Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta.

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.

The impact of non-medical cannabis legalization and other exposures on retention in longitudinal cannabis research: a survival analysis of a prospective study of Canadian medical cannabis patients.

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.

Self-reported reductions in tobacco and nicotine use following medical cannabis initiation: Results from a cross-sectional survey of authorized medical cannabis patients in Canada.

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.

A highly charged field: Mapping energies, currents and desires for reform in Canadian expert responses to drug law.

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.

Heroin and the illegal drug overdose death epidemic: A history of missed opportunities and resistance.

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.

Cannabis Significantly Reduces the Use of Prescription Opioids and Improves Quality of Life in Authorized Patients: Results of a Large Prospective Study.

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.

Reductions in alcohol use following medical cannabis initiation: results from a large cross-sectional survey of medical cannabis patients in Canada.

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.

Sustainably reducing device utilization and device-related infections with DeCATHlons, device alternatives, and decision support.

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).

Problematizing the DSM-5 criteria for opioid use disorder: A qualitative analysis.

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.

From risky places to safe spaces: Re-assembling spaces and places in Vancouver's Downtown Eastside.

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.

A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation.

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.

Primary Hepatic Neuroendocrine Carcinoma Treated with Doxorubicin and Cyclophosphamide in a Dog.

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.

Gendered drug policy: Motherisk and the regulation of mothering in Canada.

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.

BioTIME: A database of biodiversity time series for the Anthropocene.

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 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2). 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.

Persistent reticulocytosis in a case of poodle macrocytosis.

A healthy 14-year-old, male neutered, Miniature Poodle was found to have a persistent erythrocyte macrocytosis and reticulocytosis with a normal and stable HCT. The hematologic features of macrocytosis, increased Howell-Jolly bodies, and metarubricytosis, in the absence of anemia or other cytopenias, combined with the cytologic evidence of bone marrow erythroid dysplasia, including megaloblastosis, binuclearity, increased mitotic activity, and nuclear fragmentation, are consistent with previous reports of congenital dyserythropoiesis termed poodle macrocytosis. We speculate that the additional presence of persistent reticulocytosis in the absence of an identifiable stimulus for accelerated erythropoiesis may represent a phenotypic variation of this inherited condition, and the morphologic abnormalities of the dyserythropoiesis are described.

Telling our stories: heroin-assisted treatment and SNAP activism in the Downtown Eastside of Vancouver.

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.

Molecular diagnosis of Pneumocystis pneumonia in dogs.

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

Evaluation of an integrated group cognitive-behavioral treatment for comorbid mood, anxiety, and substance use disorders: A pilot study.

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.