Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.

BACKGROUND: Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs). METHODS: Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score. RESULTS: Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001). CONCLUSIONS: In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.

Structured learning in time-dependent Cox models.

Cox models with time-dependent coefficients and covariates are widely used in survival analysis. In high-dimensional settings, sparse regularization techniques are employed for variable selection, but existing methods for time-dependent Cox models lack flexibility in enforcing specific sparsity patterns (ie, covariate structures). We propose a flexible framework for variable selection in time-dependent Cox models, accommodating complex selection rules. Our method can adapt to arbitrary grouping structures, including interaction selection, temporal, spatial, tree, and directed acyclic graph structures. It achieves accurate estimation with low false alarm rates. We develop the sox package, implementing a network flow algorithm for efficiently solving models with complex covariate structures. sox offers a user-friendly interface for specifying grouping structures and delivers fast computation. Through examples, including a case study on identifying predictors of time to all-cause death in atrial fibrillation patients, we demonstrate the practical application of our method with specific selection rules.

Acute kidney injury in the pediatric intensive care unit: outpatient follow-up.

BACKGROUND: Few studies have characterized follow-up after pediatric acute kidney injury (AKI). Our aim was to describe outpatient AKI follow-up after pediatric intensive care unit (PICU) admission. METHODS: Two-center retrospective cohort study (0-18 years; PICU survivors (2003-2005); noncardiac surgery; and no baseline kidney disease). Provincial administrative databases were used to determine outcomes. EXPOSURE: AKI (KDIGO (Kidney Disease: Improving Global Outcomes) definitions). OUTCOMES: post-discharge nephrology, family physician, pediatrician, and non-nephrology specialist visits. Regression was used to evaluate factors associated with the presence of nephrology follow-up (Cox) and the number of nephrology and family physician or pediatrician visits (Poisson), among AKI survivors. RESULTS: Of n = 2041, 355 (17%) had any AKI; 64/355 (18%) had nephrology; 198 (56%) had family physician or pediatrician; and 338 (95%) had family physician, pediatrician, or non-nephrology specialist follow-up by 1 year post discharge. Only 44/142 (31%) stage 2-3 AKI patients had nephrology follow-up by 1 year. Inpatient nephrology consult (adjusted hazard ratio (aHR) 7.76 [95% confidence interval (CI) 4.89-12.30]), kidney admission diagnosis (aHR 4.26 [2.21-8.18]), and AKI non-recovery by discharge (aHR 2.65 [1.55-4.55]) were associated with 1-year nephrology follow-up among any AKI survivors. CONCLUSIONS: Nephrology follow-up after AKI was uncommon, but nearly all AKI survivors had follow-up with non-nephrologist physicians. This suggests that AKI follow-up knowledge translation strategies for non-nephrology providers should be a priority. IMPACT: Pediatric AKI survivors have high long-term rates of chronic kidney disease (CKD) and hypertension, justifying regular kidney health surveillance after AKI. However, there is limited pediatric data on follow-up after AKI, including the factors associated with nephrology referral and extent of non-nephrology follow-up. We found that only one-fifth of all AKI survivors and one-third of severe AKI (stage 2-3) survivors have nephrology follow-up within 1 year post discharge. However, 95% are seen by a family physician, pediatrician, or non-nephrology specialist within 1 year post discharge. This suggests that knowledge translation strategies for AKI follow-up should be targeted at non-nephrology healthcare providers.

Epilepsy in children with cerebral palsy: a data linkage study.

AIM: To compare the prevalence of epilepsy in children with cerebral palsy (CP) to peer controls and their differences in healthcare utilization. METHOD: The Quebec CP registry was linked to the provincial administrative health database. Two CP cohorts were identified from the registry (n=302, 168 males, 1y 2mo-14y) and administrative data (n=370, 221 males, 2y 2mo-14y). A control cohort (n=6040, 3340 males, 10-14y) was matched by age, sex, and region to the CP registry cohort. Administrative data algorithms were used to define epilepsy cases. Data on hospitalizations and emergency department presentations were obtained. RESULTS: Using the most sensitive epilepsy definition, prevalence was 42.05% in the CP registry, 43.24% in the CP administrative data, and 1.39% in controls. Prevalence rose with increasing Gross Motor Function Classification System level. Children with CP and epilepsy had increased number and length of hospitalizations and emergency department presentations compared to children with CP or epilepsy alone. Epilepsy accounted for approximately 5% of emergency department presentations and 10% of hospitalizations in children with epilepsy, with and without CP. INTERPRETATION: Children with CP have an increased risk of epilepsy compared to their peers. Children with CP and coexisting epilepsy represent a unique subset with complex developmental disability and increased healthcare service utilization.

Association of pediatric cardiac surgery-associated acute kidney injury with post-discharge healthcare utilization, mortality and kidney outcomes.

BACKGROUND: Acute kidney Injury (AKI) in children undergoing cardiac surgery (CS) is strongly associated with hospital morbidity. Post-discharge CS AKI outcomes are less clear. We evaluated associations between AKI and post-discharge (a) healthcare utilization, (b) chronic kidney disease (CKD) or hypertension and (c) mortality. METHODS: This is a retrospective two-centre cohort study of children surviving to hospital discharge after CS. Primary exposures were post-operative ≥Stage 1 AKI and ≥Stage 2 AKI defined by Kidney Disease Impoving Global Outcomes. Association of AKI with time to outcomes was determined using multivariable Cox-Proportional Hazards analysis. RESULTS: Of 350 participants included (age 3.1 (4.5) years), 180 [51.4%] developed AKI and 60 [17.1%] developed ≥Stage 2 AKI. Twenty-eight (9%) participants developed CKD or hypertension (composite outcome), and 17 (5%) died within 5 years of discharge. Post-operative ≥Stage 1 and ≥Stage 2 AKI were not associated with post-discharge hospitalizations, emergency room (ER) visits, physician visits or CKD or hypertension in adjusted analyses. A trend was observed between ≥Stage 2 AKI and mortality but was not statistically significant. In unadjusted stratified analyses, AKI was associated with post-discharge hospitalizations in children with RACHS-1 score ≥3, complex chronic disease classification and children living in urban areas. CONCLUSIONS: Post-CS AKI is not associated with post-discharge healthcare utilization, death and CKD or hypertension, though it may be associated with healthcare utilization in more complex paediatric CS children. Studies should aim to better understand post-CS healthcare utilization patterns and non-AKI risk factors for CKD, hypertension and mortality, to reduce adverse long-term outcomes after CS.

Emergency Department Use in Children with Cerebral Palsy: A Data Linkage Study.

OBJECTIVE: To describe the pattern of emergency department (ED) consultations in children with cerebral palsy (CP) compared to controls and factors predictive of ED consultations. METHODS: This retrospective cohort study linked data from the Registre de la paralysie cérébrale du Québec (REPACQ) and provincial administrative health databases. The CP cohort was comprised of children enrolled in REPACQ born between 1999 and 2002. REPACQ covers 6 of 17 Quebec health administrative regions. Region-, age-, and gender-matched controls were identified from administrative health databases in a 20:1 ratio. The primary outcome was high use of ED services (≥4 ED visits during the study period). Relative risk (RR) and 95% confidence interval (CI) were calculated. RESULTS: In total, 301 children with CP were linked to administrative data and 6040 peer controls were selected. Ninety-two percent (92%) of the CP cohort had at least one ED visit in the study period, compared to 74% among controls (RR 1.24, 95% CI 1.19-1.28). Children with CP were more likely than their peers to have high ED use (RR 1.40; 95% CI 1.30-1.52). Factors predictive of high ED use were comorbid epilepsy (RR 1.23; 95% CI 1.04-1.46) and severity of motor impairment (RR 1.14; 95% CI 0.95-1.37). CONCLUSION: Children with CP are more likely to present to the ED than their peers, resulting in increased use of ED services. Coordinated care with improved access to same-day evaluations could decrease ED use. Health system factors and barriers should be investigated to ensure optimal and appropriate use of ED services.

Hospitalizations in School-Aged Children with Cerebral Palsy and Population-Based Controls.

OBJECTIVE: To compare hospitalizations among children with cerebral palsy (CP) and healthy controls and to identify factors associated with hospitalizations in children with CP. METHODS: This retrospective cohort study linked data from a provincial CP Registry and administrative health databases. The CP cohort was comprised of children born from 1999 to 2002. Age, sex, and region-matched controls were identified from administrative health databases. Mean differences, relative risk (RR), and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 301 children with CP were linked to administrative health data and matched to 6040 controls. Mean hospitalizations per child during the study period were higher in children with CP compared to controls (raw mean difference (RMD) 5.0 95% CI 4.7 to 5.2) with longer length of stay (RMD 2.8 95% CI 1.8 to 3.8) and number of diagnoses per hospitalization (RMD 1.6 95% CI 1.4 to 1.8). Increased risk of hospitalization was observed in non-ambulant children with CP (RR 1.12 95% CI 1.01 to 1.22) compared to ambulant children and among those with spastic tri/quadriplegic CP compared to other CP subtypes (RR 1.15, 95% CI 1.05 to 1.27). Feeding difficulties (RR 1.20 95% CI 1.13 to 1.27), cortical visual (RR 1.22 95% CI 1.13 to 1.32), cognitive (RR 1.16 95% CI 1.04 to 1.30), and communication impairment (RR 1.26 95% CI 1.10 to 1.44) were associated with increased hospitalizations. CONCLUSIONS: Children with CP face more frequent, longer hospital stays than peers, especially those with a more severe CP profile. Coordinated interdisciplinary care is needed in school-aged children with CP and medical complexity.

The burden of waiting: wait times for pediatric surgical procedures in Quebec and compliance with national benchmarks.

Background: Wait time information and compliance with national guidelines are limited to a few adult conditions in the province of Quebec. We aimed to assess compliance with Paediatric Canadian Access Targets for Surgery (P-CATS) guidelines and determine the burden incurred due to waiting for 3 common elective surgical conditions (inguinal hernia, cryptorchidism and hypospadias) in a pediatric population. Methods: We carried out a population-based retrospective cohort study of randomly selected children residing in Quebec without complex chronic medical conditions, using administrative databases belonging to the Régie de l'assurance maladie du Québec for the period 2010-2013. Disability-adjusted life years (DALYs) were calculated to measure the burden due to waiting. Multivariate forward regression identified risk factors for compliance with national guidelines. Results: Surgical wait time information was assessed for 1515 patients, and specialist referral wait time was assessed for 1389 patients. Compliance with P-CATS benchmarks was 76.6% for seeing a specialist and 60.7% for receiving surgery. Regression analysis identified older age (p < 0.0001) and referring physician specialty (p = 0.001) as risk factors affecting specialist referral wait time target compliance, whereas older age (p = 0.040), referring physician specialty (p = 0.043) and surgeon specialty (p = 0.002) were significant determinants in surgical wait time compliance. The total burden accrued due to waiting beyond benchmarks was 35 DALYs. Conclusion: Our results show that provincial compliance rates with wait time benchmarks are still inadequate and need improvement. Patient age and physician specialty were both found to have significant effects on wait time target compliance.

Contexte: L'information sur les temps d'attente et le respect des lignes directrices nationales au Québec est limitée à quelques affections chez les adultes. Nous avons voulu évaluer le respect des objectifs canadiens en matière d'accès aux chirurgies pédiatriques (P-CATS) et déterminer le fardeau associé à l'attente pour 3 affections courantes nécessitant une intervention chirurgicale non urgente (hernie inguinale, cryptorchidie et hypospadias) chez une population pédiatrique. Méthodes: Pour ce faire, nous avons mené une étude de cohorte populationnelle rétrospective portant sur des enfants vivant au Québec et n'ayant pas de problèmes de santé chroniques complexes. Leur sélection aléatoire a été faite à partir de bases de données administratives appartenant à la Régie de l'assurance maladie du Québec pour la période de 2010 à 2013. Nous avons calculé les années de vie ajustées en fonction de l'incapacité (AVAI) pour mesurer le fardeau associé à l'attente. Une régression ascendante multivariée a permis de relever les facteurs de risque relatifs au respect des lignes directrices nationales. Résultats: Nous avons évalué les données sur le temps d'attente pour une intervention chirurgicale chez 1515 patients, et sur le temps d'attente pour la consultation d'un spécialiste chez 1389 patients. Les valeurs de référence pour le respect des P-CATS étaient de 76,6 % pour la consultation d'un spécialiste et de 60,7 % pour la réalisation d'une intervention. L'analyse de régression a montré que l'âge plus avancé (p < 0,0001) et la spécialité du médecin traitant (p = 0,001) étaient des facteurs de risque pour la consultation d'un spécialiste, tandis que l'âge plus avancé (p = 0,040), la spécialité du médecin traitant (p = 0,043) et la spécialité du chirurgien (p = 0,002) étaient des déterminants significatifs du respect des objectifs d'attente pour une intervention. Le fardeau total causé par l'attente au-delà des valeurs de référence était de 35 AVAI. Conclusion: Nos résultats montrent que le taux provincial de respect des lignes directrices d'attente demeure inadéquat et doit être amélioré. L'âge des patients et la spécialité des médecins ont tous deux un effet significatif sur le respect des objectifs d'attente.

An international, multicentre, double-blind, randomized study (DISSCO): effect of diacerein vs celecoxib on symptoms in knee osteoarthritis.

OBJECTIVE: The objective of this study was to investigate whether diacerein has comparable efficacy with celecoxib in pain reduction for treatment in symptomatic knee OA patients. METHODS: This randomized double-blind multicentre non-inferiority trial evaluated diacerein vs celecoxib treatment in patients with Kellgren-Lawrence grade 2-3 and pain scoring ≥4 (10-cm VAS). Patients were randomized to 6 months of treatment with diacerein 50 mg (n = 187) once daily for 1 month and twice daily thereafter, or celecoxib 200 mg (n = 193) once daily. The primary outcome was the change in WOMAC pain score (0-50 cm) at 6 months, and the secondary outcomes were WOMAC sub-scores, VAS pain score, and the OMERACT-OARSI responder rate. RESULTS: In the per protocol population, the adjusted mean change from baseline in the WOMAC pain score was -11.1 ( 0.9) with diacerein (n = 140) and -11.8 (0.9) with celecoxib (n = 148). The intergroup difference was 0.7 (95% CI: -1.8, 3.2; P = 0.597), meeting the non-inferiority margin. Supportive analysis of the intention-to-treat population gave similar results. Other outcomes showed no significant difference between treatment groups. The incidence of treatment-related adverse events was low and balanced between groups, but a greater incidence of diarrhoea occurred with diacerein (10.2% vs 3.7%). Diarrhoea was considered mild-to-moderate in all but one case with complete resolution. CONCLUSIONS: Diacerein was non-inferior to celecoxib in reducing knee OA pain and improving physical function. Diacerein also demonstrated a good safety profile. TRIAL REGISTRATION: A multicentre study on the effect of DIacerein on Structure and Symptoms vs Celecoxib in Osteoarthritis is a National Institutes of Health (NCT02688400) and European Clinical Trial Database (2015-002933-23) registered phase III (Canada) or IV (Europe) study.

Acute kidney injury in critically ill children and 5-year hypertension.

BACKGROUND: To develop a pediatric-specific hypertension algorithm using administrative data and use it to evaluate the association between acute kidney injury (AKI) in the intensive care unit (ICU) and hypertension diagnosis 5 years post-discharge. METHODS: Two-center retrospective cohort study of children (≤ 18 years old) admitted to the pediatric ICU in Montreal, Canada, between 2003 and 2005 and followed until 2010. Patients with a valid healthcare number and without end-stage renal disease were included. Patients who could not be merged with the provincial database, did not survive admission, underwent cardiac surgery, had pre-existing renal disease associated with hypertension or a prior diagnosis of hypertension were excluded. AKI defined using the Kidney Disease: Improving Global Outcomes (KDIGO) definition. Using diagnostic codes and medications from administrative data, novel pediatric-specific hypertension definitions were designed. Both the evaluation of the prevalence of hypertension diagnosis and the association between AKI and hypertension occurred. RESULTS: Nineteen hundred and seventy eight patients were included (median age at admission [interquartile range] 4.3 years [1.1-11.8], 44% female, 325 (16.4%) developed AKI). Of these patients, 130 (7%) had a hypertension diagnosis 5 years after discharge. Patients with AKI had a higher prevalence of hypertension diagnosis [non-AKI: 84/1653 (5.1%) vs. AKI: 46/325 (14.2%), p < .001]. Children with AKI had a higher adjusted risk of hypertension diagnosis (hazard ratio [95% confidence interval] 2.19 [1.47-3.26]). CONCLUSIONS: Children admitted to the ICU have a high prevalence of hypertension post-discharge and children with AKI have over two times higher risk of hypertension compared to those with no AKI.

Is there a potential association between spironolactone and the risk of new-onset diabetes in a cohort of older patients with heart failure?

PURPOSE: Some evidence suggests that spironolactone may have a deleterious effect on glucose homeostasis. The objective of this study was to assess whether spironolactone use is associated with a higher risk of developing diabetes in a large cohort of patients with heart failure (HF). METHODS: Two Quebec government administrative databases were used to identify a cohort of hospitalized patients discharged between January 1995 and December 2009 with a primary discharge diagnosis of HF and without secondary discharge diagnosis of diabetes. Patients were categorized as new users of spironolactone and non-users. The primary outcome was defined as new-onset diabetes (NOD) during 5 years of follow-up and was ascertained using ICD codes for diabetes or use of hypoglycemic agents. RESULTS: Among the 2974 patients that were included in the cohort analysis, 769 were given a new prescription of spironolactone. The incidence rate of NOD was similar among spironolactone users (5.0 per 100 person-years) and non-users (4.9 per 100 person-years). There was no significant association between the use of spironolactone and NOD in the crude, unadjusted model (hazard ratio (HR) 1.01; 95% confidence interval (CI) 0.80-1.28; p = 0.9217), and it remained unchanged in the adjusted Cox proportional hazard model (HR = 0.92; 95% CI = 0.72-1.18; p = 0.5227). The results were consistent with those observed in sensitivity analyses of a 1:3 propensity score-matched cohort (HR = 0.97; CI = 0.76-1.25; p = 0.8169). CONCLUSION: We found no evidence supporting the claim that use of spironolactone is associated with a higher risk of diabetes among patients hospitalized for HF.

Association Between Metformin Adherence and All-Cause Mortality Among New Users of Metformin: A Nested Case-Control Study.

BACKGROUND: Metformin presents better survival rates than other oral antidiabetics in the treatment of type 2 diabetes. However, these benefits may be dampened by inadequate treatment adherence. OBJECTIVE: We aimed to investigate the relationship between adherence level to metformin therapy and all-cause mortality over 10 years in incident metformin users. METHODS: A nested case-control study was conducted using a large cohort of beneficiaries of the Quebec public drug insurance plan, aged 45 to 85 years, who initiated metformin between 2000 and 2009. Each case of all-cause death during follow-up was matched with up to 10 controls. Adherence to metformin was measured using the medication possession ratio (MPR). Conditional logistic regression models were used to estimate rate ratios (RRs) for mortality between adherent (MPR ≥ 80%) and nonadherent patients (MPR < 80%). Subgroup analyses were conducted according to age (45-64 and 65-85 years) and comedication use (antihypertensive/cardiovascular drugs and statins). RESULTS: The cohort included 82 720 incident metformin users, followed up for 2.4 [0.8-4.4] years (median [interquartile range]) and 4747 cases of all-cause deaths. Analyses revealed decreased mortality risks after long-term adherence to metformin. Specifically, RRs were 0.84 (95% CI = [0.71-0.98]) and 0.69 [0.57-0.85] after 4 to 6 and ≥6 years of adherence to metformin, respectively. Survival benefits of long-term adherence (≥4 years) were also observed across most subgroups and particularly in patients using neither antihypertensive/cardiovascular drugs nor statins (0.57 [0.41-0.77]). CONCLUSIONS: Long-term adherence to metformin is associated with decreased risks of all-cause mortality in incident metformin users. Further research should investigate whether survival benefits vary according to the comorbidity burden of patients.

Anticoagulation management services in community pharmacy: Feasibility of implementing a quality improvement programme through a practice-based research network.

WHAT IS KNOWN AND OBJECTIVE: The literature has reported suboptimal real-world use of oral anticoagulants in patients with atrial fibrillation (AF). Anticoagulation management services (AMSs) in community pharmacy have rarely been evaluated, and no formal process is available to enable pharmacists to evaluate and improve their clinical practices. Our objective was to assess the feasibility of implementing, through a practice-based research network (PBRN), a quality improvement programme on AMSs by community pharmacists for AF patients and explore its impact on the quality of clinical practices and pharmacists' knowledge. METHODS: An uncontrolled pre/post-pilot study was conducted through a PBRN. Pharmacists identified 5-20 AF patients on oral anticoagulants per pharmacy and completed questionnaires at baseline (T0) and after 6 months (T6). Clinical practices were evaluated using a set of quality indicators (QIs). QI scores ranged from 0% (no QI achieved) to 100% (all QIs achieved). The programme included an audit and feedback based on QIs and a personalized training programme (including online videos). Participation rates and satisfaction were documented. Mean changes (T6-T0), with 95% confidence interval (CI), in QIs and knowledge scores were computed. RESULTS AND DISCUSSION: A total of 37 pharmacies (50 pharmacists) identified 222 patients who had received either vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), or both. All pharmacies received their baseline quality report (audit), and facilitators contacted by phone 97% of pharmacies (feedback). Each of the six online videos was completed by at least 48% of pharmacists. Baseline mean global QI scores for VKAs and DOACs were 39.1% (95% CI: 35.7%-42.4%) and 12.3% (7.8%-16.8%), respectively. Over a 6-month period, they increased by 12.5% points (7.5%-17.5%) and 9.9% points (3.8%-16.1%), respectively. Baseline mean global knowledge score was 68.7% (65.4%-72.0%) and increased by 4.3% points (1.2%-7.4%). WHAT IS NEW AND CONCLUSION: Implementing a quality improvement programme for AMS in community pharmacy is relevant and feasible and may improve pharmacists' practices and knowledge.

Epidemiology and outcome of antimicrobial resistance to gram-negative pathogens in bacteriuric kidney transplant recipients.

BACKGROUND: In kidney transplant recipients, episodes of bacteriuria are often treated regardless of the presence of symptoms because of the lack of clear treatment guidelines suggesting otherwise. This practice may lead to the development of antimicrobial resistance. Our aim was to determine the incidence, determinants, and impact of antimicrobial resistance in kidney transplant recipients with gram-negative bacteriuria. METHOD: We conducted a single-center, retrospective cohort study in patients who underwent kidney transplantation between January 2008 and June 2013. To identify risk factors for the development of resistance, we used a logistic regression model with generalized estimating equations to account for within-subject correlation. RESULTS: Among the 318 patients who underwent kidney transplantation during the study period, 147 patients developed 555 gram-negative episodes of bacteriuria. Resistance to trimethoprim-sulfamethoxazole and quinolones, and production of extended-spectrum ß-lactamase (ESBL) occurred in 52%, 21%, and 5% of isolated microorganisms, respectively. An increased risk of resistance to quinolones and production of ESBL were associated with concomitant diabetes (odds ratio [OR]: 2.29, 95% confidence interval [CI]: 1.11-4.74), the first year post transplantation (OR: 2.88, 95% CI: 1.36-6.09), and antibiotic treatment in the previous 6 months (OR: 3.36, 95% CI: 1.66-6.81). This resistance profile was also associated with the presence of symptoms, a longer duration of antibiotic treatment, and a higher rate of hospitalization. CONCLUSION: Antimicrobial resistance to quinolones and production of ESBL were commonly seen, and were shown to demonstrate an adverse impact on outcomes in kidney transplant recipients with gram-negative bacteriuria. The decision on treatment for asymptomatic bacteriuria should be made with caution, given the potential for the selection of resistant strains.

