Structural Barriers to Primary Care Among Sex Workers: Findings from a Community- Based Cohort in Vancouver, Canada (2014-2021).

Background: Due to structural marginalization, sex workers experience health inequities including a high prevalence of sexually transmitted and blood-borne infections, mental health disorders, trauma, and substance use, alongside a multitude of barriers to HIV and substance use services. Given limited evidence on sex workers' broader primary healthcare access, we aimed to examine structural factors associated with primary care access among sex workers over a 7-year period. Methods: Data were derived from An Evaluation of Sex Workers Health Access (AESHA), a community-based open prospective cohort of women (cis and trans) sex workers in Metro Vancouver, from 2014 to 2021. Descriptive statistics were used to summarize the proportion of primary care use in the past six months and to assess primary care trends over time from 2014-2021. We used multivariate logistic regression with generalized estimating equations (GEE) to identify structural factors associated with primary care access (seeing a family doctor in the last six months), after adjusting for confounders. Results: Amongst 646 participants, most (87.4%) accessed primary care at some point during the study period, and primary care use in the in the last 6 months was relatively stable (ranging from 60-78%) across each follow-up period. At first available observation, participants faced a high burden of sexually transmitted and blood-borne infections (STBBIs) (48.0%, 11.5%, and 10.4% were HCV, HIV, or STI seropositive, respectively), 56.8% were diagnosed with a mental health disorder, 8.1% had recently overdosed, and 14.7% were recently hospitalized. In multivariable GEE analysis, exposure to intimate partner violence was associated with reduced access to primary care (Adjusted odds ratios (AOR) 0.63, 95% Confidence interval (CI): 0.49 - 0.82), and limited English fluency was marginally associated (AOR 0.76 CI: 0.51 - 1.14). Conclusions: This study characterized primary care access and its structural determinants among sex workers over 7-years. Participants faced a high burden of STBBIs and other health disparities, and a proportion faced gaps in primary care access. Scale-up of trauma-informed, culturally and linguistically tailored, sex worker-friendly primary care models are needed, alongside structural interventions to decriminalize and destigmatize sex work and substance use.

Discovery of orally bioavailable ALK PROTACs based ceritinib against ALK positive cancers.

Anaplastic lymphoma kinase (ALK) fusion genes promote a variety of human malignancies. Although several ALK inhibitors have significantly improved disease prognosis in patients with ALK positive cancers, the persistent emergence of acquired drug-resistant mutations remain the major problem in clinic treatment. Adoption of new therapeutic strategies such as proteolysis targeting chimera (PROTAC) to overcome drug resistance in BTK/AR-related cancers have shown promising prospect. Herein, we reported the integrate ALK PROTACs through overall optimization of linker, revealed that subtle structural differences can lead to significant activity difference, indicating the key role of conformation of PROTACs in inducing the formation of E3-PROTAC-target protein ternary complexes. A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F = 14.22 %) was obtained by overall optimization of molecular properties. 4B effectively induced long lasting degradation of ALK fusion proteins and strong repression of downstream pathway in Karpas 299 cells (DC50 = 119.33 nM, Dmax = 97.1 %) and showed comparable anti-proliferative activity to Ceritinib (IC50 = 3.11 ± 0.08 nM vs IC50 = 1.31 ± 0.43 nM). Furthermore, 4B significantly inhibited the growth of Karpas 299 xenografts in vivo with TGI of 49.5 % and showed superior anti-proliferative activity against G1202R mutation to Ceritinib (IC50 = 52.82 nM vs IC50 = 109.5 nM). Overall, 4B is expected to be a potential treatment for ALK-driven malignancies.

Prevalence, correlates, and quality-of-life outcomes of major or persistent pain among women living with HIV in Metro Vancouver, Canada.

