Canadian cannabis education resources to support youth health literacy: A scoping review and environmental scan.

Background: The 2018 legalisation of cannabis in Canada sparked concern and conversation about the potential negative impacts of youth cannabis use. It is clear that young people are already engaging in cannabis use for a variety of reasons; therefore, youth cannabis education is desirable to promote harm reduction and reduce the risk of adverse physical and mental health outcomes. Objective: To identify and categorise Canadian cannabis education resources using a social-ecological approach informed by the youth health literacy framework, considering multiple factors at the micro-, meso- and macro-levels that influence health literacy and impact behaviour. Methods: In line with scoping review methodology, database searches and an environmental scan of materials were completed. Specific inclusion criteria were identified to encompass all Canadian cannabis education resources directed towards young people aged 9-18 years and adults in contact with youth. Results: A total of 60 resources were identified and categorised using the youth health literacy framework in terms of their focus on (1) micro influences (resources for youth); (2) meso influences (resources for teachers, parents, mentors); and (3) macro influences (resources for indigenous communities and medical professionals). Conclusions: While many resources were identified, issues exist with the accessibility, quality and multicultural considerations of such resources, warranting the development of comprehensive, evidence-based and harm reduction-focused cannabis education for youth.

Predictors of atrial fibrillation on implantable cardiac monitoring for cryptogenic stroke.

BACKGROUND: Since the CRYSTAL-AF trial, implantation and usage of implantable loop recorder (ICM) after cryptogenic stroke (CS) for detection of atrial fibrillation (AF) has increased. However, it is unclear which CS patients would most benefit from long term ICM monitoring. This study aims to determine the risk factors in patients that would confer maximum benefit from ICM placement following CS. METHODS: A Columbia University Institutional Review Board (IRB) approved retrospective analysis of medical records of 125 patients with CS followed by implantation of ICM was evaluated. Univariable and multivariable time-to-event analyses were performed on demographics, hours of activity and variability (HRV), stroke location, thrombosis etiology, and CHA2DS2 - VASc score. The primary outcome was presence of ICM-detected AF defined as AF lasting at least 2 min. RESULTS: One hundred twenty-five patients (mean 67.6 years ± 2.4 years, 60% male) were followed for at least 3 months. Twenty-two patients (18%) were found to have clinically verified detected AF; median of time to detection was 95 days. Upon univariable demographic analysis followed by multivariable Cox regression analysis, individuals with age 75 or older (HR: 3.987, p = 0.0046) or LVEF 40% and lower (HR: 3.056, p = 0.0213) had significantly higher risk of AF. Diabetics also had a lower AF detection in multivariable analysis (HR: 0.128, p = 0.0466). CONCLUSIONS: Age 75 or older and LVEF ≤40% were the factors on multivariable analysis that predicted AF detection. Diabetes is a possible significant factor which should be evaluated further. CHA2DS2 - VASc score was notably not predictive of AF detected on ICM.

Leveraging the potential of nature to meet net zero greenhouse gas emissions in Washington State.

The State of Washington, USA, has set a goal to reach net zero greenhouse gas emissions by 2050, the year around which the Intergovernmental Panel on Climate Change (IPCC) recommended we must limit global warming to 1.5 °C above that of pre-industrial times or face catastrophic changes. We employed existing approaches to calculate the potential for a suite of Natural Climate Solution (NCS) pathways to reduce Washington's net emissions under three implementation scenarios: Limited, Moderate, and Ambitious. We found that NCS could reduce emissions between 4.3 and 8.8 MMT CO2eyr-1 in thirty-one years, accounting for 4% to 9% of the State's net zero goal. These potential reductions largely rely on changing forest management practices on portions of private and public timber lands. We also mapped the distribution of each pathway's Ambitious potential emissions reductions by county, revealing spatial clustering of high potential reductions in three regions closely tied to major business sectors: private industrial forestry in southwestern coastal forests, cropland agriculture in the Columbia Basin, and urban and rural development in the Puget Trough. Overall, potential emissions reductions are provided largely by a single pathway, Extended Timber Harvest Rotations, which mostly clusters in southwestern counties. However, mapping distribution of each of the other pathways reveals wider distribution of each pathway's unique geographic relevance to support fair, just, and efficient deployment. Although the relative potential for a single pathway to contribute to statewide emissions reductions may be small, they could provide co-benefits to people, communities, economies, and nature for adaptation and resiliency across the state.

Impacts of stormwater on coastal ecosystems: the need to match the scales of management objectives and solutions.

Despite their limited area relative to the global ocean, coastal zones-the regions where land meets the sea-play a disproportionately important role in generating ecosystem services. However, coastal ecosystems are under increasing pressure from human populations. In particular, urban stormwater is an increasingly important threat to the integrity of coastal systems. Urban catchments exhibit altered flow regimes that impact ecosystem processes and coastal foodwebs. In addition, urban stormwater contains complex and unpredictable mixtures of chemicals that result in a multitude of lethal and sublethal impacts on species in coastal systems. Along the western coast of the United States, we estimate that hundreds of billions of kilograms of suspended solids flow off land surfaces and enter the Northern California Current each year. However, 70% of this pollution could be addressed by treating only 1.35% of the land area. Determining how to prioritize treatment of stormwater in this region requires a clear articulation of objectives-spatial distribution of appropriate management actions is dependent on the life histories of species, and management schemes optimized for one species may not achieve desired objectives for other species. In particular, we highlight that the scale of stormwater interventions must match the ecological scale relevant to species targeted by management. In many cases, management and policy will require mechanisms in order to ensure that local actions scale-up to efficiently and effectively achieve management objectives. In the face of rapid urbanization of coastal zones, failure to consider the match of management and ecological scales will result in the continued decline of coastal ecosystems and the species they support. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.

Proton pump inhibitors and 180-day mortality in the elderly after Clostridium difficile treatment.

BACKGROUND: There is a reported association between proton pump inhibitor (PPI) exposure and increased risk of Clostridium difficile infection (CDI), but less is known about how this class of medications taken during treatment might influence mortality after CDI. Here we examine 180-day mortality rates in a cohort of CDI elders and its association with exposure to PPIs. We conducted a retrospective cohort study of elderly patients (> 65 years of age) diagnosed and treated for CDI in the years 2014-2016 (n = 874) in the Umass Memorial Health Care system, which represents both academic and community healthcare. Patient characteristics and medication use was extracted from the electronic medical record (EMR) and 6 month mortality data was obtained via the Center for Disease Control National Death Index. A Cox proportional hazards model was used to estimate hazard ratios associated with medication exposures and other relevant variables. RESULTS: Of the 874 elderly adults treated for CDI, 180-day all-cause mortality was 12.4%. Exposure to a PPI was associated with a 55% reduced risk of mortality (adjusted hazard ratio (aHR) 0.45; 95% confidence interval (CI) 0.28-0.72). In our Cox model, increasing age (aHR 1.45; 95% CI 1.14-1.84), those with severe CDI infections (aHR 1.87; 95% CI 1.22-2.88), and those with hospital acquired CDI (aHR 3.01; 95% CI 1.81-4.99) also had increased 180 day mortality risk. There were similar associations noted with both 90 day and 1-year mortality. CONCLUSION: Use of PPIs during CDI treatment in elderly patients is associated with decreased 180-day mortality. Although use of PPIs has been associated with an increased risk of CDI, it appears to be protective against mortality when used during the treatment phase.

Medication Exposure and Risk of Recurrent Clostridium difficile Infection in Community-Dwelling Older People and Nursing Home Residents.

BACKGROUND/OBJECTIVES: It is unclear how medication exposures differ in their association with recurrent Clostridium difficile infection (rCDI) in elderly nursing home (NH) residents and community-dwelling individuals. This study examined these exposures to determine whether the risk of rCDI differs according to living environment. DESIGN: Retrospective. SETTING: Academic and community healthcare settings. PARTICIPANTS: Individuals aged 65 and older with CDI (N = 616). MEASUREMENTS: Information on participant characteristics and medications was extracted from the electronic medical record (EMR). We used separate extended Cox models according to living environment to identify the association between medication use and risk of rCDI. RESULTS: Of the 616 elderly adults treated for CDI, 24.1% of those living in the community and 28.1% of NH residents experienced recurrence within 1 year. For community-dwelling participants, the risk of rCDI was 1.6 times as high with antibiotic exposure and 2.5 times as high with acid-reducing medication exposure, but corticosteroid exposure was associated with a 39% lower risk of recurrence. For NH residents, the risk of rCDI was 2.9 times as high with acid-reducing medication exposure and 5.9 times as high with corticosteroid medication exposure. Antibiotic exposure was associated with an increased risk of recurrence only in community-dwelling participants (adjusted hazard ratio = 1.63, 95% confidence interval = 1.00-2.67). CONCLUSION: Risk of rCDI is greater with acid-reducing medication use than antibiotic use after initial CDI treatment, although the risk varied depending on living environment. Corticosteroid use is associated with greater risk of recurrence in NH residents but lower risk in community-dwelling elderly adults.

Detrital shadows: estuarine food web connectivity depends on fluvial influence and consumer feeding mode.

We measured the influence of landscape setting on estuarine food web connectivity in five macrotidal Pacific Northwest estuaries across a gradient of freshwater influence. We used stable isotopes (δ13 C, δ15 N, δ34 S) in combination with a Bayesian mixing model to trace primary producer contributions to suspension- and deposit-feeding bivalve consumers (Mytilus trossulus and Macoma nasuta) transplanted into three estuarine vegetation zones: emergent marsh, mudflat, and eelgrass. Eelgrass includes both Japanese eelgrass (Zostera japonica) and native eelgrass (Zostera marina). Fluvial discharge and consumer feeding mode strongly influenced the strength and spatial scale of observed food web linkages, while season played a secondary role. Mussels displayed strong cross-ecosystem connectivity in all estuaries, with decreasing marine influence in the more fluvial estuaries. Mussel diets indicated homogenization of detrital sources within the water column of each estuary. In contrast, the diets of benthic deposit-feeding clams indicated stronger compartmentalization in food web connectivity, especially in the largest river delta where clam diets were trophically disconnected from marsh sources of detritus. This suggests detritus deposition is patchy across space, and less homogenous than the suspended detritus pool. In addition to fluvial setting, other estuary-specific environmental drivers, such as marsh area or particle transport speed, influenced the degree of food web linkages across space and time, often accounting for unexpected patterns in food web connectivity. Transformations of the estuarine landscape that alter river hydrology or availability of detritus sources can thus potentially disrupt natural food web connectivity at the landscape scale, especially for sedentary organisms, which cannot track their food sources through space.

EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis.

PURPOSE: PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients. EXPERIMENTAL DESIGN: We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) were assessed using RECIST v1.1. PD-L1 expression and CD8(+) tumor-infiltrating lymphocytes (TIL) were evaluated by IHC. RESULTS: Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced EGFR-mutant (N = 68) and ALK-positive (N = 27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre-tyrosine kinase inhibitor (TKI) biopsies using cutoffs of ≥1%, ≥5%, and ≥50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI-resistant biopsies (N = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8(+) TILs (grade ≥2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK-positive, pre- or post-TKI specimens. CONCLUSIONS: NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8(+) TILs within the tumor microenvironment may underlie these clinical observations. Clin Cancer Res; 22(18); 4585-93. ©2016 AACRSee related commentary by Gettinger and Politi, p. 4539.

Kinetic Investigations of the Role of Factor Inhibiting Hypoxia-inducible Factor (FIH) as an Oxygen Sensor.

The hypoxia-inducible factor (HIF) hydroxylases regulate hypoxia sensing in animals. In humans, they comprise three prolyl hydroxylases (PHD1-3 or EGLN1-3) and factor inhibiting HIF (FIH). FIH is an asparaginyl hydroxylase catalyzing post-translational modification of HIF-α, resulting in reduction of HIF-mediated transcription. Like the PHDs, FIH is proposed to have a hypoxia-sensing role in cells, enabling responses to changes in cellular O2 availability. PHD2, the most important human PHD isoform, is proposed to be biochemically/kinetically suited as a hypoxia sensor due to its relatively high sensitivity to changes in O2 concentration and slow reaction with O2. To ascertain whether these parameters are conserved among the HIF hydroxylases, we compared the reactions of FIH and PHD2 with O2. Consistent with previous reports, we found lower Km(app)(O2) values for FIH than for PHD2 with all HIF-derived substrates. Under pre-steady-state conditions, the O2-initiated FIH reaction is significantly faster than that of PHD2. We then investigated the kinetics with respect to O2 of the FIH reaction with ankyrin repeat domain (ARD) substrates. FIH has lower Km(app)(O2) values for the tested ARDs than HIF-α substrates, and pre-steady-state O2-initiated reactions were faster with ARDs than with HIF-α substrates. The results correlate with cellular studies showing that FIH is active at lower O2 concentrations than the PHDs and suggest that competition between HIF-α and ARDs for FIH is likely to be biologically relevant, particularly in hypoxic conditions. The overall results are consistent with the proposal that the kinetic properties of individual oxygenases reflect their biological capacity to act as hypoxia sensors.

RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.

Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

Patient-derived models of acquired resistance can identify effective drug combinations for cancer.

Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.