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Hippuristanol is a marine derived steroidal natural product with promising anticancer activity. However, instability at low pH has precluded its development as an efficient therapy. We addressed this limitation by replacing one of the oxygen atoms of the spiroketal moiety with a carbon atom. Key steps in the synthesis include a Meyer-Schuster/Nazarov cascade, a hypoiodite mediated oxyfunctionalization, and the late-stage installation of a hydroxyl group on the C-ring of the steroid.

Cyclin dependent kinase 7 (CDK7) is an important therapeutic kinase best known for its dual role in cell cycle regulation and gene transcription. Here, we describe the application of protein engineering to generate constructs leading to high resolution crystal structures of human CDK7 in both active and inactive conformations. The active state of the kinase was crystallized by incorporation of an additional surface residue mutation (W132R) onto the double phosphomimetic mutant background (S164D and T170E) that yielded the inactive kinase structure. A novel back-soaking approach was developed to determine crystal structures of several clinical and pre-clinical inhibitors of this kinase, demonstrating the potential utility of the crystal system for structure-based drug design (SBDD). The crystal structures help to rationalize the mode of inhibition and the ligand selectivity profiles versus key anti-targets. The protein engineering approach described here illustrates a generally applicable strategy for structural enablement of challenging molecular targets., Competing Interests: Declaration of interests At the time of work, M.M., P.J.D., D.L., J.A.B-C., A.J.W., C.G-J., S.H., C.E., and M.O’R. were all employees of Astex Pharmaceuticals. At the time of work, S.B. was a paid consultant for Astex Pharmaceuticals working on this project., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.

Background: Despite decades of campaigns aimed at reducing tobacco/nicotine (T/N) use and the development of many different T/N reduction and cessation strategies, the impacts on international public health remain significant. Some studies have found an association between medical and non-medical cannabis use and T/N use, although the evidence on whether cannabis/cannabinoids increase or decrease the odds of reducing or ceasing T/N use remain contradictory. This paper explores the self-reported use of cannabis and associated changes in T/N use among a Canadian medical cannabis patient population., Methods: This study examines the impact of medical cannabis on T/N use by comparing self-reported patterns of use before and after the initiation of medical cannabis. Participants completed an online cross-sectional survey examining demographics, patterns of medical cannabis use, and the impact of medical cannabis on the use of T/N and other substances. The survey also included novel measures examining whether patients intended to use medical cannabis to reduce T/N use or had experience with other pharmacological or psychobehavioral T/N cessation strategies. We conducted a series of descriptive analyses and univariate and multivariate logistic regressions to explore the potential association between primary variables of interest and T/N reduction and cessation., Results: In total, the study recruited 2102 individuals, of whom 650 were current or former T/N users. Following initiation of medical cannabis use 320 (49%) T/N users self-reported reductions in use, with 160 (24.6%) reporting no T/N use in the 30 days prior to the survey. Odds of T/N cessation were greater among those who were age 55 or older (Adjusted Odds Ratio [AOR] = 2.56, 95% Confidence Interval [CI] 1.53-4.26), or those who reported >25 T/N uses per day in the pre-period (AOR = 2.11, 95% CI 1.14-3.92). Specific intent to use medical cannabis to quit resulted in significantly greater odds of reducing T/N use (AOR = 2.79, 95% CI 1.49-5.22); however, involvement with traditional T/N cessation treatments (pharmacological or psychobehavioral) was negatively associated with T/N cessation (AOR 0.39, 95% CI 0.18-0.86)., Conclusions: Results from this retrospective survey of medical cannabis users suggest that initiation of medical cannabis use was associated with self-reported reductions and/or cessation of T/N use in nearly half of study participants. In light of the significant morbidity, mortality, and health care costs related to T/N dependence, future research should further evaluate the potential of cannabis-based treatments to support efforts to reduce or cease T/N use., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Despite repeated calls by medical associations to gather evidence on the harms and benefits of cannabis, there are ongoing methodological challenges to conducting observational and clinical studies on cannabis, including a high rate of patients that are lost to follow-up (LTFU). This study explores factors potentially associated with retention in a large prospective study of Canadian medical cannabis patients, with the goal of reducing the probability that patients will be lost to follow-up in future cannabis research., Methods: The Tilray Observational Patient Study (TOPS) was a multi-site, prospective study assessing the impact of medical cannabis over 6 months in a broad population of authorized Canadian cannabis patients. The study took place from 2016 to 19, and we conducted a series of exploratory analyses including a Kaplan-Meier survival analysis and logistic regressions to assess the potential association between study retention and variables including patient characteristics, cannabis and prescription drug use, quality of life, and the legalization of non-medical cannabis., Results: Overall, 1011 participants were included in this analysis, contributing 287 patient-years of data. Retention was 728 (72%) at 3 months, and 419 (41.4%) at 6 months. Our analyses found significantly lower adjusted odds of retention following legalization (AOR 0.28, 95% CI 0.18-0.41), and in patients that used prescription opioids at baseline (AOR 0.62, 95% CI 0.46-0.85), while increased odds of retention were found in patients with a higher baseline psychological score (AOR 1.43, 95% CI 1.08-1.90) or that used anti-seizure medications at baseline (AOR 1.91, 95% CI 1.30-2.81)., Discussion: TOPS provided a unique opportunity to examine patient characteristics and other variables that may be associated with retention in prospective medical cannabis studies. Our findings highlight some of the challenges of conducting medical cannabis research at a time when patients have a multitude of cannabis access options, including legal adult dispensaries and a robust illicit market. High LTFU rates can impact the validity of studies, and potentially lead to misestimations of the harms and benefits of medical cannabis use. Despite being a multi-site prospective study, this was a convenience sample, thereby limiting the generalizability of these findings. Additionally, data regarding the use of cannabis was self-reported by patients, so is subject to potential recall bias., Conclusion: We found evidence that external policy changes that affect access to cannabis such as the legalization of non-medical adult use and patient characteristics associated with patient physical/psychological capacity can impact retention in prospective medical cannabis studies. Evidence-based strategies to reduce study burden on participants, such as minimizing in-person visits by providing digitized internet-based surveys and phone or telemedicine follow-up options as well as ensuring adequate participant compensation could improve retention. Additionally, policy-related changes aimed at improving access to medical cannabis, including increased cost-coverage and community-based distribution, could encourage patients to remain in the federal medical cannabis program and thereby reduce LTFU in associated studies., (© 2021. The Author(s).)

Background: Due to prohibitionist policies and practices, a poisoned illegal drug supply, and inadequate access to flexible substitution programs, Canada is currently experiencing the worst illegal drug overdose death epidemic in its history. In examining past policies, practices, and discourse that support heroin regulation and drug prohibition, the drivers of the current illegal drug overdose death epidemic in Canada are brought more clearly into focus., Methods: This article provides a critical socio-historical analysis of heroin (opioid) regulation with a focus on Canadian federal and provincial policies in the province of B.C., especially the city of Vancouver. Drawing from primary and secondary sources, this article provides a critical socio-historical analysis of heroin (opioid) regulation in Canada., Results: Examining Canada's history of heroin criminalization provides a window to understand the systemic discrimination against people who use illegal heroin and other opioids. From its inception, heroin prohibition has worked to brutally punish a small segment of the population, especially those who are poor, racialized, and gendered. Negative heroin discourse and stereotyping about people who use heroin had an effect, shaping drug law, policing, prisons, and policy and treatment options., Conclusion: Little attention has been given to the increase in heroin possession offences across Canada over nine consecutive years and the lack of heroin substitution programs. Resistance to drug prohibition and criminal approaches to drug use emerged in the 1950s and continue today. Those most affected by drug policies demand inclusion and representation, access to a legal heroin supply, and the establishment and maintenance of heroin buyer clubs, contesting the very foundations of drug control in the twenty-first century., Competing Interests: Declarations of Interest The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

While many experts consider major changes to legal approaches to drug use necessary, achieving such change has proven to be difficult. The political process is often seen as integral to bringing about change, largely due to orthodox understandings of the 'nature' of law, in which law is made by parliaments and capable of revision in only limited instances. In recent years, theorists such as Bruno Latour (2009, 2013), Andreas Philippopoulos-Mihalopoulos (2015) and Serge Gutwirth (2015) have taken a more expansive view of the nature of law and its effects. According to these theorists, law also emerges from outside the political process, including through various practices such as those of professionals working within legal systems, and those engaged in resistance, navigation and subversion (Seear, 2020). This article explores these processes using Karen Barad's (2015) work on lightning. As we will explain, Barad presents lightning as a 'queer', non-linear, uncertain and indeterminate phenomenon, using it to understand causation in new ways. Along with Barad's ideas, the article draws on interview data (N = 35) collected for two research projects in Canada. These interviews were conducted with senior drug use-related policy makers, service providers, advocates and lawyers based in British Columbia and Ontario, Canada. The interviews explore how key Canadian experts view drug law, debates about law and policy and whether they support reform. We also explore how these experts navigate the criminalisation of drugs and whether any insights can be drawn from their practices, including their attempts to navigate, subvert or change the law. First we consider experts' concern about current prohibitionist legal frameworks, finding it widespread, along with appetite for change. Second, we examine experts' accounts of strategies used for working around or challenging punitive frameworks. We find that change, like lightning, is complicated and messy; simplistic approaches to changes are not always possible, and may in fact make matters worse. There are multiple, unpredictable effects in engaging and resisting law, and thus difficulty in tackling criminalisation in any clear and simple way. Practices and processes of responding to and resisting drug-use criminalisation can thus be understood in terms that reflect the 'queer', indeterminate, unpredictable and multidirectional nature of Barad's lightning. In concluding, we note that this way of understanding legal processes and resistance has implications for the future of Canadian drug policy, including debates about whether it is possible to work within a framework of overarching criminalisation., Competing Interests: Declarations of Interest The authors have no conflict of interest to report., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: This article presents findings from a large prospective examination of Canadian medical cannabis patients, with a focus on the impacts of cannabis on prescription opioid use and quality of life over a 6-month period., Methods: The Tilray Observational Patient Study took place at 21 medical clinics throughout Canada. This analysis includes 1,145 patients who had at least one postbaseline visit, with follow-up at 1, 3, and 6 months. Instruments included a comprehensive cannabis use inventory, the World Health Organization Quality of Life Short Form (WHOQOL-BREF), and a detailed prescription drug questionnaire., Results: Participants were 57.6% female, with a median age of 52 years. Baseline opioid use was reported by 28% of participants, dropping to 11% at 6 months. Daily opioid use went from 152 mg morphine milligram equivalent (MME) at baseline to 32.2 mg MME at 6 months, a 78% reduction in mean opioid dosage. Similar reductions were also seen in the other four primary prescription drug classes identified by participants, and statistically significant improvements were reported in all four domains of the WHOQOL-BREF., Conclusions: This study provides an individual-level perspective of cannabis substitution for opioids and other prescription drugs, as well as associated improvement in quality of life over 6 months. The high rate of cannabis use for chronic pain and the subsequent reductions in opioid use suggest that cannabis may play a harm reduction role in the opioid overdose crisis, potentially improving the quality of life of patients and overall public health., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Engagement of frontline staff, along with senior leadership, in competition-style healthcare-associated infection reduction efforts, combined with electronic clinical decision support tools, appeared to reduce antibiotic regimen initiations for urinary tract infections (P = .01). Mean monthly standardized infection and device utilization ratios also decreased (P < .003 and P < .0001, respectively).

Background: Evidence details how cannabis can influence the use of other psychoactive substances, including prescription medications, alcohol, tobacco and illicit drugs, but very little research has examined the factors associated with these changes in substance use patterns. This paper explores the self-reported use of cannabis as a substitute for alcohol among a Canadian medical cannabis patient population., Methods: Data was derived from a survey of 2102 people enrolled in the Canadian medical cannabis program. We included 973 (44%) respondents who reported using alcohol on at least 10 occasions over a 12 month period prior to initiating medical cannabis, and then used retrospective data on the frequency and amount of alcohol use pre-and post medical cannabis initiation to determine which participant characteristics and other variables were associated with reductions and/or cessation of alcohol use., Results: Overall, 419 (44%) participants reported decreases in alcohol usage frequency over 30 days, 323 (34%) decreased the number of standard drinks they had per week, and 76 (8%) reported no alcohol use at all in the 30 days prior to the survey. Being below 55 years of age and reporting higher rates of alcohol use in the pre-period were both associated with greater odds of reducing alcohol use, and an intention to use medical cannabis to reduce alcohol consumption was associated with significantly greater odds of both reducing and ceasing alcohol use altogether., Conclusions: Our findings suggest that medical cannabis initiation may be associated with self-reported reductions and cessation of alcohol use among medical cannabis patients. Since alcohol is the most prevalent recreational substance in North America, and its use results in significant rates of criminality, morbidity and mortality, these findings may result in improved health outcomes for medical cannabis patients, as well as overall improvements in public health and safety., Competing Interests: Declarations of Interests None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: This paper includes the voices of people who are members of a peer-led drug user group (SNAP) in Canada who are receiving heroin-assisted treatment (HAT) outside of a clinical trial. Drawing from critical drug studies, we problematize the criteria for severe opioid use disorder (OUD) from the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, by exploring SNAP members' experiences in relation to heroin-assisted treatment, and examining how SNAP participants' narratives challenge conventional notions of what constitutes severe opioid use disorder., Method: Drawing on critical analysis and research guidelines developed by drug user unions and organizations, and critical methodological frameworks on ethical community-based-and-responsive research for social justice, in this paper we focus on semi-structured interviews conducted with 36 SNAP members at the Vancouver Area Network of Drug Users site in the Downtown Eastside of Vancouver, Canada. We included opened ended questions about experiences prior to receiving HAT, experiences while receiving HAT, experiences of drug use and cessation, and future hopes., Results: Although SNAP participants were diagnosed as suffering from OUD, the DSM-5 criteria for OUD fails to encompass their diverse experiences of opioid use. Nor does the DSM diagnosis capture the complexities of their lived experience. The DSM OUD constructs an idea of addiction and the addicted person based on a list of symptoms thought to be associated with extended use of opioids. The problem with this is that many of these "symptoms" of drug use are, in the case of SNAP participants, tied to contextual issues of living in the DTES, experiencing structural vulnerability, and being the target of punitive drug policies and laws., Conclusion: To label someone as having a severe disorder shifts the focus from political and social issues, including the lived experiences of people who use heroin. The DSM-5 de-contextualizes drug use. How addiction and heroin are constituted has political implications that will determine what types of services and programs will be set up. Treating a disorder, or a person with a disorder, requires a much different approach than understanding heroin use as a habit. SNAP, and their allies, are rupturing conventional ideas about heroin and taken for granted assumptions about people who use heroin., Competing Interests: Conflict of Interest Statement The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Vancouver's Downtown Eastside (DTES) neighbourhood is commonly associated with stigmatized and criminalized activities and attendant risks and harms. Many spaces/places in this urban neighbourhood are customarily portrayed and experienced as risky and harmful, and are implicated in experiences of structural (and physical) violence and marginalization. Drawing on 50 qualitative interviews, this paper explores how spaces/places frequently used by structurally vulnerable people who use drugs (PWUD) in the DTES that are commonly associated with risk and harm (e.g., alleyways, parks) can be re-imagined and re-constructed as enabling safety and wellbeing. Study participants recounted both negative and positive experiences with particular spaces/places, suggesting the possibility of making these locations less risky and safer. Our findings demonstrate how spaces/places used by PWUD in this particular geographical context can be understood as assemblages, a variety of human and nonhuman forces - such as material objects, actors, processes, affect, temporal elements, policies and practices - drawn together in unique ways that produce certain effects (risk/harm or safety/wellbeing). Conceptualizing these spaces/places as assemblages provides a means to better understand how experiences of harm, or conversely wellbeing, unfold, and sheds light on how risky spaces/places can be re-assembled as spaces/places that enable safety and wellbeing., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Telomere signaling and metabolic dysfunction are hallmarks of cell aging. New agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We performed structure-activity studies on the series to develop a photoaffinity probe to deconvolute the cellular targets. In vitro binding and structural analyses confirmed these targets, suggesting that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress are linked to telomere signaling and exemplar compound CRT0063465 blocked hypoglycemic telomere shortening. Intriguingly, PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment modulates these interactions and also affects Shelterin complex composition, while conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results demonstrate therapeutic potential of the compound series., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Due to misinformation and enduring discourses about pregnant women and mothers suspected of using drugs, these women continue to experience systemic discrimination. In 2014, this fact was once again made public in Canada when the Ontario government established an independent review of hair testing practices conducted by Motherisk Drug Testing Laboratory (MDTL) at Toronto's Hospital for Sick Kids. Between 2005 and 2015, MDTL tested the hair of more than 16,000 individuals for drug consumption. The results were introduced as evidence in court and resulted in both temporary and permanent loss of custody of children. Tragically, it was later discovered that the hair testing results were unreliable. This paper provides an analysis of child protection policies and practices directed at pregnant women and mothers suspected of using drugs, with a focus on the Motherisk tragedy in Ontario., Methods: Informed by feminist and critical drug perspectives, this study draws from findings in the 2015″Report of the Motherisk Hair Analysis Independent Review," produced by Honourable Susan Lang, and provides a Bacchi-informed critical analysis of Commissioner Beaman's 2018 report of the Motherisk Commission, "Harmful Impacts: The Reliance on Hair Testing in Child Protection" (HI)., Results: The HI report is quite sympathetic to the plight of families and it acknowledges systemic issues and unequal power relations between families, social workers and the courts. Even though drug testing is an inadequate measure of parenting capacity, the HI report does not recommend banning the practice. In the HI report, the themes of harm reduction and drug prohibition are notably absent - while the use of gender-neutral terms, such as "parent" and "families," render mothers invisible., Conclusions: The Motherisk tragedy cannot be understood as an isolated event, rather it is part of a continuum of state and gendered violence against poor, Indigenous, and Black women in Canada. The HI report fails to consider how prohibitionist discourses about drugs, addiction, mothering, and risk lead to institutional practices such as drug testing and child apprehension., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

A 7 yr, 6 mo old male neutered Australian cattle dog cross presented to a referral hospital with a large abdominal mass. An abdominal ultrasound revealed multifocal lesions throughout the liver, which were suspicious for intrahepatic metastasis, with no evidence of extrahepatic metastatic disease. Cytology indicated neoplasia of epithelial origin, with neuroendocrine neoplasia the primary suspicion. The patient was started on a maximally tolerated chemotherapy protocol of doxorubicin and metronomic cyclophosphamide. Stable disease was found on repeat abdominal ultrasounds, and the patient tolerated the protocol well. On completion of five doxorubicin doses, the dog was continued on metronomic cyclophosphamide and meloxicam. Progressive hepatic disease was found at 10 mo. The patient was euthanized 15.5 mo (465 days) after commencing treatment. Histopathology and immunohistochemistry (synaptophysin) performed on liver collected postmortem indicated (primary) hepatic neuroendocrine carcinoma. Primary hepatic neuroendocrine carcinomas are rare in dogs, and there is no standard of care for treatment. To the authors' knowledge, this is the first report of a primary hepatic neuroendocrine carcinoma treated with high-dose doxorubicin and metronomic cyclophosphamide.

Motivation: The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene., Main Types of Variables Included: The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record., Spatial Location and Grain: BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km 2 (158 cm 2 ) to 100 km 2 (1,000,000,000,000 cm 2 )., Time Period and Grain: BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year., Major Taxa and Level of Measurement: BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates., Software Format: .csv and .SQL.

Pneumocystis pneumonia (PCP) is a life-threatening fungal disease that can occur in dogs. The aim of this study was to provide a preliminary genetic characterisation of Pneumocystis carinii f.sp.'canis' (P. canis) in dogs and thereby develop a reliable molecular protocol to definitively diagnose canine PCP. We investigated P. canis in a variety of lung specimens from dogs with confirmed or strongly suspected PCP (Group 1, n = 16), dogs with non-PCP lower respiratory tract problems (Group 2, n = 65) and dogs not suspected of having PCP or other lower respiratory diseases (Group 3, n = 11). Presence of Pneumocystis DNA was determined by nested PCR of the large and small mitochondrial subunit rRNA loci and by a real-time quantitative polymerase chain reaction (qPCR) assay developed using a new set of primers. Molecular results were correlated with the presence of Pneumocystis morphotypes detected in cytological/histological preparations. Pneumocystis DNA was amplified from 13/16 PCP-suspected dogs (Group 1) and from 4/76 dogs of control Groups 2 and 3 (combined). The latter four dogs were thought to have been colonized by P. canis. Comparison of CT values in 'infected' versus 'colonized' dogs was consistent with this notion, with a distinct difference in molecular burden between groups (CT ≤ 26 versus CT range (26

Background: This article highlights the experiences of a peer-run group, SALOME/NAOMI Association of Patients (SNAP), that meets weekly in the Downtown Eastside of Vancouver, British Columbia, Canada. SNAP is a unique independent peer- run drug user group that formed in 2011 following Canada's first heroin-assisted treatment trial (HAT), North America Opiate Medication Initiative (NAOMI). SNAP's members are now made up of former research participants who participated in two heroin-assisted trials in Vancouver. This article highlights SNAP members' experiences as research subjects in Canada's second clinical trial conducted in Vancouver, Study to Assess Longer-term Opioid Medication Effectiveness (SALOME), that began recruitment of research participants in 2011., Methods: This paper draws on one brainstorming session, three focus groups, and field notes, with the SALOME/NAOMI Association of Patients (SNAP) in late 2013 about their experiences as research subjects in Canada's second clinical trial, SALOME in the DTES of Vancouver, and fieldwork from a 6-year period (March 2011 to February 2017) with SNAP members. SNAP's research draws on research principles developed by drug user groups and critical methodological frameworks on community-based research for social justice., Results: The results illuminate how participating in the SALOME clinical trial impacted the lives of SNAP members. In addition, the findings reveal how SNAP member's advocacy for HAT impacts the group in positive ways. Seven major themes emerged from the analysis of the brainstorming and focus groups: life prior to SALOME, the clinic setting and routine, stability, 6-month transition, support, exiting the trial and ethics, and collective action, including their participation in a constitutional challenge in the Supreme Court of BC to continue receiving HAT once the SALOME trial ended., Conclusions: HAT benefits SNAP members. They argue that permanent HAT programs should be established in Canada because they are an effective harm reduction initiative, one that also reduces opioid overdose deaths.

This paper presents the development and preliminary evaluation of an integrated group cognitive-behavioral treatment (CBT) for comorbid mood, anxiety, and substance use disorders. The 12-session, manualized treatment was developed collaboratively by a mental health program in a teaching hospital and a community-based addictions service and administered in both settings. Results from an uncontrolled effectiveness trial of 29 treatment completers suggest that integrated group CBT may reduce stress and alcohol use symptoms and improve substance refusal self-efficacy. Changes in symptoms of anxiety, depression, and drug use were not significant, although the effect size for anxiety reduction was in the medium range. Nonetheless, the clinical significance of treatment effects on mood, anxiety, and substance use symptoms was modest. Changes in coping skills and quality of life were not significant, although medium-to-large effects were observed for changes in several coping skills. Participants reported being highly satisfied with treatment, found the treatment strategies to be useful, and noted an improvement in their functioning, particularly socially. Methodological and sample size limitations warrant more rigorous follow-up investigations of this treatment. Results are considered in the context of the current literature on integrated psychological treatments for these common comorbidities., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Little is known of the hematology of the dugong (Dugong dugon), a secretive and endangered coastal marine mammal., Objectives: This paper reports hematologic reference intervals (RI) for dugongs and characterizes morphologic, cytochemical, and ultrastructural features of dugong leukocytes., Methods: Blood was collected from live, apparently healthy dugongs and analyzed using Cell-Dyn 3700 or Sysmex XT-2000iV hematology analyzers. Blood films were subjected to a series of cytochemical stains, and leukocyte structure was examined using transmission electron microscopy., Results: Reference intervals were established for 14 hematologic variables, total solids, and fibrinogen for 92 dugongs. Significant differences in some variables were found for animal size class, sex, and pregnancy status, and between analyzers. Subadults had higher leukocyte and lymphocyte counts than adults. Males had higher total solids and fibrinogen than females. Pregnant females had higher HCT, MCV, and circulating nucleated RBC, and lower platelet counts than nonpregnant females. Lymphocytes were usually the predominant circulating leukocyte. Heterophil cytoplasmic granules were abundant, fine, round to ovoid, and intensely eosinophilic, and round to ovoid or rod-shaped, and variably electron dense in electron microscopy. Eosinophils contained larger round eosinophilic to orange cytoplasmic granules, which ultrastructurally were bicompartmental with a round eccentric electron-dense core. Cytochemical staining of dugong heterophils suggests biochemical similarity to those of manatees and elephants, and for eosinophils, similarity to those of elephants, ruminants, and equids., Conclusions: Generation of hematologic RI and characterization of leukocyte morphology improves evaluation of dugong health across this population and serves as a reference for other populations outside southern Queensland., (© 2015 American Society for Veterinary Clinical Pathology.)

As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.

In Vancouver, British Columbia, Canada's third largest city, the Vancouver Police Department (VPD), has positioned itself as being at the forefront of mental health regulation. The VPD problematization of the "mental health crisis" in Vancouver draws on discourses of addiction and dangerousness. This is partially achieved by the twinning of mental health with addiction (dual diagnoses) and a focus on illegal drug consumption, and is supported through law enforcement's role as active claims-makers. Consequently, there is a mobilization of resources to identify, discipline, and contain people identified as mentally ill and addicted with little examination of both the textual and visual discourses that serve this purpose. This article addresses this gap through an analysis of the images and discursive framing of people with mental illness and addictions by the VPD in two Vancouver Police Department reports published in 2008 and 2009., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: In 1948 the first National Film Board (NFB) documentary in Canada about illegal drugs, trafficking, and addiction was produced. The documentary is titled Drug Addict, and was directed by Robert Anderson. This paper provides a socio-historical context for the documentary Drug Addict. Viewing the film through the lens of Canadian history gives readers a better context to understand the claims and representations in the film about law enforcement, people who use illegal drugs and treatment., Methods: To examine Drug Addict, a socio-historical analysis and case study were conducted. This project's qualitative methodological framework is consistent with its critical theoretical perspective, drawing from Stuart Hall's perspectives on visual and textual representation and cultural criminology., Results: Drug Addict is a significant documentary because it provides insight into early foundational law enforcement discourses and practices about illegal drugs, addiction, and treatment, including obstacles to drug substitution and maintenance programs. It also highlights the emergence of psychiatry as a new knowledge producer in the area of drug treatment. The film also transmits ideas about the criminal nature of addicts and the need for punitive criminal justice control., Conclusion: Drug Addict captures some past and contemporary tensions related to Canadian drug policy. The film also provides another lens to understand some of the foundational frameworks of Canadian drug policy such as the dominance of criminal justice, and its practices of knowledge production, the resistance espoused by institutions to diverse models of treatment such as drug maintenance programs, and the power of visual representation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: This article highlights the experiences of a unique group. In January 2011, Dave Murray organized a group of participants from the North American Opiate Medication Initiative (NAOMI) heroin-assisted treatment clinical trials from 2005 to 2008 in the Downtown Eastside of Vancouver (DTES), B.C., Canada. The NAOMI Patients Association (NPA) is an independent group that currently meets every Saturday in the DTES. Currently, all members of the NPA are former participants in the heroin stream of the clinical trial. The NPA offers support, education, and advocacy to its members., Methods: Drawing on brainstorming sessions and focus groups that were conducted in the summer of 2011, this paper highlights the experiences of NPA members in their own words., Results: The findings provide a lens to understand how becoming a research subject for the NAOMI trial impacted the lives of NPA members, both positive and negative. The NPA members discuss ethics, consent, recommendations for future HAT programs and studies, and ongoing advocacy.

Aims: Concern about crime is a significant barrier to the establishment of methadone treatment centers (MTCs). Methadone maintenance reduces crime among those treated, but the relationship between MTCs and neighborhood crime is unknown. We evaluated crime around MTCs., Setting: Baltimore City, MD, USA., Participants: We evaluated crime around 13 MTCs and three types of control locations: 13 convenience stores (stores), 13 residential points and 10 general medical hospitals., Measures: We collected reports of Part 1 crimes from 1 January 1999 to 31 December 2001 from the Baltimore City Police Department., Design: Crimes and residential point locations were mapped electronically by street address (geocoded), and MTCs, hospitals and stores were mapped by visiting the sites with a global positioning satellite (GPS) locator. Concentric circular 'buffers' were drawn at 25-m intervals up to 300 m around each site. We used Poisson regression to assess the relationship between crime counts (incidents per unit area) and distance from the site., Findings: There was no significant geographic relationship between crime counts and MTCs or hospitals. A significant negative relationship (parameter estimate -0.3127, P < 0.04) existed around stores in the daytime (7 am-7 pm), indicating higher crime counts closer to the stores. We found a significant positive relationship around residential points during daytime (0.5180, P < 0.0001) and at night (0.3303, P < 0.0001), indicating higher crime counts further away., Conclusions: Methadone treatment centers, in contrast to convenience stores, are not associated geographically with crime., (Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)

Over the past decade, fragment-based drug discovery has developed significantly and has gained increasing popularity in the pharmaceutical industry as a powerful alternative and complement to traditional high-throughput screening approaches for hit identification. Fragment-based methods are capable of rapidly identifying starting points for structure-based drug design from relatively small libraries of low molecular weight compounds. The main constraints are the need for sensitive methods that can reliably detect the typically weak interactions between fragments and the target protein, and strategies for transforming fragments into higher molecular weight drug candidates. This approach has recently been validated as series of compounds from various programs have entered clinical trials.

This case control study of 1,000 birth certificates examined what individual and community factors predicted maternal smoking in Baltimore, Maryland. Conditional multinomial logistic regression results indicated women who were White were more likely to start smoking at a young age, but as they got older, they were less likely to smoke. Minority women were more likely to start smoking at a later age. Also, White women were more likely to smoke as the rate of poverty increased, while for minority women, smoking was unrelated to whether they lived in higher or lower poverty areas. Medical assistance status, community education level, and crime rate were not found to be related to smoking status.

Background: Cannabis withdrawal can be a negative reinforcer for relapse, but little is known about its association with demographic characteristics., Objectives: Evaluate the association of demographic characteristics with the experience of cannabis withdrawal., Methods: Retrospective self-report of a "serious" cannabis quit attempt without formal treatment in a convenience sample of 104 non-treatment-seeking, adult cannabis smokers (mean age 35 years, 52% white, 78% male) with no other current substance use disorder (except tobacco) or chronic health problems. Reasons for quitting, coping strategies to help quit, and 18 specific withdrawal symptoms were assessed by questionnaire., Results: Among withdrawal symptoms, only anxiety, increased sex drive, and craving showed significant associations with age, race, or sex. Women were more likely than men to report a physical withdrawal symptom (OR = 3.2, 95% CI = .99-10.4, p = .05), especially upset stomach. There were few significant demographic associations with coping strategies or reasons for quitting., Conclusions and Scientific Significance: This small study suggests that there are few robust associations between demographic characteristics and cannabis withdrawal. Future studies with larger samples are needed. Attention to physical withdrawal symptoms in women may help promote abstinence.

Background: Cocaine users not seeking treatment have increased regional brain mu-opioid receptor (mOR) binding that correlates with cocaine craving and tendency to relapse. In cocaine-abusing outpatients in treatment, the relationship of mOR binding and treatment outcome is unknown., Methods: We determined whether regional brain mOR binding before treatment correlates with outcome and compared it with standard clinical predictors of outcome. Twenty-five individuals seeking outpatient treatment for cocaine abuse or dependence (DSM-IV) received up to 12 weeks of cognitive-behavioral therapy and cocaine abstinence reinforcement, whereby each cocaine-free urine was reinforced with vouchers redeemable for goods. Regional brain mOR binding was measured before treatment using positron emission tomography with [¹¹C]]-carfentanil (a selective mOR agonist). Main outcome measures were: 1) overall percentage of urines positive for cocaine during first month of treatment; and 2) longest duration (weeks) of abstinence from cocaine during treatment, all verified by urine toxicology., Results: Elevated mOR binding in the medial frontal and middle frontal gyri before treatment correlated with greater cocaine use during treatment. Elevated mOR binding in the anterior cingulate, medial frontal, middle frontal, middle temporal, and sublobar insular gyri correlated with shorter duration of cocaine abstinence during treatment. Regional mOR binding contributed significant predictive power for treatment outcome beyond that of standard clinical variables such as baseline drug and alcohol use., Conclusions: Elevated mOR binding in brain regions associated with reward sensitivity is a significant independent predictor of treatment outcome in cocaine-abusing outpatients, suggesting a key role for the brain endogenous opioid system in cocaine addiction., (Published by Elsevier Inc.)

Background: Cellular senescence is a major barrier to tumour progression, though its role in pathogenesis of cancer and other diseases is poorly understood in vivo. Improved understanding of the degree to which latent senescence signalling persists in tumours might identify intervention strategies to provoke "accelerated senescence" responses as a therapeutic outcome. Senescence involves convergence of multiple pathways and requires ongoing dynamic signalling throughout its establishment and maintenance. Recent discovery of several new markers allows for an expression profiling approach to study specific senescence phenotypes in relevant tissue samples. We adopted a "senescence scoring" methodology based on expression profiles of multiple senescence markers to examine the degree to which signals of damage-associated or secretory senescence persist in various human tumours., Results: We first show that scoring captures differential induction of damage or inflammatory pathways in a series of public datasets involving radiotherapy of colon adenocarcinoma, chemotherapy of breast cancer cells, replicative senescence of mesenchymal stem cells, and progression of melanoma. We extended these results to investigate correlations between senescence score and growth inhibition in response to ~1500 compounds in the NCI60 panel. Scoring of our own mesenchymal tumour dataset highlighted differential expression of secretory signalling pathways between distinct subgroups of MPNST, liposarcomas and peritoneal mesothelioma. Furthermore, a pro-inflammatory signature yielded by hierarchical clustering of secretory markers showed prognostic significance in mesothelioma., Conclusions: We find that "senescence scoring" accurately reports senescence signalling in a variety of situations where senescence would be expected to occur and highlights differential expression of damage associated and secretory senescence pathways in a context-dependent manner.

Background: There is increasing public health evidence that women who use crack cocaine and are street-involved experience significant health problems and are more isolated with regards to accessing harm reduction and other health-related services. Simultaneously, there is growing acknowledgement that structural and 'everyday' violence are significant factors influencing the health of women who use illegal drugs. Little research has examined how these social processes play out for women who use crack cocaine., Methods: A critical ethnography informed by the theoretical constructs of structural and everyday violence and intersectionality was undertaken to explore women's use of crack cocaine within an inner-city neighbourhood in Western Canada. Data collection included baseline survey (n=126), participant observation and field notes, informal interviews (n=53), and in-depth interviews (n=13)., Results: Based on thematic and theoretical analysis two interrelated themes were identified that reflected the interrelationships between women's use of crack, poverty, discrimination, racism, gendered relations of power, and legal policies and practices: (a) the context of health care; and (b) the smoking context., Conclusions: Structural inequities and 'everyday' violence are perilously damaging for women who use crack. Interventions to reduce these inequities are urgently needed if we are to reduce the significant suffering of women who are street-involved and use crack cocaine., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Objectives: : Cocaine use is associated with cardiac arrhythmias. Markers of ventricular late potentials, which may be a precursor to malignant ventricular arrhythmias, can be detected by signal-averaged electrocardiography (SA-ECG) but not by standard ECG., Methods: : We evaluated SA-ECG parameters in 60 medically screened, physically healthy, recently abstinent cocaine users (53 males, mean [SD] age, 34.0 [4.6] years; 10.1 [6.0] years of use) and 54 nondrug-using controls (21 males, mean [SD] age 28.4 [7.8] years). SA-ECGs were done periodically for ≤12 weeks of monitored abstinence in 25 cocaine users. We analyzed 3 SA-ECG parameters considered markers of ventricular late potentials: duration of filtered QRS complex, duration of low-amplitude potentials during terminal 40 ms of QRS complex (LAS40), and root mean square voltage during terminal 40 ms of QRS complex (RMS40)., Results: : Cocaine users differed significantly from controls in filtered QRS complex (118.5 [11.2] ms versus 111.9 [11.4] ms; P = 0.03) but not in LAS40 (28.9 [8.2] ms versus 30.8 [8.3] ms; P = 0.40) or RMS40 (40.0 [19.8] μV versus 30.2 [20.1] μV; P = 0.06) values. The proportion of subjects with abnormal SA-ECG parameters did not differ significantly between male cocaine users and male controls. There were no significant changes over time in either the mean values or proportion of subjects with abnormal values for any SA-ECG parameter. There were significant gender differences among controls but not among cocaine users., Conclusion: : These findings suggest that chronic cocaine use is not associated with a higher prevalence of abnormal SA-ECG parameters in physically healthy users.

In 2004, a team comprised of researchers and service providers launched the Safer Crack Use, Outreach, Research and Education (SCORE) project in the Downtown Eastside of Vancouver, British Columbia, Canada. The project was aimed at developing a better understanding of the harms associated with crack cocaine smoking and determining the feasibility of introducing specific harm reduction strategies. Specifically, in partnership with the community, we constructed and distributed kits that contained harm reduction materials. We were particularly interested in understanding what people thought of these kits and how the kits contents were used. To obtain this information, we conducted 27 interviews with women and men who used crack cocaine and received safer crack kits. Four broad themes were generated from the data: 1) the context of crack use practices; 2) learning/transmission of harm reduction education; 3) changing practice; 4) barriers to change. This project suggests that harm reduction education is most successful when it is informed by current practices with crack use. In addition it is most effectively delivered through informal interactions with people who use crack and includes repeated demonstrations of harm reduction equipment by peers and outreach workers. This paper also suggests that barriers to harm reduction are systemic: lack of safe housing and private space shape crack use practices.

Rationale: Cocaine users have increased regional brain mu-opioid receptor (mOR) binding which correlates with cocaine craving. The relationship of mOR binding to relapse is unknown., Objective: To evaluate regional brain mOR binding as a predictor of relapse to cocaine use is the objective of the study., Materials and Methods: Fifteen nontreatment-seeking, adult cocaine users were housed on a closed research ward for 12 weeks of monitored abstinence and then followed for up to 1 year after discharge. Regional brain mOR binding was measured after 1 and 12 weeks using positron emission tomography (PET) with [11C]carfentanil (a selective mOR agonist). Time to first cocaine use (lapse) and to first two consecutive days of cocaine use (relapse) after discharge was based on self-report and urine toxicology., Results: A shorter interval before relapse was associated with increased mOR binding in frontal and temporal cortical regions at 1 and 12 weeks of abstinence (Ps < 0.001) and with a lesser decrease in binding between 1 and 12 weeks (Ps < 0.0008). There were significant positive correlations between mOR binding at 12 weeks and percent days of cocaine use during first month after relapse (Ps < 0.002). In multiple linear regression analysis, mOR binding contributed significantly to the prediction of time to relapse (R2= 0.79, P < 0.001), even after accounting for clinical variables., Conclusions: Increased brain mOR binding in frontal and temporal cortical regions is a significant independent predictor of time to relapse to cocaine use, suggesting an important role for the brain endogenous opioid system in cocaine addiction.

A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.

Macbecin compares favorably to geldanamycin as an Hsp90 inhibitor, being more soluble, stable, more potently inhibiting ATPase activity (IC50 = 2 microM) and binding with higher affinity (Kd = 0.24 microM). Structural studies reveal significant differences in their Hsp90 binding characteristics, and macbecin-induced tumor cell growth inhibition is accompanied by characteristic degradation of Hsp90 client proteins. Macbecin significantly reduced tumor growth rates (minimum T/C: 32%) in a DU145 murine xenograft. Macbecin thus represents an attractive lead for further optimization.

Background: Cocaine lengthens electrocardiographic QTc, QRS and PR intervals through blockade of sodium and potassium channels, but changes during withdrawal have not been well studied., Methods: We recorded weekly electrocardiograms (ECGs) from 25 physically healthy cocaine users (84.0% men, mean [S.D.] age 34.7 [4.1] years, 9.0 [5.2] years of cocaine use, 9.4 [3.5] days of use in the 2 weeks prior to admission) over 3 months of monitored abstinence on a closed ward. Subjects had minimal current use of other drugs. Baseline ECGs were recorded 20.5 h [16.6] after last cocaine use., Results: Baseline QTc interval correlated positively with total amount of cocaine used and amount used per day in the 2 weeks prior to ward admission. There was a significant 10.5 ms [12.9] shortening of QTc interval during the first week of withdrawal, with no further significant changes thereafter. There were no significant changes in PR or QRS intervals., Conclusions: These findings suggest that cocaine-associated QTc prolongation returns toward normal during the first week of cocaine abstinence.

We compared treadmill exercise stress testing (EST) in 28 medically screened, chronic cocaine users with the cardiovascular effects of an IV cocaine challenge (25 mg or 50 mg). All subjects had a clinically normal EST and echocardiography (except 2 subjects had septal wall hypokinesis). The EST produced significantly greater increases in heart rate and rate-pressure product than did the cocaine challenges. These findings suggest that EST may not provide additional diagnostic information in medically screened cocaine users. EST may cause more cardiac work (indicated by heart rate and blood pressure) than intravenous cocaine (at the doses in this study).

This study examined associations between three temperament dimensions measured by the Temperament and Character Inventory-125 [Cloninger, C.R. (1992). The Temperament and Character Inventory-125 (TCI-125; Version 1.)] and tobacco abstinence effects. Smokers (N=203, >/= 15 cigarettes/day) attended two laboratory sessions, one following 12 h of abstinence and the other following ad libitum smoking (order counterbalanced). Participants completed measures of withdrawal symptoms, cigarette urges, and affect. Smokers high in Novelty Seeking reported greater abstinence-induced increases in several nicotine withdrawal symptoms, negative affect, and cigarette craving. Smokers high in Harm Avoidance reported greater abstinence-induced increases in negative affect and urges to smoke to relieve distress. Reward Dependence was not associated with abstinence effects. Novelty Seeking and Harm Avoidance showed independent predictive associations with negative affect and urges, and their associations with abstinence effects persisted when controlling for FTND scores. Smokers with different temperaments display different patterns of acute tobacco withdrawal, and may benefit from treatments matched to their particular abstinence profile.

Rationale: A single 90-mg dose of the cannabinoid CB1 receptor antagonist rimonabant attenuates effects of smoked cannabis in humans., Objectives: The objective of this study is to evaluate whether repeated daily 40-mg doses of rimonabant can attenuate effects of smoked cannabis to the same extent as a single higher (90 mg) dose., Materials and Methods: Forty-two male volunteers received one of three oral drug regimens in a randomized, double blind, parallel group design: (1) 40 mg rimonabant daily for 15 days, (2) placebo for 14 days, then 90 mg rimonabant on day 15, or (3) placebo for 15 days. All participants smoked an active or placebo cannabis cigarette 2 h after medication on days 8 and 15. Subjective effects were measured with visual analog scales and the marijuana-scale of the Addiction Research Center Inventory., Results: Cannabis-induced tachycardia was significantly lower for the 40-mg group on day 8 and for the 40 and 90 mg rimonabant groups on day 15 as compared to placebo. The 40-mg dose significantly decreased peak subjective effects on day 8. Neither the 90-mg nor 40-mg doses significantly decreased peak subjective effects on day 15. Rimonabant treatment did not significantly affect Delta(9)-tetrahydrocannabinnol pharmacokinetics., Conclusions: Repeated lower daily rimonabant doses (40 mg) attenuated the acute physiological effects of smoked cannabis to a similar degree as a single 90-mg dose; repeated 40-mg doses attenuated subjective effects after 8 but not 15 days.

Understanding the factors that determine molecular shape enables scientists to begin to understand and tailor molecular properties and reactivity. Many biomolecules and bioactive compounds contain aliphatic heterocyclic rings whose conformations play a major role in their biological activity. The interplay of a number of factors, both steric and electronic, is examined for 5-hydroxyhexahydropyrimidine (1) and related compounds with use of spectroscopy and molecular modeling.

Since the 1980s there has been a gradual introduction of women-centred programmes to address the needs of women who use legal and illegal drugs. But questions related to pregnancy and birth in relation to maternal drug use have proved more difficult to address and, in the USA in particular, policy and practice remains quite punitive. This article explores contemporary moral concerns and the practices related to drugs, pregnancy and mothering. It considers how sociohistoric factors have contributed to the development, or not, of women-centred harm-reduction services for pregnant women and their infants. British programmes are seen to offer public health and harm-reduction initiatives rather than just crime control. To demonstrate this, an overview of the role of a consultant midwife in providing comprehensive primary and secondary services for drug and alcohol dependent mothers in Manchester, UK is given and compared with Canadian programmes. Finally, the possible ways forward will also be explored.

Gender differences in tobacco withdrawal are of considerable clinical importance, but research findings on this topic have been mixed. Methodological variation in samples sizes, experimental design, and measures across studies may explain the inconsistent results. The current study examined whether male (n = 101) and female (n = 102) smokers (> or =15 cigarettes/day) differed in abstinence-induced changes on a battery of self-report measures (withdrawal, affect, craving), cognitive performance tasks (attention, psychomotor performance), and physiological responses (heart rate, blood pressure, brain electroencephalogram). Participants attended 2 counterbalanced laboratory sessions, 1 following 12 hr of abstinence and the other following ad libitum smoking. Results showed that women reported greater abstinence-induced increases in negative affect, withdrawal-related distress, and urge to smoke to relieve withdrawal distress. In contrast, both genders reported similar abstinence-induced changes in positive affect and urge to smoke for pleasure. Men and women exhibited generally similar abstinence-induced changes in physiological and cognitive performance measures. In addition, gender did not moderate the association between withdrawal symptoms and baseline measures of smoking behavior and dependence. Abstinence-induced changes in withdrawal distress mediated the effect of gender on latency until the 1st cigarette of the day at trend levels ( p < .10). These findings suggest that there are qualitative gender differences in the acute tobacco withdrawal syndrome that may underlie gender-specific smoking patterns.

The potential energy surfaces of methanol clusters, (CH3OH)n, n = 2-12, have been studied using density functional theory at the B3LYP/6-31G(d) and higher levels of theory. Cyclic clusters in which n methanol molecules are joined in a ring structure formed by n hydrogen bonds are shown to be more stable than structures of the same number of methanol molecules where one or more methanol molecules are outside the ring and are hydrogen-bonded to oxygens of methanols in rings of n - 1, n - 2, and so forth. So-called chain structures are generally even less stable. Furthermore, the hydrogen-bonding energy per methanol molecule of the n-ring clusters is shown to converge to an asymptotic value of about 27 kJ/mol at B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) after five to six methanols are included in the cluster. As expected, there are many minima on the potential energy surfaces of the methanol clusters, the number increasing rapidly with n. A cyclic cluster of five to six methanol molecules appears to be sufficient to mimic liquid behavior as far as vibrational frequencies are concerned.

Cocaine is rapidly metabolized to major metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME), and minor metabolites, norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine. This IRB-approved study examined cocaine and metabolite plasma concentrations in 18 healthy humans who provided written informed consent to receive low (75 mg/70 kg) and high (150 mg/70 kg) subcutaneous cocaine hydrochloride doses. Plasma specimens, collected prior to and up to 48 h after dosing, were analyzed by gas chromatography-mass spectrometry (2.5 ng/mL limits of quantification). Cocaine was detected within 5 min, with mean+/-SE peak concentrations of 300.4+/-24.6 ng/mL (low) and 639.1+/-56.8 ng/mL (high) 30-40 min after dosing. BE and EME generally were first detected in plasma 5-15 min post-dose; 2-4 h after dosing, BE and EME reached mean maximum concentrations of 321.3+/-18.4 (low) and 614.7+/-46.0 ng/mL (high) and 47.4+/-3.0 (low) and 124.4+/-18.2 ng/mL (high), respectively. Times of last detection were BE>EME>cocaine. Minor metabolites were detected much less frequently for up to 32 h, with peak concentrations

This study examines the self-reported reasons for quitting marijuana use, changes in other substance use during the quit attempt, and reasons for the resumption of use in 104 non-treatment-seeking adult marijuana smokers. Reasons for quitting were shown to be primarily motivated by concerns about the negative impact of marijuana on health and on self- and social image. The spontaneous quitting of marijuana use is often associated with an increase in the use of legal substances such as alcohol, tobacco, and sleeping aids, but not with the initiation of new substance use. These findings suggest areas for further research on spontaneous recovery from marijuana use.