While women living with HIV (WLWH) are twice as likely to report severe or undertreated chronic pain compared to men, little is known about pain among WLWH. Our goal was to characterize the correlates of pain as well as its impact on quality-of-life outcomes among women enrolled in the Sexual Health and HIV/AIDS Women's Longitudinal Needs Assessment (SHAWNA), an open longitudinal study of WLWH accessing care in Metro Vancouver, Canada. We conducted logistic regression analyses to identify associations between self-reported major or persistent pain with sociostructural and psychosocial correlates and with quality-of-life outcomes. Data are presented as adjusted odds ratios (aORs) with 95% confidence intervals. Among 335 participants, 77.3% reported pain at ≥ 1 study visit, with 46.3% experiencing any undiagnosed pain and 53.1% managing pain with criminalized drugs. In multivariable analysis, age (aOR 1.04[1.03-1.06] per year increase), food and housing insecurity (aOR 1.54[1.08-2.19]), depression diagnosis (aOR 1.34[1.03-1.75]), suicidality (aOR 1.71[1.21-2.42]), and non-daily, non-injection opioid use (aOR 1.53[1.07-2.17]) were associated with higher odds of pain. Daily non-injection opioid use (aOR 0.46[0.22-0.96]) and health services access (aOR 0.63[0.44-0.91]) were associated with lower odds of pain. In separate multivariable confounder models, pain was associated with reduced odds of good self-rated health (aOR 0.64[0.48-0.84] and increased odds of health interference with social activities (aOR 2.21[1.63-2.99]) and general function (aOR 3.24[2.54-4.13]). In conclusion, most WLWH in our study reported major or persistent pain. Pain was commonly undiagnosed and associated with lower quality of life. We identified structural and psychosocial factors associated with pain in WLWH, emphasizing the need for low-barrier, trauma-informed, and harm reduction-based interventions.

A Novel HPLC Method for Quality Inspection of NRK Biosynthesized ß-Nicotinamide Mononucleotide.

ß-nicotinamide mononucleotide (NMN) has a good effect on delaying aging, repairing DNA and ameliorating metabolic disease. Biosynthesis with nicotinamide riboside kinase (NRK) takes a large part in NMN manufacture, but there is no available NMN quality standard and analytical method at present. In this study, we developed a specific high-performance liquid chromatography method for the assessment of NMN-related substances, including NMN and its potential impurities from NRK biological production and storage. Forced degradation study was performed under acid, base, oxidative, photolytic and thermal conditions. The separation of related substances was achieved on an Elite Hypersil ODS column using phosphate buffer-methanol gradient at a flow rate of 1.0 mL/min. The detection wavelength was maintained at 260 nm. The resolutions among all related substances were better than 1.5. Significant degradation was observed in basic and thermal conditions. All related substances showed good linearity with a coefficient of determination (R2) higher than 0.999. The accuracy values of all related substances were between 91.2% and 108.6%. Therefore, the validated analytical method is appropriate for inspecting the quality of NMN in its NRK biosynthetic manufacture and storage, thus further helping to unify NMN quality standards and facilitate related studies on NMN.

A novel benzothiazole derivative induces apoptosis via the mitochondrial intrinsic pathway producing antitumor activity in colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most common malignancies causing the third highest mortality rate in the world. It is particularly urgent to explore effective therapeutic strategies to overcome this disease. We identified a novel benzothiazole derivative (BTD) that may serve as a potentially effective agent against CRC. Method: MTT assays, cell colony formation assays, EdU staining assays, flow cytometry, RNA-seq, Western blotting, and migration and invasion assays were used to examine the effects of BTD on cell proliferation, apoptosis, metastasis, and the cell cycle. The antitumor activity of BTD in vivo was investigated in a CT26 tumor-bearing mouse model. Immunohistochemistry (IHC) was performed to examine the protein expression in mouse tumors. Hematology, biochemical analysis, and H&E staining were used to assess the biosafety of BTD. Results: We observed that BTD suppressed cell proliferation and metastasis and promoted the apoptosis of tumor cells in vitro. Treatment with BTD at a tolerable dose significantly reduced tumor growth in CT26-tumor-bearing mice and appeared to be safe. Treatment of BTD induced apoptosis by increasing the generation of reactive oxygen species (ROS) and evoking the loss of mitochondrial transmembrane potential. Overall, BTD suppressed cell proliferation and metastasis, and induced apoptosis of colorectal tumor cells through the ROS-mitochondria-mediated apoptotic pathway. The preliminary proof of the antitumor activity and relative safety of BTD were validated in a mouse model. Conclusion: Our findings suggest that BTD could serve as a potentially safe and effective candidate for CRC treatment.

