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Although rapid treatment improves outcomes for patients presenting with sepsis, early detection can be difficult, especially in otherwise healthy adults., Objectives: Using medico-legal data, we aimed to identify areas of focus to assist with early recognition of sepsis., Design Setting and Participants: Retrospective descriptive design. We analyzed closed medico-legal cases involving physicians from a national database repository at the Canadian Medical Protective Association. The study included cases closed between 2011 and 2020 that had documented peer expert criticism of a diagnostic issue related to sepsis or relevant infections., Main Outcomes and Measures: We used univariate statistics to describe patients and physicians and applied published frameworks to classify contributing factors (provider, team, system) and diagnostic pitfalls based on peer expert criticisms., Results: Of 162 involved patients, the median age was 53 years (interquartile range [IQR], 34-66 yr) and mortality was 49%. Of 218 implicated physicians, 169 (78%) were from family medicine, emergency medicine, or surgical specialties. Eighty patients (49%) made multiple visits to outpatient care leading up to sepsis recognition/hospitalization (median = two visits; IQR, 2-4). Almost 40% of patients were admitted to the ICU. Deficient assessments, such as failing to consider sepsis or not reassessing the patient prior to discharge, contributed to the majority of cases (81%)., Conclusions and Relevance: Sepsis continues to be a challenging diagnosis for clinicians. Multiple visits to outpatient care may be an early warning sign requiring vigilance in the patient assessment., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Medico-legal data show opportunities to improve safe medical care; little is published on the experience of physicians-in-training with medical malpractice. The purpose of this study was to examine closed civil legal cases involving physicians-in-training over time and provide novel insights on case and physicians characteristics., Methods: We conducted a retrospective descriptive study of closed civil legal cases at the Canadian Medical Protective Association (CMPA), a mutual medico-legal defence organization for more than 105 000 physicians, representing an estimated 95% of physicians in Canada. Eligible cases involved at least 1 physician-in-training and were closed between 1993 and 2017 (for time trends) or 2008 and 2017 (for descriptive analyses). We analyzed case rates over time using Poisson regression and the annualized change rate. Descriptive analyses addressed case duration, medico-legal outcome and patient harm. We explored physician specialties and practice characteristics in a subset of cases., Results: Over a 25-year period (1993-2017), 4921 physicians-in-training were named in 2951 closed civil legal cases, and case rates decreased significantly (β = -0.04, 95% confidence interval -0.05 to -0.03, where β was the 1-year difference in log case rates). The annualized change rate was -1.1% per year. Between 2008 and 2017, 1901 (4.1%) of 45 967 physicians-in-training were named in 1107 civil legal cases. Cases with physicians-in-training generally involved more severe patient harm than cases without physicians-in-training. In a subgroup with available information ( n = 951), surgical specialties were named most often ( n = 531, 55.8%)., Interpretation: The rate of civil legal cases involving physicians-in-training has diminished over time, but more recent cases featured severe patient harm and death. Efforts to promote patient safety may enhance medical care and reduce the frequency and severity of malpractice issues for physicians-in-training., Competing Interests: Competing interests: All authors except Taryn Taylor were employees of the Canadian Medical Protective Association (CMPA) during the preparation of this manuscript. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

Study Design: Retrospective descriptive study., Objective: The aim of this study was to describe closed medicolegal cases involving physicians and spine surgery in Canada from a trend and patient safety perspective., Summary of Background Data: Spine surgery is a source of medicolegal complaints against surgeons partly owing to the potential severity of associated complications. In previous medicolegal studies, researchers applied a medicolegal lens to their analyses without applying a quality improvement or patient safety lens., Methods: The study comprised a 15-year medicolegal trend analysis and a 5-year contributing factors analysis of cases (civil legal and regulatory authority matters) from the Canadian Medical Protective Association (CMPA), representing an estimated 95% of physicians in Canada. Included cases were closed by the CMPA between 2004 and 2018 (trends) or 2014 and 2018 (contributing factors). We fit a linear trend line to the annual rates of spine surgery cases per 1000 physician-years of CMPA membership for physicians in a neurosurgery or orthopedic surgery specialty. We then applied an ANOVA type III sum of squares test to determine the statistical significance of the annualized change rate over time. For the contributing factors analysis, we reported descriptive statistics for patient and physician characteristics, patient harm, and peer expert criticisms in each case., Results: Our trend analysis included 340 cases. Case rates decreased significantly at an annualized change rate of -4.7% (P  = 0.0017). Our contributing factors analysis included 81 civil legal and 19 regulatory authority cases. Most patients experienced health care-related harm (89/100, 89.0%). Peer experts identified intraoperative injuries (29/89, 32.6%), diagnostic errors (14/89, 15.7%), and wrong site surgeries (16/89, 18.0%) as the top patient safety indicators. The top factor contributing to medicolegal risk was physician clinical decision-making., Conclusion and Relevance: Although case rates decreased, patient harm was attributable to health care in the majority of recently closed cases. Therefore, crucial opportunities remain to enhance patient safety in spine surgery.Level of Evidence: 4., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Intraoperative injuries during abdominopelvic surgery can be associated with substantial patient harm. The objective of this study was to describe abdominopelvic intraoperative injuries and their contributing factors among medicolegal cases., Methods: This study was a descriptive analysis of medicolegal matters reported to a national body, with subgroup analyses by type of surgery. We reviewed medicolegal matters involving a population-based sample of physicians who were subject to a civil legal action or complaint to a regulatory authority that was closed between 2013 and 2017 in Canada., Results: Our analysis included 181 civil legal cases and 88 complaints to a regulatory authority. Among legal cases, 155 patients (85.6%) (median age 47 yr) underwent elective procedures. The most common injury site was the bowel (53 cases [29.3%]). Injuries frequently occurred during dissection (79 [43.6%]) and ligation (38 [21.0%]), were identified postoperatively (138 [76.2%]) and necessitated further surgery (139 [76.8%]). Many patients experienced severe harm (55 [30.4%]) or died (25 [13.8%]). Peer experts in nongynecologic cases were more likely than those in gynecologic cases to include criticisms of a provider in a harmful incident (79 [71.2%] v. 30 [42.9%], p < 0.01). Peer expert criticisms often related to clinical evaluation, decision-making and misidentification of anatomy. Criticisms of nontechnical skills identified documentation and communication deficiencies., Conclusion: This study confirms the importance of provider and team training to improve clinical evaluation and decision-making, documentation and communication. Effective protocols may help support clinicians in providing safer surgical care., Competing Interests: Kirsten Devenny, Diane Héroux, Cara Bowman, Heather Neilson, Richard Mimeault and Lisa Calder are employees of the Canadian Medical Protective Association. Sukhbir Singh reports grants and personal fees from AbbVie, Bayer and Allergan, outside the submitted work. No other competing interests were declared., (© 2021 Joule Inc. or its licensors.)

