Longitudinal study of paralytic shellfish toxins along Canada's coast.

Paralytic shellfish toxins (PST) in shellfish products have led to severe risks to human health. To monitor the risk, the Canadian Shellfish Sanitation Program has been collecting longitudinal PST measurements in blue mussel (Mytilus edulis) and soft-shell clam (Mya arenaria) samples in six coastal provinces of Canada. The spatial distributions of major temporal variation patterns were studied via Functional Principal Component Analysis. Seasonal increases in PST contamination were found to vary the most in terms of magnitude along the coastlines, which provides support for location-specific management of the time-sensitive PST contamination. In British Columbia, the first functional principal component (FPC1) indicated the variance among the magnitudes, while FPC2 indicated the seasonality of the PST levels. The temporal variations tended to be positively correlated with the abundance of dianoflagellates Alexandrium spp., and negatively with precipitation and inorganic nutrients. These findings indicate the underlying mechanism of PST variation in various geographical settings. In New Brunswick, Prince Edward, and Nova Scotia, the top FPCs indicated that the PST contamination differed mostly in the seasonal increase of the PST level during summer.

Simultaneous prediction of multiple outcomes using revised stacking algorithms.

MOTIVATION: HIV is difficult to treat because its virus mutates at a high rate and mutated viruses easily develop resistance to existing drugs. If the relationships between mutations and drug resistances can be determined from historical data, patients can be provided personalized treatment according to their own mutation information. The HIV Drug Resistance Database was built to investigate the relationships. Our goal is to build a model using data in this database, which simultaneously predicts the resistance of multiple drugs using mutation information from sequences of viruses for any new patient. RESULTS: We propose two variations of a stacking algorithm which borrow information among multiple prediction tasks to improve multivariate prediction performance. The most attractive feature of our proposed methods is the flexibility with which complex multivariate prediction models can be constructed using any univariate prediction models. Using cross-validation studies, we show that our proposed methods outperform other popular multivariate prediction methods. AVAILABILITY AND IMPLEMENTATION: An R package is being developed. In the meantime, R code can be requested by email. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Comparisons of simulation results between passive and active fluid structure interaction models for left ventricle in hypertrophic obstructive cardiomyopathy.

BACKGROUND: Patient-specific active fluid-structure interactions (FSI) model is a useful approach to non-invasively investigate the hemodynamics in the heart. However, it takes a lot of effort to obtain the proper external force boundary conditions for active models, which heavily restrained the time-sensitive clinical applications of active computational models. METHODS: The simulation results of 12 passive FSI models based on 6 patients' pre-operative and post-operative CT images were compared with corresponding active models to investigate the differences in hemodynamics and cardiac mechanics between these models. RESULTS: In comparing the passive and active models, it was found that there was no significant difference in pressure difference and shear stress on mitral valve leaflet (MVL) at the pre-SAM time point, but a significant difference was found in wall stress on the inner boundary of left ventricle (endocardium). It was also found that pressure difference on the coapted MVL and the shear stress on MVL were significantly decreased after successful surgery in both active and passive models. CONCLUSION: Our results suggested that the passive models may provide good approximated hemodynamic results at 5% RR interval, which is crucial for analyzing the initiation of systolic anterior motion (SAM). Comparing to active models, the passive models decrease the complexity of the modeling construction and the difficulty of convergence significantly. These findings suggest that, with proper boundary conditions and sufficient clinical data, the passive computational model may be a good substitution model for the active model to perform hemodynamic analysis of the initiation of SAM.

White Matter Hyperintensity Volume Influences Symptoms in Patients Presenting With Minor Neurological Deficits.

Background and Purpose- Acute minor neurological deficits are a common complaint in the emergency department and differentiation of transient ischemic attack/minor stroke from a stroke mimic is difficult. We sought to assess the ability of white matter hyperintensity (WMH) volume to aid the diagnosis in such patients. Methods- This is a post hoc analysis of the previously published SpecTRA study (Spectrometry in TIA Rapid Assessment) of adult patients that presented to the emergency department with acute minor neurological deficits between December 2013 and March 2017. WMH volumes were measured if fluid-attenuated inversion recovery imaging was available. Outcomes of interest were final diagnosis, symptoms at presentation, and 90-day stroke recurrence. Results- WMH volume was available for 1485 patients. Median age was 70 years (interquartile range, 59-80), and 46.7% were female. Mean WMH volume was higher in transient ischemic attack/minor strokes compared with stroke mimics (1.71 ln mL [95% CI, 1.63-1.79 ln mL] versus 1.15 ln mL [95% CI, 1.02-1.27 ln mL], P<0.001). In multivariable-adjusted logistic regression analysis, WMH volume was not associated with final diagnosis. However, the combination of both diffusion-weighted imaging positivity and high WMH volume led to lower odds of focal symptoms at presentation (P=0.035). Conclusions- The combination of diffusion-weighted imaging positivity and high WMH volume was associated with lower odds of focal symptoms at presentation in patients seen with minor neurological deficits in the emergency department. This suggests that WMH volume might be an important consideration and the absence of focal symptoms at presentation should not discourage clinicians from further investigating patients with suspected cerebral ischemia.

Systolic blood pressure as a predictor of transient ischemic attack/minor stroke in emergency department patients under age 80: a prospective cohort study.

BACKGROUND: Elevated blood pressure (BP) at emergency department (ED) presentation and advancing age have been associated with risk of ischemic stroke; however, the relationship between BP, age, and transient ischemic attack/minor stroke (TIA/MS) is not clear. METHODS: A multi-site, prospective, observational study of 1084 ED patients screened for suspected TIA/MS (symptom onset < 24 h, NIHSS< 4) between December 2013 and April 2016. Systolic and diastolic BP measurements (SBP, DBP) were taken at ED presentation. Final diagnosis was consensus adjudication by stroke neurologists; patients were diagnosed as either TIA/MS or stroke-mimic (non-cerebrovascular conditions). Conditional inference trees were used to define age cut-points for predicting binary diagnosis (TIA/MS or stroke-mimic). Logistic regression models were used to estimate the effect of BP, age, sex, and the age-BP interaction on predicting TIA/MS diagnosis. RESULTS: Over a 28-month period, 768 (71%) patients were diagnosed with TIA/MS: these patients were older (mean 71.6 years) and more likely to be male (58%) than stroke-mimics (61.4 years, 41%; each p < 0.001). TIA/MS patients had higher SBP than stroke-mimics (p < 0.001). DBP did not differ between the two groups (p = 0.191). SBP was predictive of TIA/MS diagnosis in younger patients, after accounting for age and sex; an increase of 10 mmHg systolic increased the odds of TIA/MS 18% (odds ratio [OR] 1.18, 95% CI 1.00-1.39) in patients < 60 years, and 23% (OR 1.23, 95% CI 11.12-1.35) in those 60-79 years, while not affecting the odds of TIA/MS in patients ≥80 years (OR 0.99, 95% CI 0.89-1.07). CONCLUSIONS: Raised SBP in patients younger than 80 with suspected TIA/MS may be a useful clinical indicator upon initial presentation to help increase clinicians' suspicion of TIA/MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03050099 (10-Feb-2017) and NCT03070067 (3-Mar-2017). Retrospectively registered.

A Bayesian group sparse multi-task regression model for imaging genetics.

MOTIVATION: Recent advances in technology for brain imaging and high-throughput genotyping have motivated studies examining the influence of genetic variation on brain structure. Wang et al. have developed an approach for the analysis of imaging genomic studies using penalized multi-task regression with regularization based on a novel group l2,1-norm penalty which encourages structured sparsity at both the gene level and SNP level. While incorporating a number of useful features, the proposed method only furnishes a point estimate of the regression coefficients; techniques for conducting statistical inference are not provided. A new Bayesian method is proposed here to overcome this limitation. RESULTS: We develop a Bayesian hierarchical modeling formulation where the posterior mode corresponds to the estimator proposed by Wang et al. and an approach that allows for full posterior inference including the construction of interval estimates for the regression parameters. We show that the proposed hierarchical model can be expressed as a three-level Gaussian scale mixture and this representation facilitates the use of a Gibbs sampling algorithm for posterior simulation. Simulation studies demonstrate that the interval estimates obtained using our approach achieve adequate coverage probabilities that outperform those obtained from the nonparametric bootstrap. Our proposed methodology is applied to the analysis of neuroimaging and genetic data collected as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), and this analysis of the ADNI cohort demonstrates clearly the value added of incorporating interval estimation beyond only point estimation when relating SNPs to brain imaging endophenotypes. AVAILABILITY AND IMPLEMENTATION: Software and sample data is available as an R package 'bgsmtr' that can be downloaded from The Comprehensive R Archive Network (CRAN). CONTACT: nathoo@uvic.ca. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Verification of a proteomic biomarker panel to diagnose minor stroke and transient ischaemic attack: phase 1 of SpecTRA, a large scale translational study.

OBJECTIVE: To derive a plasma biomarker protein panel from a list of 141 candidate proteins which can differentiate transient ischaemic attack (TIA)/minor stroke from non-cerebrovascular (mimic) conditions in emergency department (ED) settings. DESIGN: Prospective clinical study (#NCT03050099) with up to three timed blood draws no more than 36 h following symptom onset. Plasma samples analysed by multiple reaction monitoring-mass spectrometry (MRM-MS). PARTICIPANTS: Totally 545 participants suspected of TIA enrolled in the EDs of two urban medical centres. OUTCOMES: 90-day, neurologist-adjudicated diagnosis of TIA informed by clinical and radiological investigations. RESULTS: The final protein panel consists of 16 proteins whose patterns show differential abundance between TIA and mimic patients. Nine of the proteins were significant univariate predictors of TIA [odds ratio (95% confidence interval)]: L-selectin [0.726 (0.596-0.883)]; Insulin-like growth factor-binding protein 3 [0.727 (0.594-0.889)]; Coagulation factor X [0.740 (0.603-0.908)]; Serum paraoxonase/lactonase 3 [0.763 (0.630-0.924)]; Thrombospondin-1 [1.313 (1.081-1.595)]; Hyaluronan-binding protein 2 [0.776 (0.637-0.945)]; Heparin cofactor 2 [0.775 (0.634-0.947)]; Apolipoprotein B-100 [1.249 (1.037-1.503)]; and von Willebrand factor [1.256 (1.034-1.527)]. The scientific plausibility of the panel proteins is discussed. CONCLUSIONS: Our panel has the potential to assist ED physicians in distinguishing TIA from mimic patients.

Validation of a proteomic biomarker panel to diagnose minor-stroke and transient ischaemic attack: phase 2 of SpecTRA, a large scale translational study.

OBJECTIVE: To validate our previously developed 16 plasma-protein biomarker panel to differentiate between transient ischaemic attack (TIA) and non-cerebrovascular emergency department (ED) patients. METHOD: Two consecutive cohorts of ED patients prospectively enrolled at two urban medical centers into the second phase of SpecTRA study (training, cohort 2A, n = 575; test, cohort 2B, n = 528). Plasma samples were analyzed using liquid chromatography/multiple reaction monitoring-mass spectrometry. Logistic regression models which fit cohort 2A were validated on cohort 2B. RESULTS: Three of the panel proteins failed quality control and were removed from the panel. During validation, panel models did not outperform a simple motor/speech (M/S) deficit variable. Post-hoc analyses suggested the measured behaviour of L-selectin and coagulation factor V contributed to poor model performance. Removal of these proteins increased the external performance of a model containing the panel and the M/S variable. CONCLUSIONS: Univariate analyses suggest insulin-like growth factor-binding protein 3 and serum paraoxonase/lactonase 3 are reliable and reproducible biomarkers for TIA status. Logistic regression models indicated L-selectin, apolipoprotein B-100, coagulation factor IX, and thrombospondin-1 to be significant multivariate predictors of TIA. We discuss multivariate feature subset analyses as an exploratory technique to better understand a panel's full predictive potential.

Reducing time-to-unit among patients referred to an outpatient stroke assessment unit with a novel triage process: a prospective cohort study.

BACKGROUND: To evaluate the performance of a novel triage system for Transient Ischemic Attack (TIA) units built upon an existent clinical prediction rule (CPR) to reduce time to unit arrival, relative to the time of symptom onset, for true TIA and minor stroke patients. Differentiating between true and false TIA/minor stroke cases (mimics) is necessary for effective triage as medical intervention for true TIA/minor stroke is time-sensitive and TIA unit spots are a finite resource. METHODS: Prospective cohort study design utilizing patient referral data and TIA unit arrival times from a regional fast-track TIA unit on Vancouver Island, Canada, accepting referrals from emergency departments (ED) and general practice (GP). Historical referral cohort (N = 2942) from May 2013-Oct 2014 was triaged using the ABCD2 score; prospective referral cohort (N = 2929) from Nov 2014-Apr 2016 was triaged using the novel system. A retrospective survival curve analysis, censored at 28 days to unit arrival, was used to compare days to unit arrival from event date between cohort patients matched by low (0-3), moderate (4-5) and high (6-7) ABCD2 scores. RESULTS: Survival curve analysis indicated that using the novel triage system, prospectively referred TIA/minor stroke patients with low and moderate ABCD2 scores arrived at the unit 2 and 1 day earlier than matched historical patients, respectively. CONCLUSIONS: The novel triage process is associated with a reduction in time to unit arrival from symptom onset for referred true TIA/minor stroke patients with low and moderate ABCD2 scores.

A joint model for interval-censored functional decline trajectories under informative observation.

Multi-state models are useful for modelling disease progression where the state space of the process is used to represent the discrete disease status of subjects. Often, the disease process is only observed at clinical visits, and the schedule of these visits can depend on the disease status of patients. In such situations, the frequency and timing of observations may depend on transition times that are themselves unobserved in an interval-censored setting. There is a potential for bias if we model a disease process with informative observation times as a non-informative observation scheme with pre-specified examination times. In this paper, we develop a joint model for the disease and observation processes to ensure valid inference because the follow-up process may itself contain information about the disease process. The transitions for each subject are modelled using a Markov process, where bivariate subject-specific random effects are used to link the disease and observation models. Inference is based on a Bayesian framework, and we apply our joint model to the analysis of a large study examining functional decline trajectories of palliative care patients.

"Out-gel" tryptic digestion procedure for chemical cross-linking studies with mass spectrometric detection.

SDS-PAGE is one of the most powerful protein separation techniques, and in-gel digestion is the leading method for converting proteins separated by SDS-PAGE into peptides suitable for mass spectrometry-based proteomic studies. In in-gel digestion, proteins are digested within the gel matrix, and the resulting peptides are extracted into an appropriate buffer. Transfer of the digested peptides to the liquid phase for subsequent mass spectrometric analysis, however, may be hampered by peptide-specific characteristics, including size, shape, poor solubility, adsorption to the polyacrylamide, and-in the case of cross-linking applications-by the branched structure of the peptides produced. This can be a limitation in cross-linking studies where efficient recoveries of the cross-linked peptides are critical. To overcome this limitation, we have developed a modification to the standard in-gel digestion procedure for SDS-PAGE-separated cross-linked proteins, based on older passive diffusion methods. By omitting the gel staining and gel fixation steps, intact proteins or cross-linked protein complexes can move through the gel and into the buffer solution. Digestion of the entire protein in the buffer outside the gel increases the probability that most of the proteolytic peptides produced will be present in the final digest solution. The resulting peptide mixture is then freed of SDS and concentrated using SCX (strong cation exchange) zip-tips and analyzed by mass spectrometry. For standard protein identification studies and the recovery of noncross-linked peptides, the in-gel procedure outperformed the out-gel procedure, but for cross-linking studies with enrichable cross-linkers (such as CBDPS), the standard out-gel procedure allowed the recoveries of cross-links not recovered via the in-gel method. Labeling experiments showed that, with an enrichable cross-linker, 93% of the cross-links showed better or equal recoveries with the out-gel procedure, as compared to the in-gel procedure. It should be noted that this method is not designed to replace in-gel digestion for most proteomics applications. However, by using the out-gel method, we were able to detect twice as many interprotein CBDPS cross-links from the histone H2A/H2B complex as were found in the in-gel digested sample.

Metabolomic insights into system-wide coordination of vertebrate metamorphosis.

BACKGROUND: After completion of embryogenesis, many organisms experience an additional obligatory developmental transition to attain a substantially different juvenile or adult form. During anuran metamorphosis, the aquatic tadpole undergoes drastic morphological changes and remodelling of tissues and organs to become a froglet. Thyroid hormones are required to initiate the process, but the mechanism whereby the many requisite changes are coordinated between organs and tissues is poorly understood. Metabolites are often highly conserved biomolecules between species and are the closest reflection of phenotype. Due to the extensive distribution of blood throughout the organism, examination of the metabolites contained therein provides a system-wide overview of the coordinated changes experienced during metamorphosis. We performed an untargeted metabolomic analysis on serum samples from naturally-metamorphosing Rana catesbeiana from tadpoles to froglets using ultraperformance liquid chromatography coupled to a mass spectrometer. Total and aqueous metabolite extracts were obtained from each serum sample to select for nonpolar and polar metabolites, respectively, and selected metabolites were validated by running authentic compounds. RESULTS: The majority of the detected metabolites (74%) showed statistically significant abundance changes (padj < 0.001) between metamorphic stages. We observed extensive remodelling of five core metabolic pathways: arginine and purine/pyrimidine, cysteine/methionine, sphingolipid, and eicosanoid metabolism and the urea cycle, and found evidence for a major role for lipids during this postembryonic process. Metabolites traditionally linked to human disease states were found to have biological linkages to the system-wide changes occuring during the events leading up to overt morphological change. CONCLUSIONS: To our knowledge, this is the first wide-scale metabolomic study of vertebrate metamorphosis identifying fundamental pathways involved in the coordination of this important developmental process and paves the way for metabolomic studies on other metamorphic systems including fish and insects.

Temporal and spatial variation of domoic acid along Canada's coast.

Shellfish poisonings have posed severe risks to human health globally. The Canadian Shellfish Sanitation Program was established in 1948 to monitor the toxin levels at shellfish harvesting sites along the coast of six provinces in Canada. Domoic acid has been a causal toxin for amnesic shellfish poisoning, and a macro-scale analysis of the temporal and spatial variation of domoic acid along Canada's coast was conducted in this study. We aggregated the toxin levels by week in blue mussel (Mytilus edulis) and soft-shell clam (Mya arenaria) samples, respectively, over a one-year scale. The subsequent application of Functional Principal Component Analysis unveiled that magnitudes of seasonal variation and peaked DA levels around early summer, spring, or mid-fall formed the largest variation in the toxin levels in blue mussels along the coastlines of British Columbia and Prince Edward Island and in soft-shell calms along those of New Brunswick and Nova Scotia. In Quebec, the DA levels were low and varied mostly in terms of the overall magnitude from spring to fall. Downstream correlation analyses in British Columbia further discovered that, at most sites, the strongest correlations were negative between precipitation as well as inorganic nutrients (including nitrate, nitrite, phosphate, and silicate) on one side and DA a few weeks afterward on the other. These findings indicated associations between amnesic shellfish poisoning and environmental stresses.

Advanced cutaneous squamous cell carcinoma: Impact of age on the safety and efficacy of cemiplimab and the prognostic significance of blood biomarkers.

INTRODUCTION: Age-related differences in the safety profile of cemiplimab for patients with locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) have not been well described. We investigated the association of increasing age with immune related adverse events (irAE) from cemiplimab, efficacy outcomes, and the prognostic significance of pre-treatment blood biomarkers in contemporary practice. MATERIALS AND METHODS: Patients starting first-line cemiplimab for locally advanced or metastatic cSCC at British Columbia Cancer between April 2019 and January 2023 were identified. Landmark four-month logistic regression analysis compared the odds of developing irAE or sequelae amongst patients aged <75 years to those aged 75-84 or ≥ 85. Objective responses were determined using Response Evaluation Criteria in Solid Tumors version 1.1. Univariable Cox proportional hazard (PH) regression modelling of factors associated with overall survival (OS) was performed. RESULTS: Of 106 patients, the proportions aged <75, 75-84, and ≥ 85 years were 34%, 45%, and 21%, respectively. Overall, the proportion of patients with irAE ≥ grade 3, cemiplimab discontinuation, and hospitalization for immune toxicity was 27.4%, 31.1%, and 11.3%, respectively. There was no clear association between age and the odds of high grade irAE. However, increased odds of cemiplimab discontinuation was observed in patients aged 75-84 years (p = 0.05). Patients ≥85 years had increased hospitalizations due to irAE (OR = 5.00, 95% CI = 0.97-37.52) with two treatment-related deaths. Objective responses were similar across age cohorts (50.0%, 60.4%, and 54.5%) but progressive disease was higher in the age ≥ 85 group (22.2%, 18.8%, and 31.8%). On Cox PH regression analysis, age ≥ 85 years (vs. <75), Eastern Cooperative Oncology Group performance status 2-3 (vs. 0-1), and neutrophil to lymphocyte ratio (NLR) ≥7.80 (vs. <7.80) were associated with shorter survival. DISCUSSION: While the odds of high grade irAE were similar across age groups, significant age-related differences in treatment discontinuation and hospitalization due to immune toxicity were observed. Despite a higher incidence of primary progression and shorter OS in the oldest cohort, cemiplimab yielded robust objective responses regardless of age. Higher pre-treatment NLR was associated with shorter survival and the cut-point identified requires further study.

Toward a population-based approach to end-of-life care surveillance in Canada: initial efforts and lessons.

This paper describes a project undertaken by the Hospice Palliative End-of-Life Care Surveillance Team Network--one of four Cancer Surveillance and Epidemiology Networks established by the Canadian Partnership Against Cancer in 2009 to create information products that can be used to inform cancer control. The project was designed to improve the quality and use of existing electronic patient databases in its member organizations. The project's intent was to better understand terminally ill cancer patients in their final year of life, with noncancer as comparison. The network created an early design for a Web-based end-of-life care surveillance system prototype. Using a flagging process, anonymized data sets on cancer/ noncancer palliative patients and those who died in 2008-2009 were extracted and analyzed. The Australian palliative approach was adapted as the conceptual model based on the data sets available. Common data elements were defined then mapped to local data sets to create a common data set. Information products were created as online reports. Throughout the project, members were engaged in knowledge translation. Overall, the project was well received by network members. There are still major data-quality and linkage issues that require further work.

Conversion of Karnofsky Performance Status (KPS) and Eastern Cooperative Oncology Group Performance Status (ECOG) to Palliative Performance Scale (PPS), and the interchangeability of PPS and KPS in prognostic tools.

AIM: The aim of our study was to assess whether the Karnofsky Performance Status (KPS), the Eastern Cooperative Oncology Group (ECOG) Performance Status, and the Palliative Performance Scale (PPS) are interchangeable individually or within two prognostic tools: the Palliative Prognostic Score (PaP) and the Palliative Prognostic Index (PPI). METHODS: We performed a subset analysis of a prospective comparative study of functional and prognostic tools and clinician prediction of survival. We studied 955 patients with advanced life-limiting illnesses (cancer and noncancer) in the acute care and community settings. We used a descriptive statistical model and Spearman's rank correlation to assess these interchangeabilities. RESULTS: There is a direct positive linear relationship between the KPS and the PPS, and a direct negative linear relationship between these tools and the ECOG. Exchange of the KPS and the PPS was possible within the PaP and the PPI. CONCLUSION: The PPS and the KPS can be used interchangeably as functional tools and within prognostic tools. The ECOG is interchangeable with the PPS and the KPS, but this interchangeability is population-specific.

Developing a multivariate electronic medical record integration model for primary health care.

This paper describes the development of a multivariate electronic medical record (EMR) integration model for the primary health care setting. Our working hypothesis is that an integrated EMR is associated with high quality primary health care. Our assumption is that EMR integration should be viewed as a form of complex intervention with multiple interacting components that can impact the quality of care. Depending on how well the EMR is integrated in the practice setting, one can expect a corresponding change in the quality of care as measured through a set of primary health care quality indicators. To test the face validity of this model, a Delphi study is being planned where health care providers and information technology professionals involved with EMR adoption are polled for their feedback. This model has the potential to quantify and explain the factors that influence successful EMR integration to improve primary health care.

Dynamics of fecal coliform bacteria along Canada's coast.

The vast coastline provides Canada with a flourishing seafood industry including bivalve shellfish production. To sustain a healthy bivalve molluscan shellfish production, the Canadian Shellfish Sanitation Program was established to monitor the health of shellfish harvesting habitats, and fecal coliform bacteria data have been collected at nearly 15,000 marine sample sites across six coastal provinces in Canada since 1979. We applied Functional Principal Component Analysis and subsequent correlation analyses to find annual variation patterns of bacteria levels at sites in each province. The overall magnitude and the seasonality of fecal contamination were modelled by functional principal component one and two, respectively. The amplitude was related to human and warm-blooded animal activities; the seasonality was strongly correlated with river discharge driven by precipitation and snow melt in British Columbia, but such correlation in provinces along the Atlantic coast could not be properly evaluated due to lack of data during winter.

Safety and efficacy of pembrolizumab for advanced nonsmall cell lung cancer: before and during the COVID-19 pandemic.

PURPOSE: The COVID-19 pandemic changed diagnostic and treatment pathways in oncology. We compared the safety and efficacy of pembrolizumab amongst advanced nonsmall cell lung cancer (NSCLC) patients with a PD-L1 tumor proportion score (TPS) ≥ 50% before and during the pandemic. METHODS: Advanced NSCLC patients initiating pembrolizumab between June 2015 and December 2019 ("pre-pandemic cohort") and between March 2020 and March 2021 ("pandemic cohort") at BC Cancer were identified retrospectively. Multivariable logistic regression evaluated risk factors for immune-related adverse events (irAE) ≥ grade 3 at the 6 week, 3 month, and 6 month landmarks. Cox regression models of overall survival (OS) were constructed. RESULTS: The study population comprised 417 patients in the pre-pandemic cohort and 111 patients in the pandemic cohort. Between March and May 2020, 48% fewer advanced NSCLC cases with PD-L1 TPS ≥ 50% were diagnosed compared to similar intervals in 2018-2019. Telemedicine assessment [new patient consultations (p < 0.001) and follow-up (p < 0.001)] and extended interval pembrolizumab dosing (p < 0.001) were more common in the pandemic cohort. Patients initiating pembrolizumab after February 2020 (vs. before January 2020) experienced similar odds of developing severe irAE. 2/111 (1.8%) patients receiving pembrolizumab during the pandemic tested positive for COVID-19. On multivariable analysis, no association between pembrolizumab treatment period (before vs. during the COVID-19 pandemic) and OS was observed (p = 0.18). CONCLUSION: Significant changes in healthcare delivery in response to the pandemic did not result in increased high grade toxicity or lower survival outcomes in patients with advanced NSCLC treated with pembrolizumab.

First-line osimertinib for patients with EGFR-mutated advanced non-small cell lung cancer: efficacy and safety during the COVID-19 pandemic.

Background: The FLAURA trial demonstrated improved overall survival (OS) with first-line osimertinib for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). We studied the efficacy and safety of osimertinib in a cohort treated during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Patients diagnosed with EGFR-mutated advanced NSCLC between 11 March 2020 to 31 December 2021 who received first-line osimertinib in British Columbia, Canada were identified retrospectively. Kaplan-Meier curves of OS and progression-free survival (PFS) from the start of osimertinib were plotted. The associations of baseline characteristics with PFS, and development of pneumonitis or dose reductions due to toxicity with OS were evaluated with hazard ratios estimated using univariable and multivariable Cox models. Results: The cohort comprised 231 individuals. 58.7% of patients with de novo advanced NSCLC were initially diagnosed after presentation to the Emergency Room. At osimertinib initiation, 31.6% were aged ≥75 years and 45.5% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Median PFS and OS were 18.0 months [95% confidence interval (CI): 16.1-26.2] and 25.4 months (95% CI: 20.3-not reached), respectively. On multivariable analysis, age ≥75 years (vs. <75), ECOG PS 2/3 (vs. 0/1), ECOG PS 4 (vs. 0/1), current smokers (vs. never smokers), programmed death ligand 1 (PD-L1) expression ≥50% (vs. <1%), and L858R mutation (vs. exon 19 deletion) were associated with shorter PFS. Among 110 patients who progressed, 33.6% received subsequent therapy. A proportion of 16.5% of the cohort developed grade ≥3 adverse events. Pneumonitis from osimertinib (3.9% incidence) was weakly associated with shorter OS (hazard ratio: 2.59, 95% CI: 0.94-7.12, P=0.066); dose reductions were not associated with worse OS. 10.8% of patients developed COVID-19. Conclusions: In a cohort receiving first-line osimertinib during the COVID-19 pandemic, ECOG PS ≥2 was observed in nearly half of patients at treatment initiation contributing to a median OS shorter than in FLAURA. The incidence of severe adverse events was low and dose reduction for drug toxicity did not impact OS. Identifying and reducing barriers to the diagnosis of NSCLC during the COVID-19 pandemic are required.