An overview of PROTACs: a promising drug discovery paradigm.

Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin-proteasome system. Currently, about 20-25% of all protein targets are being studied, and most works focus on their enzymatic functions. Unlike small molecules, PROTACs inhibit the whole biological function of the target protein by binding to the target protein and inducing subsequent proteasomal degradation. PROTACs compensate for limitations that transcription factors, nuclear proteins, and other scaffolding proteins are difficult to handle with traditional small-molecule inhibitors. Currently, PROTACs have successfully degraded diverse proteins, such as BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 and ARV-471 exhibited excellent efficacy in clinical II trials. However, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood. And how to rationally design an efficient PROTACs and optimize it to be orally effective poses big challenges for researchers. In this review, we summarize the features of PROTAC technology, analyze the detail of general principles for designing efficient PROTACs, and discuss the typical application of PROTACs targeting different protein categories. In addition, we also introduce the progress of relevant clinical trial results of representative PROTACs and assess the challenges and limitations that PROTACs may face. Collectively, our studies provide references for further application of PROTACs.

Discovery of potent and selective HER2 PROTAC degrader based Tucatinib with improved efficacy against HER2 positive cancers.

HER2 is a validated therapeutic target for HER2 positive breast cancer and gastric cancer. TKIs have significantly improved the prognosis of patients with HER2 positive cancer. However, the pan-HER TKIs always caused gastrointestinal and skin side effects, and acquired drug resistance inevitable compromised their therapeutic efficacy. Herein, we describe the discovery of the first potent and selective HER2 PROTAC degrader based Tucatinib with improved antitumor activity in vitro and in vivo. The preferred selective HER2 PROTAC, CH7C4, efficiently degraded HER2 with DC50 of 69 nM and Dmax of 96%, and inhibited the proliferation of BT-474 cells with IC50 of 0.047 ± 0.006 nM via long lasting HER2 degradation and strong repression of downstream pathway. Moreover, CH7C4 had acceptable pharmacokinetic profiles with a half-life of 5.31 h, and significantly inhibited the growth of BT-474 xenografts in vivo with TGI of 73%. As the first selective HER2 PROTAC degrader with better activity in vitro and in vivo than Tucatinib, CH7C4 provides new insights into the development of new therapeutic strategy for HER2 positive cancer.

Validation and endorsement of health system performance measures for opioid use disorder in British Columbia, Canada: A Delphi panel study.

Background: Limited data exists on the performance of the healthcare system in opioid use disorder (OUD). We evaluated the face validity and potential risks of a set of health system performance measures for OUD collaboratively with clinicians, policymakers and people with lived experience of opioid use (PWLE) in the interest of establishing an endorsed set of measures for public reporting. Methods: Through a two-stage Delphi-panel approach, a panel of clinical and policy experts validated and considered 102 previously constructed OUD performance measures for endorsement using information on measurement construction, sensitivity analyses, quality of evidence, predictive validity, and feedback from local PWLE. We collected quantitative and qualitative survey responses from 49 clinicians and policymakers, and 11 PWLE. We conducted inductive and deductive thematic analysis to present qualitative responses. Results: A total of 37 measures of 102 were strongly endorsed (9/13 cascade of care, 2/27 clinical guideline compliance, 17/44 healthcare integration, and 9/18 healthcare utilization measures). Thematic analysis of responses revealed several themes regarding measurement validity, unintended consequences, and key contextual considerations. Overall, measures related to the cascade of care (excluding opioid agonist treatment dose tapering) received strong endorsements. PWLE highlighted barriers to accessing treatment, undignified aspects of treatment, and lack of a full continuum of care as their concerns. Conclusion: We defined 37 endorsed health system performance measures for OUD and presented a range of perspectives on their validity and use. These measures provide critical considerations for health system improvement in the care of people with OUD.