Background: Evidence-based campaigns are available to support appropriate diagnostic testing in cardiology, but medico-legal concerns can impede implementation., Methods: We conducted a retrospective descriptive analysis of medico-legal cases (civil legal, regulatory authority, hospital matters) involving cardiologists in Canada. For eligibility, cases must have closed at the Canadian Medical Protective Association between January 1, 2009 and December 31, 2018. We defined test underuse and overuse using criticisms in the medico-legal record from peer experts, regulatory authorities, or hospitals. We used a contributing factors framework and descriptive statistics for analysis., Results: From 2009 to 2018, the Canadian Medical Protective Association closed 60,598 cases with 368 (0.6%) involving a cardiologist. Within those cases, there was no criticism of cardiac diagnostic test overuse and 15 cases (4.1%) with criticism of underuse (tests not ordered, not expedited, delayed). In 12 of 15 cases of underuse (80.0%), the patient experienced severe harm or death. Of 8 civil legal cases, 6 were decided in favour of the plaintiff (75.0%) and 2 were dismissed by consent before proceeding to trial (25.0%). Decisions on regulatory authority matters did not favour the cardiologist (7 of 7 cases). In all cases of underuse, there was need for focused testing to investigate new or worsening symptoms. The most common contributing factors included clinical decision-making, situational awareness, and communication with teams and patients., Conclusions: Medico-legal cases involving cardiologists and the overuse or underuse of cardiac diagnostic tests were extremely rare in Canada, despite the potential for harm. The criticisms of cardiac diagnostic test underuse related to issues with diagnosing symptomatic patients., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

Surgical fires and unintended intraoperative burns cause serious patient harm, yet surveillance data are lacking in Canada. Medico-legal data provide unique descriptions of these events which can inform burn prevention strategies. We extracted 5 years of data on closed (2012-2016) medico-legal cases involving surgical fires and burns from the database of our organization which, in 2016, provided medico-legal support to >93,000 Canadian physicians. We performed a retrospective descriptive analysis of contributing factors using an in-house coding system and case reviews. We identified 53 eligible burn cases: 26 from thermal sources (49.1%), 16 from fires (30.2%), 5 from chemical sources (9.4%), and 6 from undetermined sources (11.3%). Common burn sources were electrosurgical equipment, lasers, lighting, and improper temperatures (causing thermal burns), cautery or lasers combined with supplemental oxygen and/or a flammable fuel source (causing fire), and improperly applied solutions including antiseptics (causing chemical burns). Nontechnical factors also contributed to patient outcomes, such as nonadherence to protocols (15 cases, 28.3%), failures in surgical team communication (3 cases, 5.7%), and lost situational awareness leading to delays in recognizing and treating burns (7 cases, 13.2%). This retrospective study highlights a need for improved surgical safety interventions to address surgical fires and burns. These interventions could include: effectively implemented surgical safety protocols, surgical team communication strategies, and raising awareness about preventing, diagnosing, and managing surgical burns., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Sedentary behavior, defined as lying or sitting, is a global health concern. As researchers continue to identify modern-day risk factors for sedentary behavior, few have explored the role of illicit drug use., Objective: To examine the association between leisure-time sedentary behavior and cannabis use, in adolescents and adults., Methods: We conducted a cross-sectional study relating cannabis use to total leisure-time sedentary behavior (hr/wk using the computer, playing video games, watching television or videos, and reading for leisure) using data from the 2011-2012 Canadian Community Health Survey (CCHS), a population-based survey of Canadians age ≥12 years. Analyses were possible for 48,240 respondents in Saskatchewan, Ontario, and Nunavut who reported on sedentary behavior. We used logistic regression modeling to relate frequency of cannabis use (never, occasional, heavy) to high-risk sedentary behavior (<35 versus ≥35 hr/wk) overall and stratified by sex, age, and rural location., Results: Approximately 80% of respondents were ≥25 years old. In the fully-adjusted model, the odds of ≥35 hr/wk of sedentary behavior were 80% higher for heavy cannabis users versus never users (OR = 1.8, 95% CI: 1.4-2.3); in occasional cannabis users, the odds were 30% higher (OR = 1.3, 95% CI: 1.1-1.5). In stratified analyses, odds ratios were statistically significant among adults age 25-44 years and people living in nonrural settings. Conclusions/Importance: Our findings support dual lifestyle interventions targeting heavy cannabis use and excessive sedentary behavior simultaneously. Moreover, leisure-time sedentary behavior should be considered as a covariate in future epidemiologic models relating cannabis to health.

Physical activity is emerging from epidemiologic research as a lifestyle factor that may improve survival from colorectal, breast, and prostate cancers. However, there is considerably less evidence relating physical activity to cancer recurrence and the biologic mechanisms underlying this association remain unclear. Cancer patients are surviving longer than ever before, and fear of cancer recurrence is an important concern. Herein, we provide an overview of the current epidemiologic evidence relating physical activity to cancer recurrence. We review the biologic mechanisms most commonly researched in the context of physical activity and cancer outcomes, and, using the example of colorectal cancer, we explore hypothesized mechanisms through which physical activity might intervene in the colorectal recurrence pathway. Our review highlights the importance of considering pre-diagnosis and post-diagnosis activity, as well as cancer stage and timing of recurrence, in epidemiologic studies. In addition, more epidemiologic research is needed with cancer recurrence as a consistently defined outcome studied separately from survival. Future mechanistic research using randomized controlled trials, specifically those demonstrating the exercise responsiveness of hypothesized mechanisms in early stages of carcinogenesis, are needed to inform recommendations about when to exercise and to anticipate additive or synergistic effects with other preventive behaviors or treatments.

Objective: To better understand the pathogenesis of inflammatory-related diseases after menopause, we studied the adiposity-independent association between endogenous sex hormones and C-reactive protein (CRP), a biomarker of inflammation., Methods: We conducted a secondary, cross-sectional analysis of baseline data from the Alberta Physical Activity and Breast Cancer Prevention Trial (2003-2007), including 319 healthy, postmenopausal women not using hormone therapy. Multivariable linear regression models related serum CRP levels to estrogens, androgens, and sex hormone-binding globulin (SHBG), all on the natural logarithmic scale. Models were adjusted for age, lipids, medication, and former menopausal hormone therapy use, and also for adiposity (body mass index [BMI], per cent body fat [via whole-body dual x-ray absorptiometry], or intra-abdominal fat area [via computed tomography])., Results: Without adiposity adjustment, estrone, total estradiol, and free estradiol were significantly positively associated with CRP, whereas SHBG was significantly inversely associated with CRP. Of all adiposity measures, adjustment for BMI caused the greatest attenuation of CRP-estrogen associations; only free estradiol (β = 0.24, 95% confidence interval [CI] 0.06, 0.43) and SHBG (β = -0.37, 95% CI -0.60, -0.13) associations remained significant. Inverse associations between CRP-total testosterone became stronger with BMI adjustment (β = -0.20, 95% CI -0.40, -0.01). Differential associations across categories of BMI, former hormone therapy use, and years since menopause were suggestive, but not statistically significant (Pheterogeneity > 0.05)., Conclusions: Prospective and systems epidemiological studies are needed to understand whether or not the cross-sectional associations we observed, independent of adiposity, between CRP-SHBG, CRP-total testosterone, and CRP-free estradiol, are causal.

Objective: Physical inactivity increases postmenopausal and possibly premenopausal breast cancer risk, although different biologic mechanisms are proposed. Our primary objective was to estimate breast cancer risk associated with high versus low levels of moderate-vigorous recreational activity, separately for premenopausal and postmenopausal women., Methods: We conducted a systematic review of literature published to July 2015. Included reports were cohort or case-control studies relating moderate-vigorous recreational physical activity (metabolic equivalent ≥3.0) to breast cancer incidence, exclusively (≥90%) in premenopausal or postmenopausal women. We appraised study quality and performed meta-analyses using random effects modeling. Subgroup meta-analyses were based on tumor subtype, race, body mass index, parity, hormone therapy use, family history of cancer, and statistical adjustment for body fatness. Dose-response relations were examined., Results: Pooled relative risks (RRs, 95% CI) for women with higher versus lower levels of moderate-vigorous recreational activity were RR = 0.80 (0.74-0.87) and RR = 0.79 (0.74-0.84) for premenopausal (43 studies) and postmenopausal (58 studies) breast cancer, respectively, with high heterogeneity. Inverse associations were weaker among postmenopausal cohort studies (RR = 0.90 [0.85-0.95]) and studies that statistically adjusted for nonrecreational (eg, occupational, household) activity (RR = 0.91 [0.77-1.06] premenopausal, RR = 0.96 [0.86-1.08] postmenopausal). Risk estimates with versus without body fatness adjustment did not vary by menopause status, although other subgroup effects were menopause-dependent. Among studies of overweight/obese women, there was an inverse association with postmenopausal but not premenopausal breast cancer (RR = 0.88 [0.82-0.95] and RR = 0.99 [0.98-1.00], respectively). Dose-response curves were generally nonlinear., Conclusions: Although risk estimates may be similar for premenopausal and postmenopausal breast cancer, subgroup effects may be menopause-dependent.

There is increasing interest in applying a precision medicine approach to understanding exercise as a potential treatment for cancer. We aimed to inform this new approach by appraising epidemiologic literature relating postdiagnosis physical activity to cancer outcomes overall and by molecular/genetic subgroups. Across 26 studies of breast, colorectal, and prostate cancer patients, a 37% reduction was seen in risk of cancer-specific mortality, comparing the most versus the least active patients (pooled relative risk = 0.63; 95% confidence interval: 0.54-0.73). Risks of recurrence or recurrence/cancer-specific death (combined outcome) were also reduced based on fewer studies. We identified ten studies of associations between physical activity and cancer outcomes by molecular or genetic markers. Two studies showed statistically significant risk reductions in breast cancer mortality/recurrence for the most (versus least) physically active estrogen receptor-positive/progesterone receptor-positive (ER + /PR + ) patients, while others showed risk reductions among ER - PR - and triple-negative patients. In colorectal cancer, four studies showed statistically significant risk reductions in cancer-specific mortality for patients with high (versus low) physical activity and P21 expression, P27 expression, nuclear CTNNB1 - , PTGS2 (COX-2) + , or IRS1 low/negative status. One prostate cancer study showed effect modification by Gleason score. As a means to enhance this evidence, future observational studies are needed that will measure physical activity objectively before and after diagnosis, use standardized definitions for outcomes, control for competing risks, assess nonlinear dose-response relations, and consider reverse causality. Ultimately, randomized controlled trials with clinical cancer outcomes and a correlative component will provide the best evidence of causality, relating exercise to cancer outcomes, overall and for molecular and genetic subgroups. Clin Cancer Res; 22(19); 4766-75. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Despite the high global prevalence of prostate cancer (PCa), few epidemiologic studies have assessed physical activity in relation to PCa survival., Objective: To evaluate different types, intensities, and timing of physical activity relative to PCa survival., Design, Setting, and Participants: A prospective study was conducted in Alberta, Canada, in a cohort of 830 stage II-IV incident PCa cases diagnosed between 1997 and 2000 with follow-up to 2014 (up to 17 yr). Prediagnosis lifetime activity was self-reported at diagnosis. Postdiagnosis activity was self-reported up to three times during follow-up., Outcome Measurements and Statistical Analysis: Cox proportional hazards models related physical activity to all-cause and PCa-specific deaths and to first recurrence/progression of PCa., Results and Limitations: A total of 458 deaths, 170 PCa-specific deaths, and, after first follow-up, 239 first recurrences/progressions occurred. Postdiagnosis total activity (>119 vs ≤42 metabolic equivalent [MET]-hours/week per year) was associated with a significantly lower all-cause mortality risk (hazard ratio [HR]: 0.58; 95% confidence interval [CI], 0.42-0.79; p value for trend <0.01). Postdiagnosis recreational activity (>26 vs ≤4 MET-hours/week per year) was associated with a significantly lower PCa-specific mortality risk (HR: 0.56; 95% CI, 0.35-0.90; p value for trend = 0.01). Sustained recreational activity before and after diagnosis (>18-20 vs <7-8 MET-hours/week per year) was associated with a lower risk of all-cause mortality (HR: 0.66; 95% CI, 0.49-0.88). Limitations included generalisability to healthier cases and an observational study design., Conclusions: These findings support emerging recommendations to increase physical activity after the diagnosis of PCa and would inform a future exercise intervention trial examining PCa outcomes., Patient Summary: In a 17-yr prostate cancer (PCa) survival study, men who survived at least 2 yr who were more physically active postdiagnosis or performed more recreational physical activity before and after diagnosis survived longer. Recreational physical activity after diagnosis was associated with a lower risk of PCa death., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Exercise dose comparison trials with biomarker outcomes can identify the amount of exercise required to reduce breast cancer risk and also strengthen the causal inference between physical activity and breast cancer. The Breast Cancer and Exercise Trial in Alberta (BETA) tested whether or not greater changes in estradiol (E2), estrone, and sex hormone-binding globulin (SHBG) concentrations can be achieved in postmenopausal women randomized to 12 months of HIGH (300 min/week) vs MODERATE (150 min/week) volumes of aerobic exercise. BETA included 400 inactive postmenopausal women aged 50-74 years with BMI of 22-40 kg/m(2). Blood was drawn at baseline and 6 and 12 months. Adiposity, physical fitness, diet, and total physical activity were assessed at baseline and 12 months. Intention-to-treat analyses were performed using linear mixed models. At full prescription, women exercised more in the HIGH vs MODERATE group (median min/week (quartiles 1,3): 253 (157 289) vs 137 (111 150); P<0.0001). Twelve-month changes in estrogens and SHBG were <10% on average for both groups. No group differences were found for E2, estrone, SHBG or free E2 changes (treatment effect ratios (95% CI) from linear mixed models: 1.00 (0.96-1.06), 1.02 (0.98-1.05), 0.99 (0.96-1.02), 1.01 (0.95, 1.06), respectively, representing the HIGH:MODERATE ratio of geometric mean biomarker levels over 12 months; n=382). In per-protocol analyses, borderline significantly greater decreases in total and free E2 occurred in the HIGH group. Overall, no dose effect was observed for women randomized to 300 vs 150 min/week of moderate to vigorous intensity exercise who actually performed a median of 253 vs 137 min/week. For total and free E2, the lack of differential effect may be due to modest adherence in the higher dose group., (© 2015 Society for Endocrinology.)

