105 persons included a high proportion of men (67%), people of color (49%), and homeless persons (71%). The most common syringe source was a syringe exchange program (SEP) (80%), with pharmacies being accessed by 39% of respondents. The most commonly cited source of disposal was a SEP (65%), with very few reports of pharmacy disposal (2%). Adjusted analysis showed that unsuccessful attempts to purchase syringes at a pharmacy increased the odds of both injecting with a used syringe and giving away a used syringe. Using a SEP decreased the odds of unsafe injection and disposal practices. Thus, 2 years after the initiation of the California Disease Prevention Demonstration Project, results from this small study suggest that SEPs still provide the majority of syringe distribution and disposal services to San Francisco IDUs; however, pharmacies now augment syringe access. In addition, unsafe injection behavior is reported more often among those who do not use these syringe sources. These results are consistent with prior studies in suggesting that increasing the availability of syringes through SEPs and pharmacies, and developing bridges between them, may further reduce syringe-related risk

Circulating microRNAs in Cerebrospinal Fluid and Plasma: Sensitive Tool for Detection of Secondary CNS Involvement, Monitoring of Therapy and Prediction of CNS Relapse in Aggressive B-NHL Lymphomas

Lymphoma with secondary central nervous system (CNS) involvement represents one of the most aggressive malignancies, with poor prognosis and high mortality. New diagnostic tools for its early detection, response evaluation, and CNS relapse prediction are needed. We analyzed circulating microRNAs in the cerebrospinal fluid (CSF) and plasma of 162 patients with aggressive B-cell non-Hodgkin’s lymphomas (B-NHL) and compared their levels in CNS-involving lymphomas versus in systemic lymphomas, at diagnosis and during treatment and CNS relapse. We identified a set of five oncogenic microRNAs (miR-19a, miR-20a, miR-21, miR-92a, and miR-155) in CSF that detect, with high sensitivity, secondary CNS lymphoma involvement in aggressive B-NHL, including DLBCL, MCL, and Burkitt lymphoma. Their combination into an oncomiR index enables the separation of CNS lymphomas from systemic lymphomas or nonmalignant controls with high sensitivity and specificity, and high Receiver Operating Characteristics (DLBCL AUC = 0.96, MCL = 0.93, BL = 1.0). Longitudinal analysis showed that oncomiR levels reflect treatment efficacy and clinical outcomes, allowing their monitoring and prediction. In contrast to conventional methods, CSF oncomiRs enable detection of early and residual CNS involvement, as well as parenchymal involvement. These circulating oncomiRs increase 1–4 months before CNS relapse, allowing its early detection and improving the prediction of CNS relapse risk in DLBCL. Similar effects were detectable, to a lesser extent, in plasma

Prostate MR image quality of apparent diffusion coefficient maps versus fractional intracellular volume maps from VERDICT MRI using the PI-QUAL score and a dedicated Likert scale for artefacts

PURPOSE: This study aimed to assess the image quality of apparent diffusion coefficient (ADC) maps derived from conventional diffusion-weighted MRI and fractional intracellular volume maps (FIC) from VERDICT MRI (Vascular, Extracellular, Restricted Diffusion for Cytometry in Tumours) in patients from the INNOVATE trial. The inter-reader agreement was also assessed. METHODS: Two readers analysed both ADC and FIC maps from 57 patients enrolled in the INNOVATE prospective trial. Image quality was assessed using the Prostate Imaging Quality (PI-QUAL) score and a subjective image quality Likert score (Likert-IQ). The image quality of FIC and ADC were compared using a Wilcoxon Signed Ranks test. The inter-reader agreement was assessed with Cohen's kappa. RESULTS: There was no statistically significant difference between the PI-QUAL score for FIC datasets compared to ADC datasets for either reader (p = 0.240 and p = 0.614). Using the Likert-IQ score, FIC image quality was higher compared to ADC (p = 0.021) as assessed by reader-1 but not for reader-2 (p = 0.663). The inter-reader agreement was 'fair' for PI-QUAL scoring of datasets with FIC maps at 0.27 (95% confidence interval; 0.08-0.46) and ADC datasets at 0.39 (95% confidence interval 0.22-0.57). For Likert scoring, the inter-reader agreement was also 'fair' for FIC maps at 0.38 (95% confidence interval; 0.10-0.65) and substantial for ADC maps at 0.62 (95% confidence interval; 0.39-0.86). CONCLUSION: Image quality was comparable for FIC and ADC. The inter-reader agreement was similar when using PIQUAL for both FIC and ADC datasets but higher for ADC maps compared to FIC maps using the image quality Likert score

Strategies used to reduce harms associated with fentanyl exposure among rural people who use drugs: Multi-site qualitative findings from the rural opioid initiative

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.</p

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common efectors that can lead to the development of resistance to drug inhibitors. Most current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein expression, as well as their functional efcacy. We have determined that around 20% of prostate cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a high Gleason grade tumour (≥Gleason 8). A co-targeted inhibition approach ofered broader inhibition of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition. The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional outcome compared with combined AZD-1208 +BEZ235, which have been investigated in clinical trials, and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is a viable therapeutic strategy that should be developed further in pre-clinical studies

Houselessness and syringe service program utilization among people who inject drugs in eight rural areas across the USA: A cross-sectional analysis

Background: Research conducted in urban areas has highlighted the impact of housing instability on people who inject drugs (PWID), revealing that it exacerbates vulnerability to drug-related harms and impedes syringe service program (SSP) use. However, few studies have explored the effects of houselessness on SSP use among rural PWID. This study examines the relationship between houselessness and SSP utilization among PWID in eight rural areas across 10 states. Methods: PWID were recruited using respondent-driven sampling for a cross-sectional survey that queried self-reported drug use and SSP utilization in the prior 30 days, houselessness in the prior 6 months and sociodemographic characteristics. Using binomial logistic regression, we examined the relationship between experiencing houselessness and any SSP use. To assess the relationship between houselessness and the frequency of SSP use, we conducted multinomial logistic regression analyses among participants reporting any past 30-day SSP use. Results: Among 2394 rural PWID, 56.5% had experienced houselessness in the prior 6 months, and 43.5% reported past 30-day SSP use. PWID who had experienced houselessness were more likely to report using an SSP compared to their housed counterparts (adjusted odds ratio [aOR] = 1.24 [95% confidence intervals [CI] 1.01, 1.52]). Among those who had used an SSP at least once (n = 972), those who experienced houselessness were just as likely to report SSP use two (aOR = 0.90 [95% CI 0.60, 1.36]) and three times (aOR = 1.18 [95% CI 0.77, 1.98]) compared to once. However, they were less likely to visit an SSP four or more times compared to once in the prior 30 days (aOR = 0.59 [95% CI 0.40, 0.85]). Conclusion: This study provides evidence that rural PWID who experience houselessness utilize SSPs at similar or higher rates as their housed counterparts. However, housing instability may pose barriers to more frequent SSP use. These findings are significant as people who experience houselessness are at increased risk for drug-related harms and encounter additional challenges when attempting to access SSPs.</p

Mating First, Mating More: Biological Market Fluctuation in a Wild Prosimian

In biology, economics, and politics, distributive power is the key for understanding asymmetrical relationships and it can be obtained by force (dominance) or trading (leverage). Whenever males cannot use force, they largely depend on females for breeding opportunities and the balance of power tilts in favour of females. Thus, males are expected not only to compete within their sex-class but also to exchange services with the opposite sex. Does this mating market, described for humans and apes, apply also to prosimians, the most ancestral primate group? To answer the question, we studied a scent-oriented and gregarious lemur, Propithecus verreauxi (sifaka), showing female dominance, promiscuous mating, and seasonal breeding. We collected 57 copulations involving 8 males and 4 females in the wild (Berenty Reserve, South Madagascar), and data (all occurrences) on grooming, aggressions, and marking behaviour. We performed the analyses via exact Spearman and matrix correlations. Male mating priority rank correlated with the frequency of male countermarking over female scents but not with the proportion of fights won by males over females. Thus, males competed in an olfactory tournament more than in an arena of aggressive encounters. The copulation frequency correlated neither with the proportion of fights won by males nor with the frequency of male countermarking on female scents. Male-to-female grooming correlated with female-to-male grooming only during premating. Instead, in the mating period male-to-female grooming correlated with the copulation frequency. In short, the biological market underwent seasonal fluctuations, since males bargained grooming for sex in the mating days and grooming for itself in the premating period. Top scent-releasers gained mating priority (they mated first) and top groomers ensured a higher number of renewed copulations (they mated more). In conclusion, males maximize their reproduction probability by adopting a double tactic and by following market fluctuations

Evaluation of PSA and PSA Density in a Multiparametric Magnetic Resonance Imaging-Directed Diagnostic Pathway for Suspected Prostate Cancer: The INNOVATE Trial

OBJECTIVES: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. METHODS: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging–Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. RESULTS: 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. CONCLUSIONS: The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing