Analysis of chemical exposures in racial populations in Canada: An investigation based on the Canadian health measures survey.

Despite demonstrated disparities in environmental chemical exposures by racial identity, no Canadian study has systematically assessed the feasibility of using a nationally representative dataset to examine differences in chemical concentrations by race. We assessed the feasibility and constraints of analysing chemical exposures in racial populations, including visible minorities and populations of Indigenous identity, using biomonitoring data collected through the Canadian Health Measures Survey (CHMS). Our primary objectives were to assess the ability to 1) generate geometric means and percentiles of chemical concentrations for racial populations by age or sex, 2) statistically compare concentrations among racial populations, and 3) calculate time trends of concentrations by race. We conducted these analyses for several priority chemicals: lead, cadmium, benzene, bisphenol A (BPA), and di(2-ethylhexyl) phthalate (DEHP). Survey participants self-identified as one of the following: White, Black, East and Southeast Asian, South Asian, Middle Eastern, Latin American, First Nations, Metis, and Inuit. Analyses were conducted for individual and combined cycles of the CHMS. Using data from the latest CHMS cycle in which each chemical was measured, we observed that sample sizes were sufficient to report geometric mean concentrations for all races except Inuit. Due to privacy considerations associated with small sample sizes, the 5th and 95th percentile concentrations could not be consistently reported for all racial populations in this analysis. While we were able to statistically compare concentrations among racial populations, the analysis was constrained by the limited number of statistical degrees of freedom available in a single CHMS cycle. Both of these constraints were alleviated by combining multiple cycles of data. The analysis of time trends was less subject to privacy and statistical limitations; we were able to calculate time trends of chemical concentrations for all racial populations. Our findings provide an important baseline for follow-up investigations of descriptive and etiological analyses of environmental chemical exposures and race in the CHMS.

Predicting heart failure outcomes by integrating breath-by-breath measurements from cardiopulmonary exercise testing and clinical data through a deep learning survival neural network.

Aims: Mathematical models previously developed to predict outcomes in patients with heart failure (HF) generally have limited performance and have yet to integrate complex data derived from cardiopulmonary exercise testing (CPET), including breath-by-breath data. We aimed to develop and validate a time-to-event prediction model using a deep learning framework using the DeepSurv algorithm to predict outcomes of HF. Methods and results: Inception cohort of 2490 adult patients with high-risk cardiac conditions or HF underwent CPET with breath-by-breath measurements. Potential predictive features included known clinical indicators, standard summary statistics from CPETs, and mathematical features extracted from the breath-by-breath time series of 13 measurements. The primary outcome was a composite of death, heart transplant, or mechanical circulatory support treated as a time-to-event outcomes. Predictive features ranked as most important included many of the features engineered from the breath-by-breath data in addition to traditional clinical risk factors. The prediction model showed excellent performance in predicting the composite outcome with an area under the curve of 0.93 in the training and 0.87 in the validation data sets. Both the predicted vs. actual freedom from the composite outcome and the calibration of the prediction model were excellent. Model performance remained stable in multiple subgroups of patients. Conclusion: Using a combined deep learning and survival algorithm, integrating breath-by-breath data from CPETs resulted in improved predictive accuracy for long-term (up to 10 years) outcomes in HF. DeepSurv opens the door for future prediction models that are both highly performing and can more fully use the large and complex quantity of data generated during the care of patients with HF.

Quantitative systems pharmacology-based exploration of relevant anti-amyloid therapy challenges in clinical practice.

INTRODUCTION: Addressing practical challenges in clinical practice after the recent approvals of amyloid antibodies in Alzheimer's disease (AD) will benefit more patients. However, generating these answers using clinical trials or real-world evidence is not practical, nor feasible. METHODS: Here we use a Quantitative Systems Pharmacology (QSP) computational model of amyloid aggregation dynamics, well validated with clinical data on biomarkers and amyloid-related imaging abnormality-edema (ARIA-E) liability of six amyloid antibodies in clinical trials to explore various clinical practice challenges. RESULTS: Treatment duration to reach amyloid negativity ranges from 12 to 44, 16 to 40, and 6 to 20 months for lecanemab, aducanumab, and donanemab, respectively, for baseline central amyloid values between 50 and 200 Centiloids (CL). Changes in plasma cerebrospinal fluid Aß42 and the plasma Aß42/ Aß40 ratio-fluid biomarkers to detect central amyloid negativity-is greater for lecanemab than for aducanumab and donanemab, indicating that these fluid amyloid biomarkers are only suitable for lecanemab. After reaching amyloid negativity an optimal maintenance schedule consists of a 24-month, 48-month and 64-month interval for 10 mg/kg (mpk) lecanemab, 10 mpk aducanumab, and 20 mpk donanemab, respectively, to keep central amyloid negative for 10 years. Cumulative ARIA-E liability could be reduced to almost half by introducing a drug holiday in the first months. For patients experiencing ARIA-E, restarting treatment with a conservative titration strategy resulted in an additional delay ranging between 3 and 4 months (donanemab), 5 months (lecanemab), and up to 7 months (aducanumab) for reaching amyloid negativity, depending upon the timing of the incident. Clinical trial designs for Down syndrome patients suggested the same rank order for central amyloid reduction, but higher ARIA-E liability especially for donanemab, which can be significantly mitigated by adopting a longer titration period. DISCUSSION: This QSP platform could support clinical practice challenges to optimize real-world treatment paradigms for new and existing amyloid drugs.

Harmonizing the assessment of allostatic load across cycles of the Canadian Health Measures Survey: Variable selection and calculation method.

Background: The availability of measures to operationalize allostatic load - the cumulative toll on the body of responding to stressor demands - in population health surveys may differ across years or surveys, hampering analyses on the entire sampled population. Here, impacts of variable selection and calculation method were evaluated to generate an allostatic load index applicable across all cycles of the Canadian Health Measures Survey (CHMS). Methods: Data from CHMS cycles 1 to 4 were used to compare allostatic load scores when replacing the most prevalent risk factor, waist-to-hip ratio - available in cycles 1 to 4 but not 5 and 6 - with body mass index (BMI), waist circumference, waist circumference within BMI groups (classified as normal, overweight, or obese), or waist-to-height ratio. Indexes were generated using clinical or sex-specific empirically defined risk thresholds and as count-based or continuous scores. Logistic regression models that included age and sex were used to relate each potential index to socioeconomic indicators (educational attainment, household income). Results: Of the variables assessed, waist-to-height ratio and waist circumference were closest to waist-to-hip ratio according to an individual's percentile ranking and in classifying "at risk" using either clinical or empirically defined cut-offs. Allostatic load profiles generated using waist-to-height ratios most closely resembled profiles constructed using waist-to-hip ratios. Sex-dependent associations with educational attainment and household income were maintained across constructs whether indexes were count-based or continuous. Interpretation: Allostatic load profiles and associations with socioeconomic indicators were robust to variable substitution and method of calculation, supporting the use of a harmonized index across survey cycles to assess the cumulative toll on health of stressor exposure.

Analysis of clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration using a quantitative systems pharmacology model.

Misfolded proteins in Alzheimer's disease and Parkinson's disease follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit in clinical trials despite substantial target engagement in the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake of oligomeric protein from the synaptic cleft. We built a quantitative systems pharmacology (QSP) model to quantitatively simulate intrasynaptic secretion, diffusion and antibody capture in the synaptic cleft, postsynaptic membrane binding and internalization of monomeric and oligomeric tau and aSyn proteins. Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. Maximal target engagement for monomeric tau was simulated as 45% (semorinemab) to 99% (gosuranemab) in CSF, 30% to 99% in ISF but only 1% to 3% in the synaptic cleft, leading to a reduction of less than 1% in uptake of oligomeric tau. Simulations for prasineuzumab and cinpanemab suggest target engagement of free monomeric aSyn of only 6-8% in CSF, 4-6% and 1-2% in the ISF and synaptic cleft, while maximal target engagement of aggregated aSyn was predicted to reach 99% and 80% in the synaptic cleft with similar effects on neuronal uptake. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies.

A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator.

BACKGROUND: Loss-of-function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA-PD). GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), a promising target for a possible first disease-modifying therapy. LTI-291 is an allosteric activator of GCase, which increases the activity of normal and mutant forms of GCase. OBJECTIVES: This first-in-patient study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of 28 daily doses of LTI-291 in GBA-PD. METHODS: This was a randomized, double-blind, placebo-controlled trial in 40 GBA-PD participants. Twenty-eight consecutive daily doses of 10, 30, or 60 mg of LTI-291 or placebo were administered (n = 10 per treatment allocation). Glycosphingolipid (glucosylceramide and lactosylceramide) levels were measured in peripheral blood mononuclear cells (PBMCs), plasma, and cerebrospinal fluid (CSF), and a test battery of neurocognitive tasks, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale and the Mini-Mental State Exam, were performed. RESULTS: LTI-291 was generally well tolerated, no deaths or treatment-related serious adverse events occurred, and no participants withdrew due to adverse events. Cmax , and AUC0-6 of LTI-291 increased in a dose-proportional manner, with free CSF concentrations equal to the free fraction in plasma. A treatment-related transient increase in intracellular glucosylceramide (GluCer) in PBMCs was measured. CONCLUSION: These first-in-patient studies demonstrated that LTI-291 was well tolerated when administered orally for 28 consecutive days to patients with GBA-PD. Plasma and CSF concentrations that are considered pharmacologically active were reached (ie, sufficient to at least double GCase activity). Intracellular GluCer elevations were detected. Clinical benefit will be assessed in a larger long-term trial in GBA-PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A combined physiologically-based pharmacokinetic and quantitative systems pharmacology model for modeling amyloid aggregation in Alzheimer's disease.

Antibody-mediated removal of aggregated ß-amyloid (Aß) is the current, most clinically advanced potential disease-modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aß monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aß40 and Aß42 aggregation and clearance of aggregated Aß by activated microglia cells, which is enhanced by the interaction of antibody-bound Aß. The model allows for the prediction of Aß positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology-based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aß42 and plasma Aß42 /Aß40 ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody-bound, plaque-mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid-related imaging abnormalities with edema (ARIA-E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aß42 /Aß40 ratio while slightly overestimating the change in CSF Aß42 . ARIA-E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid-modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.

Self-Reported Physical Activity, QoL, Cardiac Function, and Cardiorespiratory Fitness in Women With HER2+ Breast Cancer.

Background: Women treated for breast cancer are at risk for worsening health-related quality of life (QoL), cardiac function, and cardiorespiratory fitness. Objectives: The aim of this study was to assess the associations of self-reported moderate to vigorous intensity physical activity (MVPA) during cancer treatment with concurrent measures of QoL and cardiac function and with post-treatment cardiorespiratory fitness in women with human epidermal growth factor receptor 2-positive breast cancer receiving sequential anthracyclines and trastuzumab. Methods: EMBRACE-MRI 1 (Evaluation of Myocardial Changes During Breast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier With MRI) study participants who completed questionnaires for MVPA (modified Godin Leisure Time Physical Activity Questionnaire) and QoL (EQ-5D-3L, Minnesota Living With Heart Failure Questionnaire) and cardiac imaging every 3 months during treatment and post-treatment cardiopulmonary exercise testing were included. Participants engaging in ≥90 minutes of MVPA each week were labeled "active." Generalized estimation equations and linear regression analyses were used to assess concurrent and post-treatment associations with MVPA and activity status, respectively. Results: Eighty-eight participants were included (mean age 51.4 ± 8.9 years). Mean MVPA minutes, QoL, and cardiac function (left ventricular ejection fraction, global longitudinal strain, E/A ratio, and E/e' ratio) worsened by 6 months into trastuzumab therapy. Higher MVPA (per 30 minutes) during treatment was associated with better concurrent overall (ß = -0.42) and physical (ß = -0.24) Minnesota Living With Heart Failure Questionnaire scores, EQ-5D-3L index (ß = 0.003), visual analogue scale score (ß = 0.43), diastolic function (E/A ratio; ß = 0.01), and global longitudinal strain (ß = 0.04) at each time point (P ≤ 0.01 for all). Greater cumulative MVPA over the treatment period was associated with higher post-treatment cardiorespiratory fitness (peak oxygen consumption; ß = 0.06 per 30 minutes; P < 0.001). Conclusions: Higher self-reported MVPA during treatment for human epidermal growth factor receptor 2-positive breast cancer was associated with better QoL and diastolic and systolic left ventricular function measures during treatment and better post-treatment cardiorespiratory fitness.

Recent Developments at the CMA: 2021-22.

This article discusses three important pieces of work that the Competition and Markets Authority has completed over the last year. The first two are market studies: The Mobile Ecosystems Market Study was launched over concerns that Apple and Google have too much control over operating systems (iOS and Android), app stores (App Store and Play Store), and web browsers (Safari and Chrome) that together form their 'ecosystems'; the Electric Vehicles Charging Market Study took actions and provided recommendations in a nascent but critically important market. The final piece of work is "State of Competition": a research project that assesses the evolution of competition in the UK over the past two decades.

Human skin through the ages.

As the largest organ of the human body the skin offers a protective role, providing a tough but pliable covering that provides the major barrier between the internal organs and the environment. It actively regulates water loss and is both oxygen and carbon dioxide permeable, and influences temperature regulation and immunological functions through its sensory properties. Both intrinsic and enhanced environmental factors contribute to the progressive deterioration of the skin with increasing age. Cutaneous problems are therefore an unavoidable and inevitable consequence of aging skin, which can prove to be both cosmetically unacceptable to those who succumb to these problems, as well as even life threatening if skin breakdown becomes chronic as is case with leg ulceration. This in turn has major implications for long-term impact on those looking after them (e.g., family, carers, etc.) and a huge burden on the health care system.

Recent Developments at the CMA: 2020-2021.

We discuss three important projects that economists at the Competition and Markets Authority have completed over the past year. First, our work on the Funerals Market Investigation provides an illustration of how demand-side problems can lead to a lack of competition, as well as demonstrating the CMA's willingness to consider price control and regulatory remedies where necessary. Second, on the Sabre/Farelogix merger case, we point to how our assessment dealt with uncertainty in innovative markets, the importance of preventing incumbents from acquiring start-ups, and the risks of following formalistic market definitions, especially in multi-sided platform sectors. Third, we set out the most notable developments in our revised Mergers Assessment Guidelines-including the assessment of future competition even when subject to significant uncertainty-and the assessment of the loss of dynamic competition and its effect on innovation incentives.

Teaching Undergraduates to Communicate Science, Cultivate Mentoring Relationships, and Navigate Science Culture.

The historic underrepresentation of women, certain racial and ethnic minorities, and members of other marginalized groups in careers in science, technology, engineering, and mathematics (STEM) reflects a disproportionate exit of individuals from these academic and career paths due to both environmental and personal factors. To transition successfully from classroom-based learning to the research environment, students must acquire various forms of capital nested within a largely hidden curriculum that most scientists learn informally. We have developed a semester-long course for undergraduate researchers that makes explicit concepts and strategies that contribute to STEM persistence. The course teaches skills for: 1) scientific communication; 2) maximizing the effectiveness of research mentoring relationships; and 3) navigating scientific culture and its interactions with multiple social identities. We offered the course for three consecutive semesters at the University of Massachusetts Boston to 33 students from different backgrounds, academic majors, and educational experiences. Quantitative and qualitative assessments demonstrated student learning in all three areas of emphasis. By deliberately combining instruction and practice in skills, such as those needed to present and critique scientific research, with skills needed to optimize personal interactions and key research relationships, we have created a novel learning experience to promote persistence in STEM.

Trends in environmental chemical concentrations in the Canadian population: Biomonitoring data from the Canadian Health Measures Survey 2007-2017.

Ten years of nationally representative biomonitoring data collected between 2007 and 2017 are available from the Canadian Health Measures Survey (CHMS). These data establish baseline environmental chemical concentrations in the general population. Here we sought to evaluate temporal trends in environmental chemical exposures in the Canadian population by quantifying changes in biomarker concentrations measured in the first five two-year cycles of the CHMS. We identified 39 chemicals that were measured in blood or urine in at least three cycles and had detection rates over 50% in the Canadian population. We calculated geometric mean concentrations for each cycle using the survey weights provided. We then conducted analyses of variance to test for linear trends over all cycles. We also calculated the percent difference in geometric means between the first and most recent cycle measured. Of the 39 chemicals examined, we found statistically significant trends across cycles for 21 chemicals. Trends were decreasing for 19 chemicals from diverse chemical groups, including metals and trace elements, phenols and parabens, organophosphate pesticides, per- and polyfluoroalkyl substances, and plasticizers. Significant reductions in chemical concentrations included di-2-ethylhexyl phthalate (DEHP; 75% decrease), perfluorooctane sulfate (PFOS; 61% decrease), perfluorooctanoic acid (PFOA; 58% decrease), dimethylphosphate (DMP; 40% decrease), lead (33% decrease), and bisphenol A (BPA; 32% decrease). Trends were increasing for two pyrethroid pesticide metabolites, including a 110% increase between 2007 and 2017 for 3-phenoxybenzoic acid (3-PBA). No significant trends were observed for the remaining 18 chemicals that included arsenic, mercury, fluoride, acrylamide, volatile organic compounds, and polycyclic aromatic hydrocarbons. National biomonitoring data indicate that concentrations, and therefore exposures, have decreased for many priority chemicals in the Canadian population. Concentrations for other chemical groups have not changed or have increased, although average concentrations remain below thresholds of concern derived from human exposure guidance values. Continued collection of national biomonitoring data is necessary to monitor trends in exposures over time.

Exposure Load: Using biomonitoring data to quantify multi-chemical exposure burden in a population.

People are often concurrently exposed to numerous chemicals. Here we sought to leverage existing large biomonitoring datasets to improve our understanding of multi-chemical exposures in a population. Using nationally-representative data from the 2012-2015 Canadian Health Measures Survey (CHMS), we developed Exposure Load, a metric that counts the number of chemicals measured in people above a defined concentration threshold. We calculated Exposure Loads based on five concentration thresholds: the analytical limit of detection (LOD) and the 50th, 75th, 90th and 95th percentiles. Our analysis considered 44 analyte biomarkers representing 26 chemicals from the 2012-2015 CHMS; complete biomarker data were available for 1858 participants aged 12-79 years following multiple imputation of results that were missing due to sample loss. Chemicals may have one or more biomarkers, and for the purposes of Exposure Load calculation, participants were considered to be exposed to a chemical if at least one biomarker was above the threshold. Distributions of Exposure Loads are reported for the total population, as well as by age group, sex and smoking status. Canadians had an Exposure Load between 9 and 21 (out of 26) when considering LOD as the threshold, with the majority between 13 and 18. At higher thresholds, such as the 95th percentile, the majority of Canadians had an Exposure Load between 0 and 3, although some people had an Exposure Load of up to 15, indicating high exposures to multiple chemicals. Adolescents aged 12-19 years had significantly lower Exposure Loads than adults aged 40-79 years at all thresholds and adults aged 20-39 years at the 50th and 75th percentiles. Smokers had significantly higher Exposure Loads than nonsmokers at all thresholds except the LOD, which was expected given that tobacco smoke is a known source of certain chemicals included in our analysis. No differences in Exposure Loads were observed between males and females at any threshold. These findings broadly suggest that Canadians are concurrently exposed to many chemicals at lower concentrations and to fewer chemicals at high concentrations. They should assist in identifying vulnerable subpopulations disproportionately exposed to numerous chemicals at high concentrations. Future work will use Exposure Loads to identify prevalent chemical combinations and their link with adverse health outcomes in the Canadian population. The Exposure Load concept can be applied to other large datasets, through collaborative efforts in human biomonitoring networks, in order to further improve our understanding of multiple chemical exposures in different populations.

A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator.

AIMS: A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI-291 is an allosteric modulator of GCase, enhancing its activity. These first-in-human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI-291 in healthy volunteers. METHODS: In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI-291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle-aged or elderly volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI-291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed. RESULTS: LTI-291 was generally well tolerated and no deaths or treatment-related SAEs occurred and no subject withdrew from a study due to AEs. Cmax , AUC0-24 and AUC0-inf increased in a dose proportional manner. The median half-life was 28.0 hours after multiple dosing. No dose-dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected. CONCLUSIONS: These first-in-human studies demonstrated that LTI-291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI-291 effects in a GBA1-mutated Parkinson population.

A tale of two alginates.

BACKGROUND: All fibrous wound dressings are considered to have the same action and value to the support of wound healing. Although clear distinction has been accepted between cotton gauze and calcium alginates, there is still no formally recognised distinction between calcium alginates and the more rapidly gelling fibre dressings. METHOD: Scientific and clinical evaluations were used to differentiate two different fibrous wound care products. One is derived from polymer extraction of algae (alginate dressings); the other has been manufactured from a uniquely patented carboxymethylation process that produces 100% carboxymethyl cellulose (CMC)-based dressings. Structural differences between these dressings were evaluated with respect to three important areas of wound care management: optimal wound moisture control; the ability to reduce risk of complication by locking away harmful components (e.g. bacteria); and reducing the overall cost of wound care by promoting more efficient use of nursing time. RESULTS: Clear differentiation was illustrated through both scientific and clinical evaluations. CONCLUSION: This study supports the potential advantages of using a technically advanced fibrous wound dressing over the traditional fibrous alginate wound care product.

Clinical, Echocardiographic, and Biomarker Associations With Impaired Cardiorespiratory Fitness Early After HER2-Targeted Breast Cancer Therapy.

BACKGROUND: Cardiorespiratory fitness (CRF) is reduced in cancer survivors and predicts cardiovascular disease (CVD)-related and all-cause mortality. However, routine measurement of CRF is not always feasible. OBJECTIVES: The purpose of this study was to identify clinical, cardiac biomarker, and imaging measures associated with reduced peak oxygen consumption (VO2peak) (measure of CRF) early post-breast cancer therapy to help inform CVD risk. METHODS: Consecutive women with early-stage HER2+ breast cancer receiving anthracyclines and trastuzumab were recruited prospectively. Within 6 ± 2 weeks of trastuzumab completion, we collected clinical information, systolic/diastolic echocardiographic measures, high-sensitivity troponin I, B-type natriuretic peptide, and VO2peak using a cycle ergometer. Regression models were used to examine the association between VO2peak and clinical, imaging, and cardiac biomarkers individually and in combination. RESULTS: Among 147 patients (age 52.2 ± 9.3 years), the mean VO2peak was 19.1 ± 5.0 mL O2·kg-1·min-1 (84.2% ± 18.7% of predicted); 44% had a VO2peak below threshold for functional independence (<18 mL O2·kg-1·min-1). In multivariable analysis, absolute global longitudinal strain (GLS) (ß = 0.58; P = 0.007), age per 10 years (ß: -1.61; P = 0.001), and E/e' (measure of diastolic filling pressures) (ß = -0.45; P = 0.038) were associated with VO2peak. GLS added incremental value in explaining the variability in VO2peak. The combination of age ≥50 years, E/e' ≥7.8, and GLS <18% identified a high probability (85.7%) of compromised functional independence, whereas age <50 years, E/e' <7.8, and GLS ≥18% identified a low probability (0%). High-sensitivity troponin I and B-type natriuretic peptide were not associated with VO2peak. CONCLUSIONS: Readily available clinical measures were associated with VO2peak early post-breast cancer therapy. A combination of these parameters had good discrimination to identify patients with compromised functional independence and potentially increased future CVD risk.

Recent Developments at the CMA: 2019-2020.

We discuss three important cases that the Competition and Markets Authority (CMA) has completed over the past year: First, the coronavirus pandemic has had implications for a wide range of the CMA's work; we describe the work on price gouging conducted by the CMA's Covid-19 taskforce and respond to the argument that competition authorities should not be concerned about such behaviour. Second, a number of high-profile studies have considered the appropriate application of competition policy in digital industries. The second two cases-the Online Platforms and Digital Advertising market study, and the Google/Looker merger-show the work the CMA has continued to do in this area.

Regional variations in human chemical exposures in Canada: A case study using biomonitoring data from the Canadian Health Measures Survey for the provinces of Quebec and Ontario.

The Canadian Health Measures Survey (CHMS), an ongoing national health survey conducted in two-year cycles, collects extensive biomonitoring data that is used to assess the exposure of Canadians to environmental chemicals of concern. Combining data from multiple cycles of the CHMS allows for the calculation of robust regional estimates of chemical concentrations in blood and urine. The objective of this work was to compare biomarkers of exposure to several environmental chemicals for the provinces of Quebec and Ontario, two major CHMS regions, as well as the entire CHMS (representing Canada) minus Quebec (CMQ), and the entire CHMS minus Ontario (CMO), and to interpret differences between regions. Geometric means and 95th percentiles of blood and/or urinary concentrations of 45 environmental chemicals or their metabolites for Ontario, Quebec, CMQ, and CMO were calculated by combining the two most recent cycles of data available for a chemical (cycles 1 and 2, or cycles 2 and 3) from the first three cycles of the CHMS (2007-2013). Weighted one-way ANOVA was used to test the differences between regional estimates. After applying a Bonferonni-Holm adjustment for multiple comparisons, the following measures were significantly higher in Quebec as compared to Ontario and CMQ: blood lead, urinary lead and the urinary polyaromatic hydrocarbon (PAH) metabolites, 9-hydroxyfluorene, 1-hydroxyphenanthrene, 2- hydroxyphenanthrene and 3-hydroxyphenanthrene. In Quebec compared to CMQ only, urinary 2-hydroxfluorene, 3-hydroxyfluorene, 2-hydroxynaphthalene, and 4-hydroxyphenanthrene were higher. The concentration of urinary fluoride was significantly higher in Ontario as compared to Quebec and CMO. Blood manganese and urinary fluoride were significantly lower in Quebec compared to CMQ, and blood and urinary selenium were significantly lower in Ontario compared to CMO. Regional differences in tobacco use, age of dwellings and drinking water fluoridation are among the possible contributing factors to some of the observed differences. In conclusion, this is the first study where biomonitoring data from multiple cycles of CHMS were combined in order to generate robust estimates for subsets of the Canadian population. Such assessments can contribute to a regional-level prioritization of control measures to reduce the exposure of Canadians to chemicals in their environment.

Cumulative toll of exposure to stressors in Canadians: An allostatic load profile.

BACKGROUND: The cumulative toll of exposure to stressors (psychosocial, chemical, physical) can contribute to disease processes. The concept of allostatic load, essentially the cost of maintaining physiological stability in response to environmental demands, may be useful in assessing broad population health impacts of stressors beyond morbidity and mortality. In the present study, allostatic load scores were generated for Canadians and associations with age, sex, education and household income were examined. DATA AND METHODS: Data from cycles 1, 2, and 3 (2007 to 2013) of the Canadian Health Measures Survey (CHMS) were used to generate a composite index of cumulative health burden (allostatic load score) for adults aged 20 to 79 (n=8,678) based on risk thresholds for nine biological measures: diastolic blood pressure, systolic blood pressure, heart rate, high-density lipoprotein (HDL), total cholesterol, glycated hemoglobin (HBA1c), waist-to-hip ratio, C-reactive protein (CRP), and albumin. Logistic regression models that included age (continuous), sex, education and household income were fit to generate model-adjusted predicted allostatic load scores. RESULTS: The most prevalent individual risk factors were elevated waist-to-hip ratio, elevated CRP, total cholesterol, and low HDL. Allostatic load scores increased with age. Males generally exhibited higher scores than females. Lower educational attainment and lower household income were found to be significantly associated with higher allostatic load scores after taking account of the effects of age and sex. DISCUSSION: Age and socioeconomic gradients are associated with differences in allostatic load scores in the Canadian population. This composite measure of multisystem dysfunction, generated from a nationally representative survey that includes measurement of numerous health-relevant behaviours, biomarkers, and chemical levels, can be used in future to quantify sub-clinical impacts on health.