Importance: Body fat increases postmenopausal breast cancer risk. Physical activity may decrease risk through adiposity changes, but the optimal dose of activity is unknown., Objective: To compare the effects of 300 vs 150 min/wk of moderate to vigorous aerobic exercise on body fat in postmenopausal women., Design, Setting, and Participants: The Breast Cancer and Exercise Trial in Alberta was a 12-month, 2-armed, 2-center randomized dose-comparison trial conducted from June 2010 through June 2013. Participants were 400 inactive postmenopausal women with body mass index 22 to 40, disease-free, nonsmokers, and nonusers of exogenous hormones., Interventions: Five d/wk of aerobic exercise (3 d/wk supervised, 2 d/wk unsupervised) for 30 min/session (moderate-volume) or 60 min/session (high volume) achieving 65% to 75% of heart rate reserve for at least 50% of each session. Participants were asked not to change usual diet., Main Outcomes and Measures: Total body fat, measured from dual energy x-ray absorptiometry scans, was the primary outcome. Other measures included subcutaneous and intra-abdominal fat from computed tomography scans, weight, and waist and hip circumferences., Results: Of 400 women, 384 provided baseline and follow-up adiposity measurements. Median (interquartile range) adherence at full prescription for the high- and moderate-volume groups was 254 (166-290) and 137 (111-150) min/wk, respectively. Mean reductions in total fat were significantly larger in the high- vs moderate-volume group (least-squares mean difference, -1.0% [95% CI, -1.6% to -0.4%], P = .002). Subcutaneous abdominal fat and waist to hip ratio decreased significantly more in the high-volume group (least-squares mean difference, -10.8 [95% CI, -19.5 to -2.2] cm², P = .01, and -0.01 [95% CI, -0.02 to 0.00], P = .04, respectively). Changes in weight and intra-abdominal fat were not significantly different between groups (least-squares mean difference, -0.7 [95% CI, -1.6 to 0.2] kg, P = .11, and -1.5 [95% CI, -5.9 to 2.9] cm², P = .50, respectively). Some dose-response effects were stronger for obese women., Conclusions and Relevance: In previously inactive postmenopausal women, a 1-year prescription of moderate to vigorous exercise for 300 min/wk was superior to 150 min/wk for reducing total fat and other adiposity measures, especially in obese women. These results suggest additional benefit of higher-volume aerobic exercise for adiposity outcomes and possibly a lower risk of postmenopausal breast cancer., Trial Registration: clinicaltrials.gov: NCT01435005.

Background: Exercise has favorable effects on biomarkers associated with a lower risk of breast cancer, however it is unclear if higher doses of exercise provide additional effects. No clinical trial has systematically examined how different exercise volumes influence the mechanisms underlying breast cancer etiology. The Breast Cancer and Exercise Trial in Alberta (BETA) - a follow-up study to the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial - is examining how a one-year, high versus moderate volume aerobic exercise intervention influences several biomechanisms hypothesized to influence breast cancer risk in a group of postmenopausal women. Secondary aims are to compare intervention effects on psychosocial and quality of life outcomes as well as understand exercise adherence at 12 and 24 months, and maintenance of all study outcomes at 24 months., Methods/design: The BETA Trial is a two-center, two-armed randomized controlled exercise intervention trial conducted in 400 previously inactive, postmenopausal women aged 50-74 years, in Alberta, Canada. Participants were randomly assigned to a one-year aerobic exercise intervention of either high volume (300 minutes/week) or moderate volume (150 minutes/week). Blood draws and accelerometry were performed at baseline, six and 12 months. Baseline and 12-month measurements were taken of adiposity (including dual energy X-ray absorptiometry and computed tomography scans), physical fitness, dietary intake, self-reported physical activity and sedentary behavior, quality of life, perceived stress, happiness, sleep, and determinants of exercise adherence. Exercise maintenance was assessed and all study measurements were repeated at 24 months. Blood will be analyzed for endogenous estrogens, insulin resistance indicators, and inflammatory markers., Discussion: The BETA Trial will compare the impact of a high versus moderate volume of aerobic exercise on a variety of biological, physiological, and psychological outcomes of relevance to postmenopausal women. A tightly controlled exercise intervention and objective outcome measurements are methodological strengths. The BETA Trial will inform future prevention initiatives by assessing adherence to a high volume of exercise over 12 months by postmenopausal women, and the ability of these women to maintain activity over the longer-term. The ultimate objective is to inform public health guidelines for reducing breast cancer risk through physical activity., Clinical Trials Registration Number: NCT01435005.

We determined measurement properties of the Sedentary Time and Activity Reporting Questionnaire (STAR-Q), which was designed to estimate past-month activity energy expenditure (AEE). STAR-Q validity and reliability were assessed in 102 adults in Alberta, Canada (2009-2011), who completed 14-day doubly labeled water (DLW) protocols, 7-day activity diaries on day 15, and the STAR-Q on day 14 and again at 3 and 6 months. Three-month reliability was substantial for total energy expenditure (TEE) and AEE (intraclass correlation coefficients of 0.84 and 0.73, respectively), while 6-month reliability was moderate. STAR-Q-derived TEE and AEE were moderately correlated with DLW estimates (Spearman's ρs of 0.53 and 0.40, respectively; P < 0.001), and on average, the STAR-Q overestimated TEE and AEE (median differences were 367 kcal/day and 293 kcal/day, respectively). Body mass index-, age-, sex-, and season-adjusted concordance correlation coefficients (CCCs) were 0.24 (95% confidence interval (CI): 0.07, 0.36) and 0.21 (95% CI: 0.11, 0.32) for STAR-Q-derived versus DLW-derived TEE and AEE, respectively. Agreement between the diaries and STAR-Q (metabolic equivalent-hours/day) was strongest for occupational sedentary time (adjusted CCC = 0.76, 95% CI: 0.64, 0.85) and overall strenuous activity (adjusted CCC = 0.64, 95% CI: 0.49, 0.76). The STAR-Q demonstrated substantial validity for estimating occupational sedentary time and strenuous activity and fair validity for ranking individuals by AEE., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess the inter-method reliability of the Ovarian Cancer in Alberta (OVAL) survey developed to estimate adult vitamin D exposure from sun and diet for every tenth year, against the longer Geraldton Skin Cancer Prevention Survey (the assumed 'gold standard'). We also estimated total vitamin D exposure using the OVAL survey., Design: A randomized crossover design to assess the inter-method reliability of sun exposure (OVAL v. Geraldton survey), using intra-class correlation and estimated total vitamin D exposure from sun and diet., Setting: Calgary, Alberta, Canada., Subjects: Randomly selected women (n 90) aged 40-79 years., Results: The average lifetime sun exposure of 13,913 h (average 411 h/year) from the Geraldton survey was not significantly different from the 13,034 h (average 385 h/year) from the OVAL survey for periods with sufficient UV radiation to stimulate vitamin D production. The intra-class correlation coefficient for average lifetime sun exposure was 0.77 (95% CI 0.69, 0.86); the annual average was 0.60 (95% CI 0.47, 0.74). Estimated vitamin D from diet and supplements increased with age., Conclusions: Our OVAL survey reliably estimated adult sun exposure relative to the Geraldton survey, suggesting that assessing sun exposure every tenth year is a reliable and efficient method for estimating sun contributions to lifetime vitamin D exposure.

Purpose: Alcohol consumption is hypothesized to increase the risk of endometrial cancer by increasing circulating estrogen levels. This study sought to investigate the association between lifetime alcohol consumption and endometrial cancer risk., Methods: We recruited 514 incident endometrial cancer cases and 962 frequency age-matched controls in this population-based case-control study in Alberta, Canada, from 2002 to 2006. Participants completed in-person interviews querying lifetime alcohol consumption and other relevant health and lifestyle factors. Participants reported the usual number of drinks of beer, wine, and liquor consumed; this information was compiled for each drinking pattern reported over the lifetime to estimate average lifetime exposure to alcohol., Results: Lifetime average alcohol consumption was relatively low (median intake: 3.9 g/day for cases, 4.9 g/day for controls). Compared with lifetime abstainers, women consuming >2.68 and ≤8.04 g/day alcohol and >8.04 g/day alcohol on average over the lifetime showed 38 and 35 % lower risks of endometrial cancer, respectively (p trend = 0.023). In addition, average lifetime consumption of all types of alcohol was associated with decreased risks. There was no evidence for effect modification by body mass index, physical activity, menopausal status, and hormone replacement therapy use combined and effects did not differ by type of endometrial cancer (type I or II)., Conclusion: This study provides epidemiologic evidence for an inverse association between relatively modest lifetime average alcohol consumption (approximately 1/4 to 1/2 drink/day) and endometrial cancer risk. The direction of this relation is consistent with previous studies that examined similar levels of alcohol intake.

Purpose: The qualitative attributes and quantitative measurement properties of physical activity questionnaires are equally important considerations in questionnaire appraisal, yet fundamental aspects such as question comprehension are not often described in the literature. Here we describe the use of cognitive interviewing to evaluate the Sedentary Time and Activity Reporting Questionnaire (STAR-Q), a self-administered questionnaire designed to assess overall activity energy expenditure and sedentary behavior., Methods: Several rounds of one-on-one interviews were conducted by an interviewer trained in qualitative research methods. Interviewees included a convenience sample of volunteers and participants in the Tomorrow Project, a large cohort study in Alberta, Canada. Following each round of interviews the STAR-Q was revised and cognitively tested until saturation was achieved., Results: Six rounds of cognitive interviewing in 22 adults (5 males, 17 females) age 23-74 years, led to revisions involving 1) use of recall aids; 2) ambiguous terms; and 3) specific tasks, such as averaging across multiple routines, reporting time asleep and self-care, and reporting by activity domain., Conclusions: Cognitive interviewing is a critical step in questionnaire development. Knowledge gained in this study led to revisions that improved respondent acceptability and comprehension of the STAR-Q and will complement ongoing validity testing.

Chronic low-grade inflammation is a possible risk factor for cancer that may be modifiable with long-term exercise. Very few randomized controlled trials (RCT) have studied the isolated effects of exercise on low-grade inflammation exclusively in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial, a 2-armed RCT in healthy postmenopausal women, examined how 1 year of moderate to vigorous aerobic exercise, compared with usual inactivity, influenced circulating inflammatory markers. Baseline, 6-month, and 12-month serum was analyzed by direct chemiluminescent immunoassays to measure high sensitivity C-reactive protein (CRP) and ELISAs to measure interleukin 6 (IL-6) and TNF-α. Intention to treat analyses were conducted with linear mixed models. Statistically significant differences in CRP were observed over 12 months for exercisers versus controls (treatment effect ratio = 0.87, 95% CI = 0.79-0.96, P = 0.005), but not in IL-6 or TNF-α. A statistically significant trend (P(trend) = 0.021) of decreasing CRP with increasing exercise adherence and stronger intervention effects on CRP in women with higher baseline physical fitness (P(heterogeneity) = 0.040) was found. The intervention effect on CRP became statistically nonsignificant with adjustment for dietary fiber intake change and seemed to be mediated by fat loss. Low-grade inflammation may be lowered with exercise, but confounding by dietary intake occurred and should be considered in future studies. Further trials are needed to corroborate our findings about the optimal dose of exercise required to lower CRP levels and effect modification of CRP changes by levels of body fatness and fitness., (©2011 AACR.)

Objective: To identify factors that mediate or moderate the effects of exercise on postmenopausal sex hormone concentrations., Methods: Postmenopausal women were randomized to 12 months of aerobic exercise for 200 min/week (n = 160) or to a control group (n = 160). Intention-to-treat analyses were performed using general linear models with sex hormone concentrations at 6 and 12 months as the outcome. Mediation by adiposity and insulin was investigated by examining changes in effect estimates after adjustment for changes in these factors over 12 months. Moderation was studied as the interaction between group assignment and eight baseline characteristics., Results: Intervention effects on sex hormone-binding globulin (SHBG) and estradiol changes were attenuated with adjustment for change in overall body fat, while there was less attenuation adjusting for intra-abdominal fat change. Intervention effects on SHBG levels were unaffected by adjustment for insulin change. Significant interactions were identified between treatment and physical fitness (for SHBG and testosterone) and age (for testosterone), implying subgroup differences in intervention effect., Conclusions: Our data suggest that overall fat loss partially mediated exercise-induced changes in estradiol and SHBG concentrations. No previous RCT in postmenopausal women has studied moderators of exercise-induced sex hormone changes; therefore, future studies are needed to corroborate our results.

Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood. Metabolic factors may be involved. In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women. A year-long aerobic exercise intervention of 225  min/week (n=160) was compared with a control group asked to maintain usual activity levels (n=160). Baseline, 6- and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated. Intention-to-treat analyses were performed using linear mixed models. The treatment effect ratio (TER) of exercisers to controls was calculated. Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months. Across the study period, statistically significant reductions in insulin (TER=0.87, 95% confidence interval (95% CI)=0.81-0.93), HOMA-IR (TER=0.86, 95% CI=0.80-0.93), and leptin (TER=0.82, 95% CI=0.78-0.87), and an increase in the adiponectin/leptin ratio (TER=1.21, 95% CI=1.13-1.28) were observed in the exercise group compared with the control group. No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio. Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer.

Breast cancer is the most commonly diagnosed invasive malignancy and the second leading cause of cancer death in women. This chapter considers epidemiologic evidence regarding the association between physical activity and breast cancer risk from 73 studies conducted around the world. Across these studies there was a 25% average risk reduction amongst physically active women as compared to the least active women. The associations were strongest for recreational activity, for activity sustained over the lifetime or done after menopause, and for activity that is of moderate to vigorous intensity and performed regularly. There is also some evidence for a stronger effect of physical activity amongst postmenopausal women, women who are normal weight, have no family history of breast cancer, and are parous. It is likely that physical activity is associated with decreased breast cancer risk via multiple interrelated biologic pathways that may involve adiposity, sex hormones, insulin resistance, adipokines, and chronic inflammation. Future research should include prospective observational epidemiologic studies relating proposed biomarkers to breast cancer risk and also randomized controlled trials to examine how physical activity influences the proposed biomarkers. Exercise trials will provide more clarity regarding the appropriate type, dose, and timing of activity that relate to breast cancer risk reduction.

Background: Physical activity is a modifiable lifestyle risk factor that has the potential to reduce the risk of most major cancer sites., Methods: We examined the strength, consistency, dose-response and biological plausibility of an association between physical activity and risk of colon, breast, endometrium, lung, prostate, ovarian, gastric, rectal, pancreatic, bladder, testicular, kidney and haematological cancers. We also estimated the population-attributable risk (PAR) for physical inactivity and cancer in 15 European countries., Results: There is convincing or probable evidence for a beneficial effect of physical activity on the risk of colon, breast and endometrial cancers. The evidence is weaker for ovarian, lung and prostate cancers and generally either null or insufficient for all remaining cancers. Several hypothesised biological mechanisms include a likely effect of physical activity on insulin resistance, body composition, sex steroid hormones and a possible effect on vitamin D, adipokines, inflammation and immune function. Somewhere between 165,000 and 330,000 cases of the six major cancers (breast, colon, lung, prostate, endometrium and ovarian) could have been prevented in 2008 in Europe alone if the population had maintained sufficient levels of physical activity., Conclusion: There is strong and consistent evidence that physical activity reduces the risk of several of the major cancer sites, and that between 9% and 19% of cancer cases could be attributed to lack of sufficient physical activity in Europe. Public health recommendations for physical activity and cancer prevention generally suggest 30-60 min of moderate or vigorous-intensity activity done at least 5d per week., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: We assessed the evidence supporting a reduction in risk for ovarian cancer occurrence or mortality with greater vitamin D exposures., Study Design: This review followed standard guidelines for systematic literature reviews. The diverse study designs precluded a quantitative metaanalysis. Therefore studies are summarized via tables and abstracted information., Results: Approximately half of the ecologic and case-control studies reported reductions in incidence or mortality with increasing geographic latitude, solar radiation levels, or dietary/supplement consumption of vitamin D, whereas the other half reported null associations. The cohort studies reported no overall risk reduction with increasing dietary/supplement consumption of vitamin D or with plasma levels of vitamin D prior to diagnosis, although vitamin D intakes were relatively low in all studies., Conclusion: There is no consistent or strong evidence to support the claim made in numerous review articles that vitamin D exposures reduce the risk for ovarian cancer occurrence or mortality., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Convincing evidence now supports a probable preventive role for physical activity in postmenopausal breast cancer. The mechanisms by which long-term physical activity affect risk, however, remain unclear. The aims of this review were to propose a biological model whereby long-term physical activity lowers postmenopausal breast cancer risk and to highlight gaps in the epidemiologic literature. To address the second aim, we summarized epidemiologic literature on 10 proposed biomarkers, namely, body mass index (BMI), estrogens, androgens, sex hormone binding globulin, leptin, adiponectin, markers of insulin resistance, tumor necrosis factor-alpha, interleukin-6, and C-reactive protein, in relation to postmenopausal breast cancer risk and physical activity, respectively. Associations were deemed "convincing," "probable," "possible," or "hypothesized" using set criteria. Our proposed biological model illustrated the co-occurrence of overweight/obesity, insulin resistance, and chronic inflammation influencing cancer risk through interrelated mechanisms. The most convincing epidemiologic evidence supported associations between postmenopausal breast cancer risk and BMI, estrogens, and androgens, respectively. In relation to physical activity, associations were most convincing for BMI, estrone, insulin resistance, and C-reactive protein. Only BMI and estrone were convincingly (or probably) associated with both postmenopausal breast cancer risk and physical activity. There is a need for prospective cohort studies relating the proposed biomarkers to cancer risk and for long-term exercise randomized controlled trials comparing biomarker changes over time, specifically in postmenopausal women. Future etiologic studies should consider interactions among biomarkers, whereas exercise trials should explore exercise effects independently of weight loss, different exercise prescriptions, and effects on central adiposity.