Opioid Use Disorder and Perinatal Outcomes.

OBJECTIVES: Evidence on the perinatal health of mother-infant dyads affected by opioids is limited. Elevated risks of opioid-related harms for people with opioid use disorder (OUD) increase the urgency to identify protective factors for mothers and infants. Our objectives were to determine perinatal outcomes after an OUD diagnosis and associations between opioid agonist treatment and birth outcomes. METHODS: We conducted a population-based retrospective study among all women with diagnosed OUD before delivery and within the puerperium period in British Columbia, Canada, between 2000 and 2019 from provincial health administrative data. Controlling for demographic and clinical characteristics, we determined associations of opioid agonist treatment on birth weight, gestational age, infant disorders related to gestational age and birth weight, and neonatal abstinence syndrome via logistic regression. RESULTS: The population included 4574 women and 6720 live births. Incidence of perinatal OUD increased from 166 in 2000 to 513 in 2019. Compared with discontinuing opioid agonist treatment during pregnancy, continuous opioid agonist treatment reduced odds of preterm birth (adjusted odds ratio: 0.6; 95% confidence interval: 0.4-0.8) and low birth weight (adjusted odds ratio: 0.4; 95% confidence interval: 0.2-0.7). Treatment with buprenorphine-naloxone (compared with methadone) reduced odds of each outcome including neonatal abstinence syndrome (adjusted odds ratio: 0.6; 95% confidence interval: 0.4-0.9). CONCLUSIONS: Perinatal OUD in British Columbia tripled in incidence over a 20-year period. Sustained opioid agonist treatment during pregnancy reduced the risk of adverse birth outcomes, highlighting the need for expanded services, including opioid agonist treatment to support mothers and infants.

The cascade of care for opioid use disorder among youth in British Columbia, 2018.

BACKGROUND: Medication for opioid use disorder (MOUD) is associated with substantial reductions in the risk of mortality, and American and Canadian guidelines recommend it as part of the full range of available treatments for youth with opioid use disorder (OUD). We estimated the OUD cascade of care for all adolescents (ages 12-18) and young adults (19-24) with OUD in British Columbia, Canada (BC) in 2018. METHODS: Using a provincial-level linkage of six health administrative databases, we classified youth with OUD as adolescents (ages 12-18) or young adults (19-24) to compare with older adults (≥25) and described key factors known to influence engagement in health care. The eight-stage cascade of care included diagnosed with OUD, ever engaged in MOUD, recently in MOUD, currently in MOUD, and retained in MOUD for ≥1 month, ≥3 months, ≥12 months, ≥24 months. RESULTS: We identified 4048 youth diagnosed with OUD as of September 30, 2018 (6.3% of all people with OUD). Most were young adults, aged 19-24 (n = 3602; 89.0% of all youth), a majority of whom were males (n = 1984; 55.1%). In contrast, adolescents diagnosed with OUD (n = 446; 11.0% of all youth) were mostly females (n = 287; 64.4%). Compared to adolescents, there were more young adults diagnosed with OUD ever engaged in MOUD (71.4% v. 36.5%), currently on MOUD (29.3% v. 16.8%), and retained in care for ≥1 year (8.6% v. 2.0%). CONCLUSIONS: A high proportion of youth aged 12-24 diagnosed with OUD in a health care setting in British Columbia received MOUD yet continued engagement is infrequent, particularly for adolescents. Long-term treatment plans for youth need to consider including MOUD when appropriate as part of tailored, youth-friendly services.

The effect of British Columbia's Pharmacare coverage expansion for opioid agonist treatment.

Opioid agonist treatment (OAT) is the evidence-based standard of care for people with opioid use disorder. In British Columbia, Canada, only social assistance registrants received full coverage for OAT prior to the introduction of the Pharmacare Plan G coverage expansion on February 1st, 2017. We aimed to determine the effect of the coverage expansion on OAT initiation, re-initiation, and retention. Using linked population-level data, we executed a difference-in-differences analysis to compare outcomes of individuals eligible for the additional coverage and social assistance registrants already receiving the most generous coverage for OAT prior to the policy change, adjusting for individual and prescriber characteristics. We found Plan G coverage expansion significantly increased OAT retention. Specifically, coverage expansion decreased the number of OAT episode discontinuations by 12.8% (95% CI: 8.4%, 17.2%).

Prioritizing Additional Data Collection to Reduce Decision Uncertainty in the HIV/AIDS Response in 6 US Cities: A Value of Information Analysis.

OBJECTIVES: The ambitious goals of the US Ending the HIV Epidemic initiative will require a targeted, context-specific public health response. Model-based economic evaluation provides useful guidance for decision making while characterizing decision uncertainty. We aim to quantify the value of eliminating uncertainty about different parameters in selecting combination implementation strategies to reduce the public health burden of HIV/AIDS in 6 US cities and identify future data collection priorities. METHODS: We used a dynamic compartmental HIV transmission model developed for 6 US cities to evaluate the cost-effectiveness of a range of combination implementation strategies. Using a metamodeling approach with nonparametric and deep learning methods, we calculated the expected value of perfect information, representing the maximum value of further research to eliminate decision uncertainty, and the expected value of partial perfect information for key groups of parameters that would be collected together in practice. RESULTS: The population expected value of perfect information ranged from $59 683 (Miami) to $54 108 679 (Los Angeles). The rank ordering of expected value of partial perfect information on key groups of parameters were largely consistent across cities and highest for parameters pertaining to HIV risk behaviors, probability of HIV transmission, health service engagement, HIV-related mortality, health utility weights, and healthcare costs. Los Angeles was an exception, where parameters on retention in pre-exposure prophylaxis ranked highest in contributing to decision uncertainty. CONCLUSIONS: Funding additional data collection on HIV/AIDS may be warranted in Baltimore, Los Angeles, and New York City. Value of information analysis should be embedded into decision-making processes on funding future research and public health intervention.

Opioid agonist treatment and risk of mortality during opioid overdose public health emergency: population based retrospective cohort study.

OBJECTIVE: To compare the risk of mortality among people with opioid use disorder on and off opioid agonist treatment (OAT) in a setting with a high prevalence of illicitly manufactured fentanyl and other potent synthetic opioids in the illicit drug supply. DESIGN: Population based retrospective cohort study. SETTING: Individual level linkage of five health administrative datasets capturing drug dispensations, hospital admissions, physician billing records, ambulatory care reports, and deaths in British Columbia, Canada. PARTICIPANTS: 55 347 people with opioid use disorder who received OAT between 1 January 1996 and 30 September 2018. MAIN OUTCOME MEASURES: All cause and cause specific crude mortality rates (per 1000 person years) to determine absolute risk of mortality and all cause age and sex standardised mortality ratios to determine relative risk of mortality compared with the general population. Mortality risk was calculated according to treatment status (on OAT, off OAT), time since starting and stopping treatment (1, 2, 3-4, 5-12, >12 weeks), and medication type (methadone, buprenorphine/naloxone). Adjusted risk ratios compared the relative risk of mortality on and off OAT over time as fentanyl became more prevalent in the illicit drug supply. RESULTS: 7030 (12.7%) of 55 347 OAT recipients died during follow-up. The all cause standardised mortality ratio was substantially lower on OAT (4.6, 95% confidence interval 4.4 to 4.8) than off OAT (9.7, 9.5 to 10.0). In a period of increasing prevalence of fentanyl, the relative risk of mortality off OAT was 2.1 (95% confidence interval 1.8 to 2.4) times higher than on OAT before the introduction of fentanyl, increasing to 3.4 (2.8 to 4.3) at the end of the study period (65% increase in relative risk). CONCLUSIONS: Retention on OAT is associated with substantial reductions in the risk of mortality for people with opioid use disorder. The protective effect of OAT on mortality increased as fentanyl and other synthetic opioids became common in the illicit drug supply, whereas the risk of mortality remained high off OAT. As fentanyl becomes more widespread globally, these findings highlight the importance of interventions that improve retention on opioid agonist treatment and prevent recipients from stopping treatment.

The cascade of care for opioid use disorder: a retrospective study in British Columbia, Canada.

BACKGROUND AND AIMS: The 'cascade of care' framework, measuring attrition at various stages of care engagement, has been proposed to guide the public health response to the opioid overdose public health emergency in British Columbia, Canada. We estimated the cascade of care for opioid use disorder and identified factors associated with care engagement for people with opioid use disorder (PWOUD) provincially. DESIGN: Retrospective study using a provincial-level linkage of four health administrative databases. SETTING AND PARTICIPANTS: All PWOUD in BC from 1 January 1996 to 30 November 2017. MEASUREMENTS: The eight-stage cascade of care included diagnosed PWOUD, ever on opioid agonist treatment (OAT), recently on OAT, currently on OAT and retained on OAT: ≥ 1, ≥ 3, ≥ 12 and ≥ 24 months). Health-care use, homelessness and other demographics were obtained from physician billing records, hospitalizations, and drug dispensation records. Receipt of income assistance was indicated by enrollment in Pharmacare Plan C. FINDINGS: A total of 55 470 diagnosed PWOUD were alive at end of follow-up. As of 2017, a majority of the population (n = 39 456; 71%) received OAT during follow-up; however, only 33% (n = 18 519) were currently engaged in treatment and 16% (n = 8960) had been retained for at least 1 year. Compared with those never on OAT, those currently engaged in OAT were more likely to be aged under 45 years [adjusted odds ratio (aOR) = 1.75, 95% confidence interval (CI) = 1.64, 1.89], male (aOR = 1.72, 95% CI = 1.64, 1.82), with concurrent substance use disorders (aOR = 2.56, 95% CI = 2.44, 2.70), hepatitis C virus (HCV) (aOR = 1.22, 95% CI = 1.14, 1.33) and either homeless or receiving income-assistance (aOR = 4.35, 95% CI = 4.17, 4.55). Regular contact with the health-care system-either in out-patient or acute care settings-was common among PWOUD not engaged in OAT, regardless of time since diagnosis or treatment discontinuation. CONCLUSIONS: People with opioid use disorder in British Columbia, Canada show high levels of out-patient care prior to diagnosis. Younger age, male sex, urban residence, lower income level and homelessness appear to be independently associated with increased opioid agonist treatment engagement.

A weak fault feature extraction of rolling element bearing based on attenuated cosine dictionaries and sparse feature sign search.

The time domain signal of bearing pitting/spalling fault always presents shock and modulation, and it is often submerged by strong noises, especially in the early stage. the conventional fault feature extraction method may have insufficient feature extraction accuracy, and even in some extreme cases, the fault feature frequency cannot be extracted because of the strong noise interference. Aiming at overcoming the noise interference problem encountered in this kind of weak fault feature extraction, a novel weak fault feature extraction algorithm termed as ACFSS of rolling bearing is proposed. The ACFSS is based on an overcomplete dictionary (or overcomplete atomic library) of Attenuated Cosines(AC) basis, which is highly matched to the bearing fault waveforms, and an improved Basis Pursuit algorithm with Feature Sign Search(FSS) is introduced into the ACFSS to improve the calculating speed. In order to select the suitable parameters of the attenuated cosine dictionary, some methods such as peak resonance frequency (PRF), power variation peak (PVK), time shift parameter (TSP), etc. are introduced. These parameters span the sparse overcomplete dictionary. Finally, the bearing fault data of Case-Western University and full life accelerated IMS bearing data are utilized to verify the validation of ACFSS. Compared with the ordinary envelope spectrum analysis(ESA) method /the ordinary Basis Pursuit Denoising(BPDN) method/ Wavelet package transform(WPT) Kurtogram method and Empirical Mode Decomposition(EMD) combining Singular Value Decomposition(SVD) method, The experiment show that the proposed method are more redundant and robust when facing strong noise interference, and it can be used to extract the weak fault feature frequency efficiently and accurately.