Clonal Lineage Tracing with Somatic Delivery of Recordable Barcodes Reveals Migration Histories of Metastatic Prostate Cancer.

The patterns by which primary tumors spread to metastatic sites remain poorly understood. Here, we define patterns of metastatic seeding in prostate cancer (PCa) using a novel injection-based mouse model - EvoCaP (Evolution in Cancer of the Prostate), featuring aggressive metastatic cancer to bone, liver, lungs, and lymph nodes. To define migration histories between primary and metastatic sites, we used our EvoTraceR pipeline to track distinct tumor clones containing recordable barcodes. We detected widespread intratumoral heterogeneity from the primary tumor in metastatic seeding, with few clonal populations (CPs) instigating most migration. Metastasis-to-metastasis seeding was uncommon, as most cells remained confined within the tissue. Migration patterns in our model were congruent with human PCa seeding topologies. Our findings support the view of metastatic PCa as a systemic disease driven by waves of aggressive clones expanding their niche, infrequently overcoming constraints that otherwise keep them confined in the primary or metastatic site.

POSITIVE: Perfusion imaging selection of ischemic stroke patients for endovascular therapy.

BACKGROUND: The PerfusiOn imaging Selection of Ischemic sTroke patIents for endoVascular thErapy (POSITIVE) trial was designed to evaluate functional outcome in patients with emergent large vessel occlusion (ELVO) presenting within 0-12 hours with pre-specified bifurcated arms of early and late window presentation, who were selected for endovascular thrombectomy with non-vendor specific commercially available perfusion imaging software. Recent trials demonstrating the benefit of thrombectomy up to 16-24 hours following ELVO removed equipoise to randomize late window ELVO patients and therefore the trial was halted. METHODS: Up to 200 patients were to be enrolled in this FDA-cleared, prospective, randomized, multicenter international trial to compare thrombectomy and best medical management in patients with ELVO ineligible for or refractory to treatment with IV tissue plasminogen activator (IV-tPA) selected with perfusion imaging and presenting within 0-12 hours of last seen normal. The primary outcome was 90-day clinical outcome as measured by the raw modified Rankin Scale (mRS) with scores 5 and 6 collapsed (mRS shift analysis). RESULTS: The POSITIVE trial suspended enrollment with the release of results from the DAWN trial and was stopped after the release of the DEFUSE 3 trial results. Thirty-three patients were enrolled (21 for medical management and 12 for thrombectomy). Twelve of the 33 patients were enrolled in the 6-12 hour cohort. Despite the early cessation, the primary outcome demonstrated statistically significant superior clinical outcomes for patients treated with thrombectomy (P=0.0060). The overall proportion of patients achieving an mRS score of 0-2 was 75% in the thrombectomy cohort and 43% in the medical management cohort (OR 4.00, 95% CI 0.84 to 19.2). CONCLUSION: POSITIVE supports the already established practice of delayed thrombectomy for appropriately selected patients presenting within 0-12 hours selected by perfusion imaging from any vendor. The results of the POSITIVE trial are consistent with other thrombectomy trials. The statistically significant effect on functional improvement, despite the small number of patients, reinforces the robust benefits of thrombectomy. CLINICAL TRIAL REGISTRATION: NCT01852201.

Opioid use disorder treatment disruptions during the early COVID-19 pandemic and other emergent disasters: a scoping review addressing dual public health emergencies.

BACKGROUND: During public health emergencies, people with opioid use disorder (PWOUD) may be particularly impacted. Emergent disasters such as the COVID-19 pandemic disrupt already-strained harm reduction efforts and treatment availability. This study aims to answer three research questions. How do public health emergencies impact PWOUD? How can health systems respond to novel public health emergencies to serve PWOUD? How can the results of this scoping review be contextualized to the province of Alberta to inform local stakeholder responses to the pandemic? METHODS: We conducted a scoping review using the 6-stage Arksey and O'Malley framework to analyse early-pandemic and pre-pandemic disaster literature. The results of the scoping review were contextualized to the local pandemic response, through a Nominal Group Technique (NGT) process with frontline providers and stakeholders in Alberta, Canada. RESULTS: Sixty one scientific journal articles and 72 grey literature resources were included after full-text screening. Forty sources pertained to early COVID-19 responses, and 21 focused on OUD treatment during other disasters. PWOUD may be more impacted than the general population by common COVID-19 stressors including loss of income, isolation, lack of rewarding activities, housing instability, as well as fear and anxiety. They may also face unique challenges including threats to drug supplies, stigma, difficulty accessing clean substance use supplies, and closure of substance use treatment centres. All of these impacts put PWOUD at risk of negative outcomes including fatal overdose. Two NGT groups were held. One group (n = 7) represented voices from urban services, and the other (n = 4) Indigenous contexts. Stakeholders suggested that simultaneous attention to multiple crises, with adequate resources to allow attention to both social and health systems issues, can prepare a system to serve PWOUD during disasters. CONCLUSION: This scoping review and NGT study uncovers how disasters impact PWOUD and offers suggestions for better serving PWOUD.

Mobile Interventional Stroke Team Model Improves Early Outcomes in Large Vessel Occlusion Stroke: The NYC MIST Trial.

BACKGROUND AND PURPOSE: Triage of patients with emergent large vessel occlusion stroke to primary stroke centers followed by transfer to comprehensive stroke centers leads to increased time to endovascular therapy. A Mobile Interventional Stroke Team (MIST) provides an alternative model by transferring a MIST to a Thrombectomy Capable Stroke Center (TSC) to perform endovascular therapy. Our aim is to determine whether the MIST model is more time-efficient and leads to improved clinical outcomes compared with standard drip-and-ship (DS) and mothership models. METHODS: This is a prospective observational cohort study with 3-month follow-up between June 2016 and December 2018 at a multicenter health system, consisting of one comprehensive stroke center, 4 TSCs, and several primary stroke centers. A total of 228 of 373 patients received endovascular therapy via 1 of 4 models: mothership with patient presentation to a comprehensive stroke center, DS with patient transfer from primary stroke center or TSC to comprehensive stroke center, MIST with patient presentation to TSC and MIST transfer, or a combination of DS with patient transfer from primary stroke center to TSC and MIST. The prespecified primary end point was initial door-to-recanalization time and secondary end points measured additional time intervals and clinical outcomes at discharge and 3 months. RESULTS: MIST had a faster mean initial door-to-recanalization time than DS by 83 minutes (P<0.01). MIST and mothership had similar median door-to-recanalization times of 192 minutes and 179 minutes, respectively (P=0.83). A greater proportion had a complete recovery (National Institutes of Health Stroke Scale of 0 or 1) at discharge in MIST compared with DS (37.9% versus 16.7%; P<0.01). MIST had 52.8% of patients with modified Rankin Scale of ≤2 at 3 months compared with 38.9% in DS (P=0.10). CONCLUSIONS: MIST led to significantly faster initial door-to-recanalization times compared with DS, which was comparable to mothership. This decrease in time has translated into improved short-term outcomes and a trend towards improved long-term outcomes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03048292.

Obesity Paradox in Intracerebral Hemorrhage.

Background and Purpose- Although obesity is an established risk factor for cardiovascular disease and stroke, studies have shown evidence of an obesity paradox-a protective effect of obesity in patients who already have these disease states. Data on the obesity paradox in intracerebral hemorrhage is limited. Methods- Clinical data for adult intracerebral hemorrhage patients were extracted from the National Inpatient Sample between 2007 and 2014. Multivariable logistic regression analyzed the association of body habitus with in-hospital mortality, discharge disposition, length of stay, tracheostomy or gastrostomy placement, and ventriculoperitoneal shunt placement. Results- There were 99 212 patients who were eligible. Patients with both obesity (OR=0.69; 95% CI=0.62-0.76; P<0.001) and morbid obesity (OR=0.85; 95% CI=0.74-0.97; P=0.02) were associated with decreased odds of in-hospital mortality. Morbid obesity was significantly associated with increased odds of a tracheostomy or gastrostomy placement (OR=1.42; 1.20-1.69; P<0.001) and decreased odds of a routine discharge disposition (OR=0.84; 0.74-0.97; P=0.014). Conclusions- Obesity and morbid obesity appear to protect against mortality in intracerebral hemorrhage.

Controlling chaos: the perceptions of long-term crack cocaine users in vancouver, british columbia, Canada.

People who smoke crack cocaine are described as chaotic and more likely to engage in risky sex, polysubstance use and contract infectious diseases. However, little is known about how individuals perceive smoking crack as compared to other forms of cocaine use, especially injection. We explored the lived experience of people who smoke crack cocaine. Six gender-specific focus groups (n = 31) of individuals who currently smoke crack in Vancouver, Canada, were conducted using a semi-structured interview guide. Focus groups were transcribed and analyzed by constant comparative methodology. We applied Rhodes' risk environment to the phenomenological understanding that individuals have regarding how crack has affected their lives. Subjects reported that smoking rather than injecting cocaine allows them to begin "controlling chaos" in their lives. Controlling chaos was self-defined using nontraditional measures such as the ability to maintain day-to-day commitments and housing stability. The phenomenological lens of smoking crack instead of injecting cocaine "to control chaos" contributes a novel perspective to our understanding of the crack-smoking population. This study examines narratives which add to prior reports of the association of crack smoking and increased chaos and suggests that, for some, inhaled crack may represent efforts towards self-directed harm reduction.

A media advocacy intervention linking health disparities and food insecurity.

Media advocacy is a well-established strategy for transmitting health messages to the public. This paper discusses a media advocacy intervention that raised issues about how the public interprets messages about the negative effects of poverty on population health. In conjunction with the publication of a manuscript illustrating how income-related food insecurity leads to disparities related to the consumption of a popular food product across Canada (namely, Kraft Dinner®), we launched a media intervention intended to appeal to radio, television, print and Internet journalists. All the media coverage conveyed our intended message that food insecurity is a serious population health problem, confirming that message framing, personal narratives and visual imagery are important in persuading media outlets to carry stories about poverty as a determinant of population health. Among politicians and members of the public (through on-line discussions), the coverage provoked on-message as well as off-message reactions. Population health researchers and health promotion practitioners should anticipate mixed reactions to media advocacy interventions, particularly in light of new Internet technologies. Opposition to media stories regarding the socio-economic determinants of population health can provide new insights into how we might overcome challenges in translating evidence into preventive interventions.