Activity energy expenditure (AEE) is the modifiable component of total energy expenditure (TEE) derived from all activities, both volitional and nonvolitional. Because AEE may affect health, there is interest in its estimation in free-living people. Physical activity questionnaires (PAQs) could be a feasible approach to AEE estimation in large populations, but it is unclear whether or not any PAQ is valid for this purpose. Our aim was to explore the validity of existing PAQs for estimating usual AEE in adults, using doubly labeled water (DLW) as a criterion measure. We reviewed 20 publications that described PAQ-to-DLW comparisons, summarized study design factors, and appraised criterion validity using mean differences (AEE(PAQ) - AEE(DLW), or TEE(PAQ) - TEE(DLW)), 95% limits of agreement, and correlation coefficients (AEE(PAQ) versus AEE(DLW) or TEE(PAQ) versus TEE(DLW)). Only 2 of 23 PAQs assessed most types of activity over the past year and indicated acceptable criterion validity, with mean differences (TEE(PAQ) - TEE(DLW)) of 10% and 2% and correlation coefficients of 0.62 and 0.63, respectively. At the group level, neither overreporting nor underreporting was more prevalent across studies. We speculate that, aside from reporting error, discrepancies between PAQ and DLW estimates may be partly attributable to 1) PAQs not including key activities related to AEE, 2) PAQs and DLW ascertaining different time periods, or 3) inaccurate assignment of metabolic equivalents to self-reported activities. Small sample sizes, use of correlation coefficients, and limited information on individual validity were problematic. Future research should address these issues to clarify the true validity of PAQs for estimating AEE.

This study aimed to identify personal factors associated with expert and respondent agreement on past occupational exposure. Epidemiologic data was collected from 1995 to 1998 in a community-based, case-control study of prostate cancer. Using longest jobs and excluding agreement on "never" exposure, self-reported and expert estimates of ever/ never exposure, by skin or ingestion, to polycyclic aromatic hydrocarbons were compared. Agreement between respondents and the expert was 53.9 percent (N=1,038), with overreporting being more common than underreporting relative to the expert (31.8 percent versus 14.4 percent). In multiple logistic regression models, white-collar occupational status was significantly associated with overreporting (odds ratio [OR] = 0.142; 95 percent confidence interval [CI]: 0.095-0.211; blue-collar versus white-collar), while age was associated with underreporting (OR=1.077; 95 percent CI: 1.043-1.112; one-year increase). Neither job satisfaction nor risk perception appeared to confound other associations. In future studies, overreporting by white-collar workers might be avoided by providing clearer definitions of exposure, whereas elderly respondents may require aids to enhance exposure recall.

The authors determined the validity and reliability of their Past Year Total Physical Activity Questionnaire (PYTPAQ), which assesses the frequency, duration, and intensity of occupational, household, and recreational activities performed over the past year. The PYTPAQ was completed twice at baseline, 9 weeks apart (on average), by 154 healthy Canadian men and women aged 35-65 years for assessment of reliability. The PYTPAQ was completed again 1 year later as a self-administered questionnaire. Four times during the year, participants wore an accelerometer for 7 days and completed 7-day physical activity logs. The authors assessed validity by comparing PYTPAQ summary values with 1-year averages of the physical activity logs and accelerometer data and with physical fitness and anthropometric data measured at baseline and 1 year. Spearman correlations for reliability (metabolic equivalent-hours/week) were 0.64 for total activity, 0.70 for occupational activity, 0.73 for recreational activity, and 0.65 for household activity. For total activity, the intraclass correlation coefficient for correlation between the PYTPAQ and the 7-day physical activity logs was 0.42 (95% confidence interval: 0.28, 0.54), and for the accelerometer data it was 0.18 (95% confidence interval: 0.03, 0.32). Spearman correlations between PYTPAQ hours/week of vigorous activity and maximal oxygen uptake were 0.37 and 0.32 at baseline and follow-up, respectively. In general, the PYTPAQ has acceptable reliability and validity for measurement of past-year physical activity that is comparable to that of similar questionnaires.

Objectives: To determine the cytotoxicity of valproic acid (VPA) and its metabolite, 4-ene-valproic acid (4-ene-VPA) in human hepatoblastoma cells (Hep G2), and to study the modulatory effect of cytochrome P450 2E1 induction in this model., Methods: Cells were exposed to VPA or 4-ene-VPA in the presence of either ethanol (EtOH), or EtOH combined with disulphiram (DS). Some cells were exposed to alpha-fluoro-VPA or to alpha-fluoro-4-ene-VPA in the absence of CYP2E1 inducers. Apoptosis and necrosis were measured by analyzing 6000 cells per sample using transmission electron microscopy, while cytokine release and apoptosis were quantitated by ELISA., Results: VPA + EtOH increased VPA cytotoxicity. 4-ene-VPA + EtOH significantly increased toxicity, while DS + EtOH significantly reduced this toxicity. Alpha-fluorinated analogues reduced cytotoxicity compared to the corresponding VPA compounds. Neither VPA nor alpha-fluorinated VPA increased the release of IL-6 or TNF-alpha in media. A significant increase in the release of TNF-alpha was observed in cells exposed to 4-ene-VPA that further increased with EtOH exposure., Conclusions: Cells exposed to 4-ene-VPA experience greater cytotoxicity than those treated with VPA. Cytochrome P450 2E1 inducers enhance toxicity in VPA-exposed cells, while alpha-fluorination of VPA diminishes cytotoxicity by directly interfering with the beta-oxidation of the 4-ene-VPA metabolite.