Estimates of healthcare utilisation and deaths from waterborne pathogen exposure in Ontario, Canada.

Burden of disease analyses can quantify the relative impact of different exposures on population health outcomes. Gastroenteritis where the causative pathogen was not determined and respiratory illness resulting from exposure to opportunistic pathogens transmitted by water aerosols have not always been considered in waterborne burden of disease estimates. We estimated the disease burden attributable to nine enteric pathogens, unspecified pathogens leading to gastroenteritis, and three opportunistic pathogens leading primarily to respiratory illness, in Ontario, Canada (population ~14 million). Employing a burden of disease framework, we attributed a fraction of annual (year 2016) emergency department (ED) visits, hospitalisations and deaths to waterborne transmission. Attributable fractions were developed from the literature and clinical input, and unattributed disease counts were obtained using administrative data. Our Monte Carlo simulation reflected uncertainty in the inputs. The estimated mean annual attributable rates for waterborne diseases were (per 100 000 population): 69 ED visits, 12 hospitalisations and 0.52 deaths. The corresponding 5th-95th percentile estimates were (per 100 000 population): 13-158 ED visits, 5-22 hospitalisations and 0.29-0.83 deaths. The burden of disease due to unspecified pathogens dominated these rates: 99% for ED visits, 63% for hospitalisations and 40% for deaths. However, when a causative pathogen was specified, the majority of hospitalisations (83%) and deaths (97%) resulted from exposure to the opportunistic pathogens Legionella spp., non-tuberculous mycobacteria and Pseudomonas spp. The waterborne disease burden in Ontario indicates the importance of gastroenteritis not traced back to a particular pathogen and of opportunistic pathogens transmitted primarily through contact with water aerosols.

An approach to estimating the environmental burden of cancer from known and probable carcinogens: application to Ontario, Canada.

BACKGROUND: Quantifying the potential cancer cases associated with environmental carcinogen exposure can help inform efforts to improve population health. This study developed an approach to estimate the environmental burden of cancer and applied it to Ontario, Canada. The purpose was to identify environmental carcinogens with the greatest impact on cancer burden to support evidence-based decision making. METHODS: We conducted a probabilistic assessment of the environmental burden of cancer in Ontario. We selected 23 carcinogens that we defined as "environmental" (e.g., pollutants) and were relevant to the province, based on select classifications provided by the International Agency for Research on Cancer. We evaluated population exposure to the carcinogens through inhalation of indoor/outdoor air; ingestion of food, water, and dust; and exposure to radiation. We obtained or calculated concentration-response functions relating carcinogen exposure and the risk of developing cancer. Using both human health risk assessment and population attributable fraction models in a Monte Carlo simulation, we estimated the annual cancer cases associated with each environmental carcinogen, reporting the simulation summary (e.g., mean and percentiles). RESULTS: We estimated between 3540 and 6510 annual cancer cases attributable to exposure to 23 environmental carcinogens in Ontario. Three carcinogens were responsible for over 90% of the environmental burden of cancer: solar ultraviolet (UV) radiation, radon in homes, and fine particulate matter (PM2.5) in outdoor air. Eight other carcinogens had an estimated mean burden of at least 10 annual cancer cases: acrylamide, arsenic, asbestos, chromium, diesel engine exhaust particulate matter, dioxins, formaldehyde, and second-hand smoke. The remaining 12 carcinogens had an estimated mean burden of less than 10 annual cancer cases in Ontario. CONCLUSIONS: We found the environmental burden of cancer in Ontario to fall between previously estimated burdens of alcohol and tobacco use. These results allow for a comparative assessment across carcinogens and offer insights into strategies to reduce the environmental burden of cancer. Our analysis could be adopted by other jurisdictions and repeated in the future for Ontario to track progress in reducing cancer burden, assess newly classified environmental carcinogens, and identify top burden contributors.

Estimated Annual Deaths, Hospitalizations, and Emergency Department and Physician Office Visits from Foodborne Illness in Ontario.

Public Health Ontario is working to estimate the burden of disease from environmental hazards in Ontario, Canada. As part of this effort, we estimated deaths and health care utilization resulting from exposure to pathogens and toxic substances in food. We applied fractions for the proportion of illness attributable to foodborne transmission to the annual (2008-2012) counts of deaths, hospitalizations, emergency department (ED) visits, and physician office visits for 15 diseases (13 pathogen-specific diseases and 2 nonspecific syndromes) captured by administrative health data. Nonspecific gastroenteritis (causative agent unknown) was the dominant disease, accounting for 98% of ED visits, 94% of hospitalizations, and 88% of deaths annually attributed to the 15 diseases. We estimated that foodborne nonspecific gastroenteritis results in ∼137,000 physician office visits (1000/100,000 population), 40,000 ED visits (310/100,000), 6200 hospitalizations (47/100,000), and 59 deaths (0.45/100,000) in Ontario per year (mean estimates). Our results indicate that pathogen-specific approaches to foodborne disease surveillance can substantially underestimate the deaths and illness resulting from exposure to foodborne pathogens and other causes of foodborne illness.

Exploring nighttime road traffic noise: A comprehensive predictive surface for Toronto, Canada.

Road traffic noise can adversely impact the health of city residents, particularly when it occurs at night. The objective of this study was to evaluate nighttime traffic ambient noise in Toronto, Canada using measured and model-estimated noise levels. Road traffic noise was measured at 767 locations over 3 seasonal sampling campaigns between June 2012 and October 2013 to fully capture noise variability in Toronto. Temporal and campaign-specific spatial models, developed using the noise measurements, were used to build a final predictive surface. The surface was capable of estimating noise across the city over a 24-hr time frame. Measured and surface-estimated noise levels were compared with guidelines from the World Health Organization and the Province of Ontario to identify areas where noise may pose a health risk. Measured mean nighttime noise in Toronto exceeded World Health Organization (40 dBA) guidelines and mean daytime noise exceeded provincial (55 dBA) guidelines. The final predictive surface, incorporating spatial variables and daily cycles in noise levels, provides noise estimates geocoded for the entire study area. This tool could be used for epidemiological studies and to inform noise mitigation efforts. Based on surface-estimated noise levels during the quietest time of night (2 a.m.-2:30 a.m.), 100% of Toronto has nighttime noise exceeding 40 dBA (mean = 57 dBA, range = 49-110 dBA). A predictive surface was developed to estimate geocoded noise levels and facilitate further study of noise in Toronto. This tool can be used to assess road traffic noise, particularly at night, as an environmental health hazard.

Diurnal floc generation from neuston biofilms in two contrasting freshwater lakes.

Selective adaptation of biofilm-forming bacteria to the nutrient-rich but environmentally challenging conditions of the surface microlayer (SML) or neuston layer was evident in littoral regions of two physically and geochemically contrasting freshwater lakes. SML bacterial communities (bacterioneuston) in these systems were depleted in Actinobacteria, enriched in either Betaproteobacteria or Gammaproteobacteria, and either unicellular Cyanobacteria were absent or microbial mat forming Cyanobacteria enriched relative to communities in the underlying shallow water column (0.5 m depth). Consistent with the occurrence of biofilm-hosted, geochemically distinct microhabitats, As-, Fe-, and S-metabolizing bacteria including anaerobic taxa were detected only in the SML in both systems. Over diurnal time scales, higher wind speeds resulted in the generation of floc from SML biofilms, identifying a transport mechanism entraining SML accumulated microorganisms, nutrients, and contaminants into the underlying water column. The energy regime experienced by the SML was more important to floc generation as larger flocs were more abundant in the larger, oligotrophic lake (higher relative energy regime) compared to the sheltered, smaller lake, despite relatively higher concentrations of bacteria, organic carbon, Fe, and PO4(3-) in the latter system.

Comparative efficacy of ofatumumab versus oral therapies for relapsing multiple sclerosis patients using propensity score analyses and simulated treatment comparisons.

Background: Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers. Objectives: A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies. Design: Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab versus the oral therapies cladribine, fingolimod, and ozanimod. Data sources and methods: As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP). Results: The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS. Conclusion: Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies.

Glucarpidase for Treating Adults with Delayed Methotrexate Elimination Due to Impaired Renal Function: An Economic Simulation Analysis.

Background: Glucarpidase is indicated for treating delayed methotrexate (MTX) elimination due to impaired renal function. Although glucarpidase is capable of rapidly eliminating MTX independent of renal clearance, its cost can be perceived as a barrier to use. However, no published economic analyses have evaluated glucarpidase relative to comparable treatments. Purpose: To assess the economic value of glucarpidase for treating adult patients in the United States (US) who experience delayed MTX elimination due to impaired renal function. Methods: A decision tree model was developed to assess the economic value of glucarpidase. The short-term inpatient management of patients as well as long-term survival were simulated. Costs associated with the use of glucarpidase were compared against other methods for treating delayed MTX elimination due to impaired renal function under two scenarios: current practice (ie, mix of timely/delayed use of glucarpidase, hemodialysis, or supportive care [SC] alone) as compared with proposed practice (ie, timely glucarpidase administration within 60 hours for all eligible patients). Hypothetical practical scenarios for US institutions were also considered. Results: For adult patients with delayed MTX elimination, proposed practice as compared to current practice was associated with an increased cost of $20,024 per patient, not considering any incremental reimbursement associated with glucarpidase administration. Importantly, early treatment with glucarpidase, within 60 hours, was shown to be less expensive per patient than delayed glucarpidase treatment or treating with hemodialysis, but more expensive than SC alone. However, proposed practice was associated with multiple clinical benefits, including shorter hospital length of stay. For hypothetical practical scenarios, minimal shifts in treatment patterns had minimal cost impacts. Conclusion: Treatment of all eligible patients with glucarpidase within 60 hours was associated with an increased cost per patient (relative to current practice) but substantial improvements in clinical outcomes. Timely glucarpidase use was less expensive than delayed glucarpidase or hemodialysis.

Comparative efficacy of therapies for relapsing multiple sclerosis: a systematic review and network meta-analysis.

Aim: To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod, ublituximab) using network meta-analysis (NMA). Materials & methods: Bayesian NMAs for annualised relapse rate (ARR) and time to 3-month and 6-month confirmed disability progression (3mCDP and 6mCDP) were conducted. Results: For each outcome, the three most efficacious treatments versus placebo were monoclonal antibody (mAb) therapies: alemtuzumab, ofatumumab, and ublituximab for ARR; alemtuzumab, ocrelizumab, and ofatumumab for 3mCDP; and alemtuzumab, natalizumab, and either ocrelizumab or ofatumumab (depending on the CDP definition used for included ofatumumab trials) for 6mCDP. Conclusion: The most efficacious DMTs for RMS were mAb therapies. Of the newer therapies, only ublituximab ranked among the three most efficacious treatments (for ARR).

Diversity of integron- and culture-associated antibiotic resistance genes in freshwater floc.

Clinically important antibiotic resistance genes were detected in culturable bacteria and class 1 integron gene cassettes recovered from suspended floc, a significant aquatic repository for microorganisms and trace elements, across freshwater systems variably impacted by anthropogenic activities. Antibiotic resistance gene cassettes in floc total community DNA differed appreciably in number and type from genes detected in bacteria cultured from floc. The number of floc antibiotic resistance gene cassette types detected across sites was positively correlated with total (the sum of Ag, As, Cu, and Pb) trace element concentrations in aqueous solution and in a component of floc readily accessible to bacteria. In particular, concentrations of Cu and Pb in the floc component were positively correlated with floc resistance gene cassette diversity. Collectively, these results identify suspended floc as an important reservoir, distinct from bulk water and bed sediment, for antibiotic resistance in aquatic environments ranging from heavily impacted urban sites to remote areas of nature reserves and indicate that trace elements, particularly Cu and Pb, are geochemical markers of resistance diversity in this environmental reservoir. The increase in contamination of global water supplies suggests that aquatic environments will become an even more important reservoir of clinically important antibiotic resistance in the future.

Unmet Need in People with Psoriasis and Skin of Color in Canada and the United States.

The experience of dermatological conditions such as psoriasis is different for people with skin of color (SoC) than for white individuals. The objective of this literature review was to understand challenges and unmet needs associated with access to care, diagnosis, and treatment of psoriasis among people with SoC in Canada and the United States. The review focused on studies published in the last 5 years. After screening 919 unique records, 26 studies were included. Importantly, lack of culturally competent care was identified as a key unmet need for psoriasis among people with SoC. In addition, cost of care and cultural views of psoriasis may influence decisions to seek care among people with SoC. Baseline patient characteristics in psoriasis studies and the prevalence/incidence of psoriasis vary across racial/ethnic groups, which may reflect differences in the rate and/or timing of diagnosis. The presentation of psoriasis differs across racial/ethnic groups, which may contribute to challenges in proper and timely diagnosis. Compared with white patients with psoriasis, individuals with SoC may be less familiar with and have different rates of treatment with biologic therapies for psoriasis, are more likely to be hospitalized for psoriasis, and their access to physicians may differ. Further, people with SoC are underrepresented in clinical trials of psoriasis therapies. Overall, the results of this literature review suggest that people with psoriasis and SoC face unique challenges in their disease experience. It is essential that clinicians and other stakeholders recognize and address these disparities to ensure equitable care.

Skin conditions such as psoriasis are experienced differently by people with skin of color (SoC) compared with white individuals. Although it is known that psoriasis can vary in how it appears between these groups, other factors that affect care for patients with SoC are not well understood. For this review, we focused on challenges associated with accessing healthcare, receiving a diagnosis, and receiving treatment for psoriasis among people with SoC. A search of the academic literature identified several such challenges for people with SoC in Canada and the United States. A major challenge for people with psoriasis and SoC is having access to care that is compatible with their cultural values and practices. The cost of healthcare and cultural views of psoriasis may influence whether individuals with SoC decide to seek care. People with SoC are more likely to be hospitalized for psoriasis, and their access to physicians may differ compared with white individuals. In addition, differences in how psoriasis appears across racial/ethnic groups may hinder diagnosis. Psoriasis treatments that patients with SoC receive may differ from those that white individuals receive, and people with SoC may be less likely to be properly represented in clinical trials evaluating psoriasis therapies. Taken together, the findings of our review indicate that people with psoriasis and SoC face unique challenges in how they receive medical care for their condition. It is essential that clinicians and other stakeholders in the healthcare system recognize these challenges and work to address them.

Simulated treatment comparison of efficacy outcomes for ofatumumab in ASCLEPIOS I/II versus ocrelizumab in OPERA I/II for the treatment of patients with relapsing multiple sclerosis.

BACKGROUND: Ofatumumab is a subcutaneously administered anti-CD20 monoclonal antibody (MoAb) therapy that has been evaluated in two identically designed randomized controlled trials (RCTs), ASCLEPIOS I (NCT02792218) and ASCLEPIOS II (NCT02792231), in patients with relapsing multiple sclerosis (RMS). Ocrelizumab is another anti-CD20 MoAb therapy, administered intravenously, that has been evaluated in two identically designed RCTs, OPERA I (NCT01247324) and OPERA II (NCT01412333) in RMS. Given the absence of published RCTs with head-to-head comparisons between these MoAbs, this study assessed the indirect comparative efficacy of ofatumumab and ocrelizumab. METHODS: Given the availability of individual patient data for ASCLEPIOS I/II and summary-level data for OPERA I/II, simulated treatment comparisons were used to assess the comparative efficacy of ofatumumab versus ocrelizumab while adjusting for differences in baseline characteristics between trials. Comparative efficacy was estimated for the proportion of patients with 3- and 6-month confirmed disability progression (CDP) and for annualized relapse rate (ARR). Exploratory analyses were conducted for the outcome of no evidence of disease activity based on three parameters (NEDA-3) and magnetic resonance imaging (MRI) outcomes (proportion of patients with gadolinium-enhancing T1 lesions and brain volume change). RESULTS: Although comparative results were not significant for 3-month CDP (hazard ratio [HR]: 0.90 [95% confidence interval [CI]: 0.57-1.42]) or 6-month CDP (HR: 0.84 [95% CI: 0.47-1.49]), ofatumumab showed a significant improvement in ARR (rate ratio: 0.60 [95% CI: 0.43-0.84]) compared with ocrelizumab. Significantly favorable results were also associated with ofatumumab for NEDA-3 and MRI outcomes. CONCLUSION: Ofatumumab was associated with more favorable efficacy results compared with ocrelizumab for clinical, NEDA-3, and MRI outcomes.

Indirect comparisons of siponimod with fingolimod and ofatumumab in multiple sclerosis: assessing the feasibility of propensity score matching analyses.

OBJECTIVE: Head-to-head trials comparing siponimod with fingolimod or ofatumumab in patients with multiple sclerosis (MS) are lacking. Instead, the comparative efficacy of siponimod can be derived from indirect treatment comparisons (ITCs). We assessed the suitability of ITCs leveraging individual patient data from relevant phase III trials across different MS phenotypes. METHODS: One siponimod trial in patients with secondary progressive MS (SPMS), four fingolimod trials (three in relapsing-remitting MS [RRMS], and one in primary progressive MS [PPMS]), and two ofatumumab trials in relapsing MS (RMS) were considered. The suitability of ITCs was evaluated based on trial design, patient eligibility criteria, baseline patient characteristics, placebo response, and outcome definitions for each trial. Analyses deemed feasible were conducted using one-to-one propensity score matching (PSM). RESULTS: An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible because of insufficient overlap in key patient characteristics (e.g. disability level and relapse history) and differences in placebo response. However, a comparison between siponimod in SPMS and fingolimod in PPMS was feasible because of sufficient overlap in eligibility criteria and baseline characteristics. One-to-one PSM demonstrated siponimod was favored relative to fingolimod for time to 6- and 3-month confirmed disability progression though not significantly different (hazard ratio 0.76 [95% confidence interval 0.48-1.20; p-value = .240] and hazard ratio 0.80 [95% confidence interval 0.52-1.22; p-value = .300], respectively). CONCLUSIONS: For trials in MS, clinical phenotype is an important determinant of ITC feasibility. An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible. The only feasible comparison was between siponimod in SPMS and fingolimod in PPMS.

Efficacy classification of modern therapies in multiple sclerosis.

Background: The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Materials & methods: Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. Results: For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Conclusion: Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.

Comparison of ofatumumab and other disease-modifying therapies for relapsing multiple sclerosis: a network meta-analysis.

Aim: To compare the efficacy of ofatumumab to other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS). Materials & methods: A network meta-analysis was conducted to determine the relative effect of ofatumumab on annualized relapse rate and confirmed disability progression at 3 months and 6 months. Results: For each outcome, ofatumumab was as effective as other highly efficacious monoclonal antibody DMTs (i.e., alemtuzumab, natalizumab and ocrelizumab). Conclusion: Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk.