Pay for Performance and Treatment Outcome in Agonist Treatment for Opioid Use Disorder.

BACKGROUND AND OBJECTIVES: Pay for performance (P4P) models have become more popular in reimbursement for medical services, including treatment for substance use disorders. However, studies have not examined whether P4P has an impact on treatment outcome in the individual in opioid agonist treatment (OAT). Thus, the present study was conducted at the individual level, rather than the programmatic level, to determine whether meeting the P4P early engagement criteria (four services in the initial 14 days of treatment and/or eight services within the initial 30 days of treatment) resulted in reduced opioid, benzodiazepine, and cocaine use. METHODS: We performed a retrospective study of 63 patients enrolled in OAT for opioid use disorder. χ2 analyses were conducted crossing P4P early engagement criteria status and urine drug screen (UDS) results for opioid, cocaine, and/or benzodiazepine use at 6 and 12 months postadmission. Methadone dosage and treatment retention were also considered. The odds ratio was used to determine the directionality of significant results. RESULTS: Significant relationships were revealed between patients meeting 30-day P4P early engagement criteria and opioid negative UDS, and with retention in treatment at 6 and 12 months. Methadone dosage was significant at a 6-month follow-up. DISCUSSION AND CONCLUSIONS: Since significant associations between opioid use and P4P as well as opioid use and methadone dose were revealed, findings partially supported hypothesis. SCIENTIFIC SIGNIFICANCE: P4P and methadone dosage may have some benefit to individuals in OAT in attaining short-term abstinence from opioids. P4P may be less useful in helping individuals achieve abstinence from other substances of abuse. (Am J Addict 2020;00:00-00).

Challenges and opportunities for future Canadian physician-scientists: Perspectives of four experts.

In this series of interviews, the Clinical and Investigative Medicine editorial team gathered expert opinions on the future of physician-scientist training and career prospects in Canada. This was inspired by recent publications that voiced concerns over the diminishing support for the physician-scientist in Canada and the United States. For this editorial, the term physician-scientist was intentionally broad and inclusive; referring to individuals who identify both clinical work and biomedical or healthcare research as major components of their career. The following leaders in medical research or research funding shared their perspectives: Roderick R. McInnes; Michel G. Bergeron; Thomas J. Marrie; and Bev J. Holmes.

Impaired behavioural flexibility related to white matter microgliosis in the TgAPP21 rat model of Alzheimer disease.

Executive dysfunction and white matter inflammation continue to be relatively understudied in rodent models of Alzheimer's disease (AD). Behavioural inflexibility is an important component of executive dysfunction that can be further categorized as perseverative or regressive, which respectively specify whether maladaptive persistence occurs early or late during a behavioural change. Previous studies of the TgAPP21 rat model of AD (expressing pathogenic hAPP) suggested a potentially spontaneous increase of regressive behavioral inflexibility. In this study, 7-8-month-old male TgAPP21 rats were tested for behavioral flexibility, learning, and memory using an operant conditioning chamber and the Morris Water Maze (MWM). TgAPP21 rats demonstrated a regressive behavioral inflexibility during set shifting in an operant conditioning chamber (regressive errors η2 = 0.32 and number of errors after criterion η2 = 0.33). Regressive behavior was also demonstrated in the MWM probe test, wherein TgAPP21 rats significantly increased their swim time in the target quadrant during the last third of the probe test (43% vs 33% in the first 2 thirds of the probe test or the Wt rats' 29%-32%); this behavioral phenotype has not been previously described in the MWM. TgAPP21 demonstrated further impairment of behavioural inflexibility as they committed a greater number of reversal errors in the operant conditioning chamber (η2 = 0.30). Diffuse microglia activation was increased in the white matter tracts of TgAPP21 (corpus callosum, cingulum, and internal capsule; η2 = 0.59-0.62), which was found to correlate with the number of reversal errors in the operant conditioning chamber (R2 = 0.42). As TgAPP21 rats do not spontaneously develop amyloid plaques but have been shown in previous studies to be vulnerable to the development of plaques, these rats demonstrate an important onset of cognitive change and inflammation in the pre-plaque phase of AD. TgAPP21 rats are also an instrumental model for studying the role and mechanism of white matter microglial activation in executive functioning. This is pertinent to clinical research of prodromal AD which has suggested that white matter inflammation may underlie impairment of executive functions such as behavioral flexibility.

Fourth Annual Clinician Scientist Trainee Symposium at the Schulich School of Medicine and Dentistry.

The Annual Clinician Scientist Trainee Symposium (CSTS) gathers the local medical research community at the Schulich School of Medicine and Dentistry, including research trainees at the medical student, resident and fellow levels. Trainees showcase their current and upcoming work, and leaders in the community impart their perspectives on the importance and future of research in medicine. At the 4th Annual CSTS, perseverance and cautious optimism emerged as the characteristics that trainees should foster through their future careers as clinician scientists. This was echoed by the challenges and encouraging findings presented by trainees, who conducted their work as part of research projects within the MD, MD/PhD and clinical investigator programs. The four oral presentations and 10 three-minute thesis presentations covered the full breadth of medical disciplines across the spectrum of translational medicine, from fundamental sciences through knowledge translation. The CSTS concluded with the keynote presentation by Michael Strong, current president of the Canadian Institutes of Health Research, who gave a glimpse into his decades-long path of overcoming and overturning dogmatic views in the world of amyotrophic lateral sclerosis research, demonstrating how roadblocks in research can become an impulse for stronger science.

Scientific overview on CSCI-CITAC Annual General Meeting and 2017 Young Investigators' Forum.

The 2017 Annual General Meeting of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was a national Annual General Meeting (AGM) held in Toronto, Ontario November 20-22, 2017, in conjunction with the University of Toronto Clinician Investigator Program Research Day. The theme for this year's meeting was "Roll up your sleeves-How to manage your physician scientist career", emphasizing lectures and workshops that were designed to provide tools for being proactive and successful in career planning. The keynote speakers were Dr. Rod McInnes (McGill University and Canadian Institutes of Health Research Acting President), who was the Distinguished Scientist Award recipient, Dr. David Goltzman (McGill University), who was the 2017 Henry Friesen Award recipient, Dr. Gillian Hawker (University of Toronto), Dr. Mike Sapieha (Université de Montréal), who was the 2017 Joe Doupe Award recipient, and Dr. Alex MacKenzie (Children's Hospital of Eastern Ontario Research Institute, University of Ottawa). The workshops, focusing on career development for clinician scientists, were hosted by Dr. Lisa Robinson, Dr. Nicola Jones, Kevin Vuong, Fran Brunelle, Dr. Jason Berman and Dr. Alan Underhill. Further to this, the Young Investigators' Forum encompasses presentations from scientist-clinician trainees from across the country. All scientific abstracts are summarized in this review. There were over 100 abstracts showcased at this year's meeting during the highlighted poster sessions, with six outstanding abstracts selected for oral presentations during the President's Forum.

Trajectories of suicidal ideation during rTMS for treatment-resistant depression.

BACKGROUND: rTMS is a safe and effective intervention for treatment-resistant depression (TRD). However, there is limited data on its specific impact on suicidal ideation (SI), and the trajectory of SI over the treatment course. OBJECTIVE: This open-label clinical trial investigated SI outcomes and trajectories in patients with TRD receiving low-frequency rTMS (LFR) to the right dorsolateral prefrontal cortex (DLPFC; N = 55). METHODS: A latent class mixed-effect model was used to identify response trajectories for SI as well as core mood symptoms. Logistic regression analyses investigated risk factors associated with identified trajectories. RESULTS: For each symptom domain, we identified two distinct trajectories during LFR, one tracking improvement (SI: n = 35, 60 %; mood: n = 29, 53 %) and the other tracking no improvement (SI: n = 20, 40 %; mood: n = 26, 47 %). Male sex, higher baseline anxiety, and higher baseline SI were risk factors for no improvement of SI; while higher baseline anxiety and benzodiazepine use were risk factors for no improvement of mood. Mediation analyses showed that anxiety was a risk factor for no improvement of SI and mood independent of benzodiazepine treatment. CONCLUSIONS: This is the first study to investigate trajectories of response to LFR to the right DLPFC. SI and mood improved with LFR in most patients but the severity of anxiety symptoms was a factor of poor prognosis for both. Nuanced characterization of SI response to rTMS may lead to critical insights for individualized targeting strategies.

Caring for youth with co-occurring substance use and severe psychiatric disorders: diagnostic challenges and clinical implications.

Appropriate interventions for psychiatric conditions that commonly emerge during adolescence and early adulthood play a crucial role in modifying both acute risks as well as long-term outcomes. Substance use disorder is a common comorbidity during the early stages of mood and psychotic disorders that further heightens acute risks and is considered a negative prognostic factor. New presentations of mood and psychotic symptoms with co-occurring substance use are inherently challenging to formulate due to the uncertainty surrounding the relative impact of multiple intrinsic and extrinsic factors. Given such uncertainty, it is natural for clinicians to rely on heuristics to guide assessment and management. These heuristics however may bring about premature diagnostic closure by favouring the primacy of substance use, which in turn can result in a missed window of opportunity for a timely and appropriate intervention. We caution clinicians against over-attributing early symptoms of mood and psychotic disorders to substances use alone.

Les interventions appropriées pour les troubles psychiatriques qui apparaissent communément durant l'adolescence et le début de l'âge adulte jouent un rôle essentiel dans la modification tant des risques aigus que des résultats à long terme. Le trouble d'utilisation de substances est une comorbidité commune durant les premières phases des troubles de l'humeur et psychotiques qui hausse davantage les risques aigus et est considéré comme un facteur pronostic négatif. Les nouvelles présentations des symptômes de l'humeur et psychotiques avec un trouble concomitant d'utilisation de substances sont intrinsèquement difficiles à formuler en raison de l'incertitude entourant l'effet relatif de multiples facteurs intrinsèques et extrinsèques. Devant cette incertitude, il est naturel pour les cliniciens d'employer l'heuristique pour guider l'évaluation et la gestion. Ces heuristiques peuvent toutefois provoquer la clôture d'un diagnostic prématuré en favorisant la primauté de l'utilisation de substances, qui à son tour peut entraîner une fenêtre d'opportunité manquée pour une intervention ponctuelle et appropriée. Nous mettons en garde les cliniciens contre l'attribution excessive des symptômes précoces de l'humeur et des troubles psychotiques à la seule utilisation de substances.

Evidence of factors influencing delays in the diagnosis and treatment of bipolar disorder in adolescents and young adults. Protocol for a systematic scoping review.

BACKGROUND: Bipolar Disorder (BD) is a complex psychiatric condition that typically manifests during late adolescence and early adulthood. Over the past two decades, international studies have reported that BD often goes unrecognized and untreated for several years, which can lead to negative clinical and functional outcomes. However, the components of delay in the diagnosis and treatment of BD and various factors influencing those components have not been systematically explored. OBJECTIVES: The scoping review described in this protocol aims to map the existing literature on potential factors that influence delays in the treatment of BD in adolescents and young adults, in order to identify the knowledge gaps and future research and policy priorities. METHODS: This protocol for a systematic scoping review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline (PRISMA-ScR). We will search the electronic databases of MEDLINE (OVID), EMBASE, PsycINFO and CINAHL for peer-reviewed primary research articles published in academic journals. Grey literature will not be explored due to resource limitations. A conceptual framework based on the Model of Pathways to Treatment by Scott and colleagues was used as a foundation for our search and extraction strategy to ensure all components of delay and potential factors influencing each component are explored. Two independent reviewers will screen the references retrieved by the literature search and select relevant studies based on our inclusion criteria. The data from included studies will be synthesized into a narrative summary, and implications for future research, practice and policy will be discussed. DISCUSSION: To the best of our knowledge, this will be the first scoping review to explore the potential factors that influence delays in the treatment of BD in adolescents and young adults. We intend to disseminate the review results through academic conferences and publication in a peer-reviewed journal.

