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OBJECTIVE Reports of amputations associated with sodium–glucose cotransporter 2 (SGLT2) inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This multicenter observational study used administrative health care databases from seven Canadian provinces and the U.K. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new-user design and time-conditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% CIs of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results. RESULTS The study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow-up time of 11 months, the amputation rate was 1.3 per 1,000 person-years among SGLT2 inhibitor users and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use was 0.88 (95% CI 0.71–1.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule. CONCLUSIONS In this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes compared with DPP-4 inhibitor use. While these findings provide some reassurance, studies with a longer duration of follow-up are needed to assess potential long-term effects.

Background Cardiovascular death is a common outcome in population-based studies about new healthcare interventions or treatments, such as new prescription medications. Vital statistics registration systems are often the preferred source of information about cause-specific mortality because they capture verified information about the deceased, but they may not always be accessible for linkage with other sources of population-based data. We assessed the validity of an algorithm applied to administrative health records for identifying cardiovascular deaths in population-based data. Methods Administrative health records were from an existing multi-database cohort study about sodium-glucose cotransporter-2 (SGLT2) inhibitors, a new class of antidiabetic medications. Data were from 2013 to 2018 for five Canadian provinces (Alberta, British Columbia, Manitoba, Ontario, Quebec) and the United Kingdom (UK) Clinical Practice Research Datalink (CPRD). The cardiovascular mortality algorithm was based on in-hospital cardiovascular deaths identified from diagnosis codes and select out-of-hospital deaths. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for the cardiovascular mortality algorithm using vital statistics registrations as the reference standard. Overall and stratified estimates and 95% confidence intervals (CIs) were computed; the latter were produced by site, location of death, sex, and age. Results The cohort included 20,607 individuals (58.3% male; 77.2% ≥70 years). When compared to vital statistics registrations, the cardiovascular mortality algorithm had overall sensitivity of 64.8% (95% CI 63.6, 66.0); site-specific estimates ranged from 54.8 to 87.3%. Overall specificity was 74.9% (95% CI 74.1, 75.6) and overall PPV was 54.5% (95% CI 53.7, 55.3), while site-specific PPV ranged from 33.9 to 72.8%. The cardiovascular mortality algorithm had sensitivity of 57.1% (95% CI 55.4, 58.8) for in-hospital deaths and 72.3% (95% CI 70.8, 73.9) for out-of-hospital deaths; specificity was 88.8% (95% CI 88.1, 89.5) for in-hospital deaths and 58.5% (95% CI 57.3, 59.7) for out-of-hospital deaths. Conclusions A cardiovascular mortality algorithm applied to administrative health records had moderate validity when compared to vital statistics data. Substantial variation existed across study sites representing different geographic locations and two healthcare systems. These variations may reflect different diagnostic coding practices and healthcare utilization patterns.

Objective: Reports of amputations associated with sodium glucose co-transporter (SGLT) 2 inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase (DPP)-4 inhibitors among patients with type 2 diabetes. Research Design and Methods: This is a multicenter observational study using administrative healthcare databases from 7 Canadian provinces and the United Kingdom. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new user design and time-conditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CI) of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results. Results: The study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow up time of 11 months, the amputation rate among SGLT2 inhibitor users was 1.3 per 1,000 person-years and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared to DPP-4 inhibitor use was 0.88 (95% CI: 0.71-1.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule. Conclusions: In this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes, compared to DPP-4 inhibitor use. While these findings provide some reassurance, studies with longer duration of follow-up are needed to assess potential long-term effects.

ObjectiveIn mammography screening, interval cancers present a problem. The metric ‘screening sensitivity’ monitors both how well a programme detects cancers and avoids interval cancers. To our knowledge, the effect of breast cancer surrogate molecular subtypes on screening sensitivity has never been evaluated. We aimed to measure the 2-year screening sensitivity according to breast cancer subtypes.MethodsWe studied 734 women with an invasive breast cancer diagnosed between 2003 and 2007 after participating in one regional division of Quebec’s Mammography Screening Program. They represented 83% of all participating women with an invasive BC diagnosis in that region for that period. Tumours were categorized into ‘luminal A-like’, ‘luminal B-like’, ‘triple-negative’ and ‘HER2-positive’ subtypes. We used logistic regression and marginal standardization to estimate screening sensitivity, sensitivity ratios (SR) and sensitivity differences. We also assessed the mediating effect of grade.ResultsAdjusted 2-year screening sensitivity was 75.4% in luminal A-like, 66.1% in luminal B-like, 52.9% in triple-negative and 45.3% in HER2-positive, translating into sensitivity ratios of 0.88 (95% confidence interval [CI] = 0.78–0.98) for luminal B-like, 0.70 (CI = 0.56–0.88) for triple-negative and 0.60 (CI = 0.39–0.93) for HER2-positive, when compared with luminal A-like. Grade entirely mediated the subtype-sensitivity association for triple negative and mediated it partly for HER2-positive. Screening round (prevalent vs. incident) did not modify results.ConclusionThere was substantial variation in screening sensitivity according to breast cancer subtypes. Aggressive phenotypes showed the lowest sensitivity, an effect that was mediated by grade. Tailoring screening according to women’s subtype risk factors might eventually lead to more efficient programs.

Purpose The study sought to examine the association between clinical image quality of mammograms and screening sensitivity. Methods Four radiologists evaluated the clinical image quality of 374 invasive screen-detected cancers and 356 invasive interval breast cancers for which quality evaluation of screening mammograms could be assessed from cancers diagnosed among participants in the Quebec Breast Cancer Screening Program in 2007. Quality evaluation was based on the Canadian Association of Radiologists accreditation criteria, which are similar to those of the American College of Radiology. The association between clinical quality and screening sensitivity was assessed by logistic regression. Adjusted sensitivity and adjusted sensitivity ratios were obtained through marginal standardization. No institutional review board approval was required. Results A proportion of 28% (206 of 730) of screening mammograms had lower overall quality for the majority of assessments. Positioning was the quality attribute that was the most frequently deficient. The 2-year screening sensitivity reached 68%. Sensitivity of screening was not statistically associated with the overall quality (ratio of 2-year sensitivity = 1.03; 95% confidence interval: 0.93-1.15) or with any quality attributes (positioning, exposure, compression, sharpness, artifacts, contrast). Results were similar for the 1-year sensitivity. Conclusions Although not all mammograms in the Quebec screening program met the optimum quality required by the Canadian Association of Radiologists or American College of Radiology accreditation, the screening mammograms produced in this population-based organized screening program reached a high enough level of quality so that the remaining variation in quality is too little to impair screening sensitivity.

Background There is no recent systematic review on the risk of cross-reactivity to cephalosporins and carbapenems in penicillin-allergic patients despite many new studies on the subject. All past reviews have several limitations such as not including any patient with a T-cell–mediated penicillin allergy. Objectives To determine the risk of cross-reactivity to cephalosporins and carbapenems in patients with a proven IgE- or T-cell–mediated penicillin allergy. To measure the association between R1 side chain similarity on cephalosporins and penicillins and the risk of cross-reactivity. Methods MEDLINE and EMBASE were searched from January 1980 to March 2019. Studies had to include at least 10 penicillin-allergic subjects whose allergy had been confirmed by a positive skin test (ST) or drug provocation test (DPT) result. Cross-reactivity had to be assessed to at least 1 cephalosporin or carbapenem through ST or DPT. Both random-effects and fixed-effect models were used to combine data. A bioinformatic model was used to quantify the similarity between R1 side chains. Results Twenty-one observational studies on cephalosporin cross-reactivity involving 1269 penicillin-allergic patients showed that the risk of cross-reactivity varied with the degree of similarity between R1 side chains: 16.45% (95% CI, 11.07-23.75) for aminocephalosporins, which share an identical side chain with a penicillin (similarity score = 1), 5.60% (95% CI, 3.46-8.95) for a few cephalosporins with an intermediate similarity score (range, 0.563-0.714), and 2.11% (95% CI, 0.98-4.46) for all those with low similarity scores (below 0.4), irrespective of cephalosporin generation. The higher risk associated with aminocephalosporins was observed whether penicillin allergy was IgE- or T-cell–mediated. Eleven observational studies on carbapenem cross-reactivity involving 1127 penicillin-allergic patients showed that the risk of cross-reactivity to any carbapenem was 0.87% (95% CI, 0.32-2.32). Conclusions Although it remains possible that these meta-analyses overestimated the risk of cross-reactivity, clinicians should consider the increased risk of cross-reactivity associated with aminocephalosporins, and to a lesser extent with intermediate-similarity-score cephalosporins, compared with the very low risk associated with low-similarity-score cephalosporins and all carbapenems when using beta-lactams in patients with a suspected or proven penicillin allergy.

Supplemental material, Supplemental Material2 for Breast cancer subtype and screening sensitivity in the Quebec Mammography Screening Program by Linda Perron, Sue-Ling Chang, Jean-Marc Daigle, Nathalie Vandal, Isabelle Theberge, Caroline Diorio, Julie Lemieux, Eric Pelletier and Jacques Brisson in Journal of Medical Screening

IntroductionOpioids are being used increasingly to treat chronic noncancer pain despite the uncertainty regarding its long-term benefits. This study served to determine if problems are associated with opioid use in Québec for new users from 2006 to 2013 without history of cancer.MethodsA retrospective longitudinal cohort study was conducted using administrative databases stored at the Régie de l'assurance maladie du Québec (RAMQ) to describe the annual proportion of new users to whom at least one of the five indicators of potentially inappropriate opioid use applied was estimated. These indicators are (i) overlapping opioid prescriptions, (ii) overlapping opioid and benzodiazepine prescriptions, (iii) the use of long-acting opioids at the start of treatment, (iv) a high mean daily dose, and (v) a rapid increase in the opioid dose.ResultsThe annual proportion of new users to whom at least one of the five indicators of potentially inappropriate opioid use applied decreased from 15.4 percent in 2006 to 12.3 percent in 2013. It was mainly the following three indicators that contributed the most to these proportions in 2013: (i) overlapping opioid prescriptions (5.8 percent), (ii) overlapping opioid and benzodiazepine prescriptions (8.2 percent), and (iii) the use of long-acting opioids at the start of treatment (1.8 percent).ConclusionsThe vast majority of new users with no history of diagnosed cancer used opioids adequately according to the five indicators of potentially inappropriate opioid use applied. Improvement could still be made to decrease mainly overlapping opioid prescriptions and overlapping opioid and benzodiazepine prescriptions.

IntroductionBeta-lactams (BLs), especially penicillins, are the most commonly used antibiotics, particularly in primary care, and one of the most reported drug allergies. Fearing cross-reactivity, clinicians refrain from prescribing another BL (e.g., cephalosporin or carbapenem) to penicillin-allergic patients. This can have significant consequences for the patients and the health-care system (e.g., exposure to broad-spectrum antibiotics, increased risk adverse effects, and increased healthcare costs).MethodsTo assess the absolute cross-reactivity risk, two systematic reviews with meta-analysis were conducted. Then, an approach based on a knowledge mobilization framework considering scientific, contextual and experiential evidences was used. Focus groups with stakeholders, including primary care clinicians, pediatricians, infectious disease specialists and allergists/immunologists, were also held to meet the needs of all actors concerned.ResultsFollowing this work, it appears that true allergies to penicillin are very rare. Indeed, in patients with a history of penicillin allergy, very few are truly allergic and thus the risk of cross-reaction with another BL is even lower, varying according to structural and physicochemical similarities with alleged-penicillin. Moreover, the risk of having an anaphylactic reaction after penicillin exposure is very low, especially among children. As well, in patients with confirmed penicillin allergy, the observed reactions are usually delayed non-severe skin reactions. However, with a confirmed penicillin allergy, it is important to remain cautious when administering a new BL, especially if the initial reaction was serious or severe. Based on these key messages, a decision aid including an algorithm was developed. Likewise, individualized algorithms for common infections met in primary care were produced.ConclusionsFrom this work, health professionals non-specialized in allergology should be able to better manage the risks attributed to penicillin allergies. Therefore, patients should receive the most effective and safe antibiotics to treat their clinical conditions in primary care.

IntroductionAntibiotic prophylaxis with a single dose of doxycycline after a tick bite is one of the tools for preventing Lyme disease, which is becoming increasingly prevalent in Quebec. The aim of this work was to revisit this practice in adults and children younger than 8 years of age.MethodsTo assess the safety and absolute risk reduction (ARR) of doxycycline for preventing Lyme disease in contraindicated populations, two systematic reviews were conducted with a re-analysis of the original efficacy data. A knowledge mobilization framework was used to consider the scientific, contextual, and experiential evidence, taking into account information on patients’ and clinicians’ experiences.ResultsA single dose of doxycycline prescribed within 72 hours of being bitten by a tick (Ixodes scapularis) could prevent cutaneous manifestation of Lyme disease (ARR -2.8%, 95% confidence interval: -11.7–6.1; p = 0.06), without serious side effects, provided that the bite occurred in a geographical region where at least 25 percent of nymph and 50 percent of adult ticks are infected with the disease. However, the level of evidence was low and its generalizability to other contexts was doubtful. The decision to prescribe antibiotic prophylaxis may be based more on the fear of Lyme disease, rather than on effectiveness data and the real risk of contracting Lyme disease.ConclusionsIt may be challenging for clinicians to discuss Lyme disease prophylaxis with patients and their families in contexts where people are fearful of the disease, and the risk of contracting it from a tick bite is uncertain. Decision aids that provide scientific evidence on the real risk of developing Lyme disease after a tick bite, particularly in Quebec, can promote informed decisions based on patient preferences and values by supporting discussion between clinicians and patients.

Purpose After imaging assessment of an abnormal screening mammogram, a follow-up examination 6 months later is recommended to some women. Our aim was to identify which characteristics of lesions, women, and physicians are associated to such short-interval follow-up recommendation in the Quebec Breast Cancer Screening Program. Methods Between 1998 and 2008, 1,839,396 screening mammograms were performed and a total of 114,781 abnormal screens were assessed by imaging only. Multivariate analysis was done with multilevel Poisson regression models with robust variance and generalized linear mixed models. Results A short-interval follow-up was recommended in 26.7% of assessments with imaging only, representing 2.3% of all screens. Case-mix adjusted proportion of short-interval follow-up recommendations varied substantially across physicians (range: 4%-64%). Radiologists with high recall rates (≥15%) had a high proportion of short-interval follow-up recommendation (risk ratio: 1.82; 95% confidence interval: 1.35-2.45) compared to radiologists with low recall rates (Conclusions Short-interval follow-up recommendation at assessment is frequent in this Canadian screening program, even when a previous mammogram is available. Characteristics related to radiologists appear to be key determinants of short-interval follow-up recommendation, rather than characteristics of lesions or patient mix. Given that it can cause anxiety to women and adds pressure on the health system, it appears important to record and report short-interval follow-up and to identify ways to reduce its frequency. Short-interval follow-up recommendations should be considered when assessing the burden of mammography screening.

To strengthen evidence on which radiologist mammography interpretive volume requirements can be based, we assessed the relation of volume to accuracy in the Quebec Breast Cancer Screening Program.Annual interpretive volume (total, screening, and diagnostic) for all 340 radiologists who interpreted 1315327 screening examinations in the period from 2000 to 2006 was obtained using provincial databases. The association of volume to sensitivity, false-positive rate, and accuracy (sensitivity/false-positive rate) was assessed by multivariable Poisson regression with robust error variance. All statistical tests were two-sided.Radiologists consistently interpreting less than 500 mammograms annually experienced a 58% reduction in accuracy (adjusted accuracy ratio = 0.42; 95% confidence interval [CI] = 0.24 to 0.74) compared with those who consistently interpreted at least 500 mammograms annually. Moreover, accuracy increased progressively as total annual volume increased (P trend = .0005). Radiologists interpreting at least 4000 mammograms annually experienced a 32% increase in accuracy (adjusted accuracy ratio = 1.32; 95% CI = 1.13 to 1.54) compared with those interpreting 500 to 999 mammograms annually. This increase in accuracy is attributable to a reduction in false-positive rate as total volume increased (P trend = .001). Sensitivity changed little with total volume (P trend = .68). Gains in accuracy were greater up to approximately 3000 mammograms interpreted annually.The minimum annual volume of 500 mammograms required in North America is justified; radiologist accuracy may be compromised if interpretive volume is consistently less than this requirement. Raising interpretive volume may help to reduce the frequency of false positives without loss of sensitivity. Possible gains in accuracy may be greater with increases in volume of up to approximately 3000 mammograms interpreted annually.

Background This study evaluated the impact of distance between women’s residences and designated screening centres (DSC) on participation in the Quebec Breast Cancer Screening Programme, whether this impact varied according to the rural–urban classification and the proportion of participants who used the DSC nearest to their home. Methods Travel distance between the residence of 833 856 women and the nearest DSC (n=85) was estimated. Data were obtained from administrative and screening programme databases. The analysis made use of a log-binomial regression model adjusting for age and material and social deprivation. The proportions of participants who used the DSC nearest to their residence were measured. Results Compared to women living

ObjectivesThe aim of this study was to determine the impact of the metabolic syndrome (MS) on operative mortality after a coronary artery bypass grafting surgery (CABG).BackgroundDiabetes and obesity are highly prevalent among patients undergoing CABG. However, it remains unclear whether these factors have a significant impact on operative mortality after this procedure. We hypothesized that the metabolic abnormalities associated with MS could negatively influence the operative outcome of CABG surgery.MethodsWe retrospectively analyzed the data of 5,304 consecutive patients who underwent an isolated CABG procedure between 2000 and 2004. Of these 5,304 patients, 2,411 (46%) patients met the National Cholesterol Education Program–Adult Treatment Panel III criteria for MS. The primary end point was operative mortality.ResultsThe operative mortality after CABG surgery was 2.4% in patients with MS and 0.9% in patients without MS (p < 0.0001). The MS was a strong independent predictor of operative mortality (relative risk 3.04 [95% confidence interval (CI) 1.73 to 5.32], p = 0.0001). After adjusting for other risk factors, the risk of mortality was increased 2.69-fold (95% CI 1.43 to 5.06; p = 0.002) in patients with MS and diabetes and 2.36-fold (95% CI 1.26 to 4.41; p = 0.007) in patients with MS and no diabetes, whereas it was not significantly increased in the patients with diabetes and no MS.ConclusionsThis is the first study to report that MS is a highly prevalent and powerful risk factor for operative mortality in patients undergoing a CABG surgery. Thus, interventions that could contribute to reduce the prevalence of MS in patients with coronary artery disease or that could acutely modify the metabolic perturbations of MS at the time of CABG might substantially improve survival in these patients.