Precocious White Matter Inflammation and Behavioural Inflexibility Precede Learning and Memory Impairment in the TgAPP21 Rat Model of Alzheimer Disease.

Neuroinflammation and behavioural inflexibility are both common in late adulthood but far more profound in Alzheimer disease (AD). To investigate the relationship between ageing, AD, neuroinflammation, and behavioural flexibility, male wild-type Fischer 344 (Wt) and the transgenic APP21 (TgAPP21) rats were aged to 4, 8, 13, and 22 months and evaluated for neuroinflammation and cognitive impairment. TgAPP21 rats overexpress a pathogenic variant of the human amyloid precursor protein (hAPP; Swedish and Indiana mutations) but do not spontaneously develop overt pathology related to AD. In both genotypes, learning and memory were similarly impaired in older rats. However, at 8 months of age, TgAPP21 rats demonstrated behavioural inflexibility in set shifting, reversal, and the Morris water maze, while Wt rats showed inflexibility at 13 and 22 months of age. This early inflexibility in TgAPP21 rats was accompanied by a precocious increase in microglia activation within the corpus callosum; 8- and 13-month-old TgAPP21 rats had similar levels of microglia activation as 13- and 22-month-old Wt rats, respectively. However, while neuroinflammation within the white matter continued to progress with age, behavioural inflexibility peaked in 8-month-old TgAPP21 rats; in older TgAPP21 rats, memory and learning impairments masked inflexibility. These findings suggest that the behavioural inflexibility and white matter inflammation seen in normal ageing are accelerated in AD and may precede impairments of learning and memory.

Neurovascular unit dysregulation, white matter disease, and executive dysfunction: the shared triad of vascular cognitive impairment and Alzheimer disease.

Executive dysfunction is the most important predictor for loss of independence in dementia. As executive function involves the coordination of distributed cerebral functions, executive function requires healthy white matter. However, white matter is highly vulnerable to cerebrovascular insults, with executive dysfunction being a core feature of vascular cognitive impairment (VCI). At the same time, cerebrovascular pathology, white matter disease, and executive dysfunction are all increasingly recognized as features of Alzheimer disease (AD). Recent studies have characterized the crucial role of glial cells in the pathological changes observed in both VCI and AD. In comorbid VCI and AD, the glial cells of the neurovascular unit (NVU) emerge as important therapeutic targets for the preservation of white matter integrity and executive function. Our synthesis from current research identifies dysregulation of the NVU, white matter disease, and executive dysfunction as a fundamental triad that is common to both VCI and AD. Further study of this triad will be critical for advancing the prevention and management of dementia.

Randomised controlled trial of corneal vs. scleral rigid gas permeable contact lenses for keratoconus and other ectatic corneal disorders.

PURPOSE: To compare the comfort and visual performance of corneal rigid gas permeable contact lenses (CoL) and scleral rigid gas permeable contact lenses (SL) in participants with corneal ectasia, successfully wearing "habitual" CoL. METHODS: In a randomised controlled trial (RCT) with a 2 × 2 crossover, 34 participants were recruited and randomised into two groups. Group 1 (sequence AB), were fitted in period 1, with new CoL and after a 4-week washout period, in which habitual CoL were worn, were fitted with and crossed-over to SL, period 2. Group 2 (sequence BA), were first fitted with SL in period 1 and after a washout period of 4 weeks, crossed-over to new CoL, period 2. The median lengths in weeks of Periods 1 and 2 were: 17.5 (IQR 12.4) and 14.5 (IQR 6.2) respectively. The outcome measures for visual performance were best corrected visual acuity and the contrast sensitivity function. Vision related quality of life (Qol) was assessed using the National Eye Institute Visual Function Questioannaire-25 and reported subjective perception of vision (SPV) and reported subjective perception of comfort (SPC) scores, recorded on a scale from 1-10. The final outcome measure was the selection of the preferred lens type at the completion of the RCT. RESULTS: For the 30 who completed the trial, significantly higher SPC scores were found for SL compared to CoL (p = 0.002). Significantly higher SPC scores for CoL were found in participants who selected CoL as their preferred lens for future use, compared to those who selected SL (p = 0.009). All other outcomes exhibited no significant difference between the experimental lenses. There was no significant difference (p=0.86) in the proportion preferring CoL (53%) and SL (47%). CONCLUSION: Significantly better comfort was reported for SL compared with CoL. Significantly higher comfort in CoL was found in those who preferred CoL, than those who preferred SL. Successful CoL wearers whose SPC in CoL is <7 are likely to achieve better comfort with SL. On average, successful CoL wearers found SL more comfortable and there are unlikely to be any significant visual or visual Qol advantage or disadvantage in refitting successful CoL wearers with keratoconus and other corneal ectasia disorders, with SL and vice versa.

Hypertension and Pathogenic hAPP Independently Induce White Matter Astrocytosis and Cognitive Impairment in the Rat.

Hypertension is recognized as a risk factor for Alzheimer disease, but the causal link remains undetermined. Although astrocytes and microglia play an important role in maintaining the neurovascular unit, astrocytes and microglia have been understudied in comorbid models of hypertension and Alzheimer disease. In this study, male transgenic Fischer 344 rats (TgAPP21) overexpressing a pathogenic human amyloid precursor protein received 8 weeks of Angiotensin II infusion to increase blood pressure, and the rats were evaluated for astrocytosis, microgliosis, and cognitive function. A linear relationship between astrocytosis and blood pressure was observed in the corpus callosum and cingulum of wildtype rats, with hypertensive wildtype rats matching the elevated baseline astrocytosis seen in normotensive transgenic rats. In contrast, hypertensive transgenic rats did not demonstrate a further increase of astrocytosis, suggesting a deficient response. Angiotensin II infusion did not affect activation of microglia, which were elevated in the white matter and hippocampus of transgenic rats. Angiotensin II infusion did impair both wildtype and transgenic rats' executive functions in the Morris Water Maze. These results present important implications for the interaction between hypertension and pathogenic human amyloid precursor protein expression, as Angiotensin II infusion produced cognitive impairments in both genotypes, but transgenic rats were additionally impaired in developing a normal astrocytic response to elevated blood pressure.

TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat.

BACKGROUND: Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer's disease and acute subcortical stroke. METHODS: Fischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [18F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6. RESULTS: [18F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P = 0.033, infarct/cerebellum uptake ratio: baseline = 0.94 ± 0.16; day 7 = 2.10 ± 0.78; day 28 = 1.77 ± 0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm2: day 7 = 555 ± 181; day 28 = 307 ± 153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm2: day 7 = 113 ± 93; day 28 = 5 ± 7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline = 0.62 ± 0.38; stroke = 4.30 ± 2.83; P = .029). CONCLUSION: TSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.

Behavioural inflexibility in a comorbid rat model of striatal ischemic injury and mutant hAPP overexpression.

Alzheimer disease (AD) and stroke coexist and interact; yet how they interact is not sufficiently understood. Both AD and basal ganglia stroke can impair behavioural flexibility, which can be reliably modeled in rats using an established operant based set-shifting test. Transgenic Fischer 344-APP21 rats (TgF344) overexpress pathogenic human amyloid precursor protein (hAPP) but do not spontaneously develop overt pathology, hence TgF344 rats can be used to model the effect of vascular injury in the prodromal stages of Alzheimer disease. We demonstrate that the injection of endothelin-1 (ET1) into the dorsal striatum of TgF344 rats (Tg-ET1) produced an exacerbation of behavioural inflexibility with a behavioural phenotype that was distinct from saline-injected wildtype & TgF344 rats as well as ET1-injected wildtype rats (Wt-ET1). In addition to profiling the types of errors made, interpolative modeling using logistic exposure-response regression provided an informative analysis of the timing and efficiency of behavioural flexibility. During set-shifting, Tg-ET1 committed fewer perseverative errors than Wt-ET1. However, Tg-ET1 committed significantly more regressive errors and had a less efficient strategy change than all other groups. Thus, behavioural flexibility was more vulnerable to striatal ischemic injury in TgF344 rats.