Evaluation of height-dependent and height-independent methods of estimating baseline serum creatinine in critically ill children.

BACKGROUND: Baseline serum creatinine (bSCr) is required for diagnosing acute kidney injury (AKI). In children, bSCr is commonly defined as the lowest measurement within 3 months of admission. Measured values are often missing and estimating bSCr using height-based glomerular filtration rate (GFR) equations is problematic when height is unavailable. METHODS: This is a retrospective cohort study including 538 children admitted to the intensive care unit (ICU) between 2003 and 2005 at two centers in Canada, with measured bSCr, height, and ICU-SCr values. We evaluated the bias, accuracy, and precision of back-calculating bSCr from height-dependent and height-independent GFR equations. Agreement of AKI defined using measured and estimated bSCr was calculated. Multivariate analyses were performed to assess the impact of bSCr estimation methods on the association between AKI and ICU mortality, length of stay, and duration of mechanical ventilation. RESULTS: Both methods underestimated bSCr by 1-3%, showed good accuracy (∼30% of patients with estimated bSCr within 10% of measured bSCr), but poor precision (wide 95% limits of agreement). The agreement between AKI defined by estimated versus measured bSCr was >80% (κ >0.5). The height-independent method performed best in children >13 years old; however, overall, both methods performed similarly across age subgroups. AKI was associated with longer stay, prolonged mechanical ventilation, and ICU mortality using measured and estimated bSCr. CONCLUSIONS: Height-dependent and height-independent bSCr estimation methods were comparable. This may have significant implications for performing pediatric AKI research using large databases, and in clinical care to define AKI when height is unknown.

Older adults with heart failure treated with carvedilol, bisoprolol, or metoprolol tartrate: risk of mortality.

PURPOSE: The long-term use of ß-blockers has been shown to improve clinical outcomes among patients with heart failure (HF). However, a lack of data persists in assessing whether carvedilol or bisoprolol are superior to metoprolol tartrate in clinical practice. We endeavored to compare the effectiveness of ß-blockers among older adults following a primary hospital admission for HF. METHODS: We conducted a cohort study using Quebec administrative databases to identify patients who were using ß-blockers, carvedilol, bisoprolol, or metoprolol tartrate after the diagnosis of HF. We characterized the patients by the type of ß-blocker prescribed at discharge of their first HF hospitalization. An adjusted multivariate Cox proportional hazards model was used to compare the primary outcome of all-cause mortality. We also conducted analyses by matching for a propensity score for initiation of ß-blocker therapy and assessed the effect on primary outcome. RESULTS: Among 3197 patients with HF with a median follow-up of 2.8 years, the crude annual mortality rates (per 100 person-years) were at 16, 14.9, and 17.7 for metoprolol tartrate, carvedilol, and bisoprolol, respectively. Adjusted hazard ratios of carvedilol (hazard ratio 0.92; 0.78-1.09) and bisoprolol (hazard ratio 1.04; 0.93-1.16) were not significantly different from that of metoprolol tartrate in improving survival. After matching for propensity score, carvedilol and bisoprolol showed no additional benefit with respect to all-cause mortality compared with metoprolol tartrate. CONCLUSIONS: Our evidence suggests no differential effect of ß-blockers on all-cause mortality among older adults with HF. Copyright © 2016 John Wiley & Sons, Ltd.

Renal Function Follow-Up and Renal Recovery After Acute Kidney Injury in Critically Ill Children.

OBJECTIVES: To evaluate factors associated with renal recovery from acute kidney injury in critically ill children and the extent to which serum creatinine is measured before discharge. DESIGN: Retrospective cohort study. SETTING: Two PICUs at tertiary centers in Montreal, QC, Canada. PATIENTS: Children (< 18 yr old) admitted to the PICU between 2003 and 2005. Patients with end-stage renal disease, no healthcare number, died during admission, or admitted postcardiac surgery were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute kidney injury was defined using internationally accepted criteria (Kidney Disease: Improving Global Outcomes). Two renal recovery outcomes commonly used in the literature were evaluated: hospital discharge serum creatinine less than 1.5 and less than 1.15 times baseline. Proportions of patients with 1) serum creatinine measurements between PICU and hospital discharge and 2) renal recovery were calculated. Univariate and multivariate analyses were performed to determine factors associated with serum creatinine monitoring and nonrecovery after acute kidney injury. Of 2,033 patients included, 829 (40.8%) had serum creatinine measurements between PICU and hospital discharge. The odds of having a discharge serum creatinine measurement increased with acute kidney injury severity (stages 1, 2, 3 adjusted odds ratio [95% CI]: 1.49 [1.03-2.15], 2.52 [1.40-4.54], 7.87 [3.16-19.60], respectively). Acute kidney injury recovery was 92.5% when defined as serum creatinine less than 1.5 times baseline versus 75.9% when defined as less than 1.15 times baseline (p < 0.001). Stage 3 acute kidney injury was associated with having a discharge serum creatinine greater than or equal to 1.5 times baseline (adjusted odds ratio = 3.51 [1.33-9.19]). CONCLUSIONS: Less than half the PICU population had serum creatinine measured before hospital discharge. More severe acute kidney injury was associated with higher likelihood of serum creatinine monitoring and lower probability of acute kidney injury recovery. Future research should address knowledge translation on post-PICU acute kidney injury follow-up before hospital discharge.

The levels of the adipokines adipsin and leptin are associated with knee osteoarthritis progression as assessed by MRI and incidence of total knee replacement in symptomatic osteoarthritis patients: a post hoc analysis.

OBJECTIVE: Limited studies have explored the association between adipokines and knee OA structural progression using quantitative MRI (qMRI), and very few have included total knee replacement (TKR) as a disease outcome. The objective of this study was to compare serum levels of five adipokines to cartilage volume loss (CVL) and investigate their predictive value for TKR. METHODS: The according-to-protocol population (n = 138) of a knee OA trial was used. Serum levels of adipsin (complement factor D), leptin, adiponectin, resistin and serpin E1, and cartilage volume were determined at baseline and 24 months with specific ELISAs and qMRI, respectively. Study knee TKR incidence up to 4 years post-trial was also assessed. RESULTS: Greater baseline values of adipsin and leptin correlated with increased CVL in the global knee and medial femur (P ⩽ 0.032) and of adipsin in the lateral compartment and femur (P ⩽ 0.028). Adiponectin showed an inverse correlation in the medial compartment and femur (P ⩽ 0.027). Resistin and serpin E1 were not associated with CVL. Multivariate analyses revealed that patients in the highest tertile at baseline of adipsin presented a greater odds ratio of CVL in the lateral compartment and femur (⩾2.87; P ⩽ 0.011), and those in the highest tertile of leptin in the medial compartment (2.78; P = 0.038). Most clinically relevant, patients in the highest tertile of adipsin or leptin at baseline had significantly greater incidence of TKR (P = 0.027). CONCLUSION: Data demonstrate that both adipsin and leptin predict greater CVL over time in the lateral and medial compartment, respectively. Importantly, this study also demonstrates that higher baseline levels of adipsin or leptin are associated with higher incidence of TKR.

Disease-modifying effect of strontium ranelate in a subset of patients from the Phase III knee osteoarthritis study SEKOIA using quantitative MRI: reduction in bone marrow lesions protects against cartilage loss.

OBJECTIVE: To explore, using MRI, the disease-modifying effect of strontium ranelate (SrRan) treatment on cartilage volume loss (CVL) and bone marrow lesions (BMLs) in a subset of patients from a Phase III clinical trial in knee osteoarthritis (OA) (SrRan Efficacy in Knee OsteoarthrItis triAl (SEKOIA)). MATERIAL AND METHODS: Patients with primary symptomatic knee OA were randomised to receive either SrRan 1 g/day or 2 g/day or placebo (SEKOIA study). A subset of these patients had MRIs at baseline, 12, 24 and 36 months to assess the knee cartilage volume and BMLs. Missing values were imputed and the analyses were adjusted according to Bonferroni. RESULTS: In this MRI subset, the distribution of patients (modified intention-to-treat; n=330) was 113, 105 and 112 for SrRan 1 g/day, 2 g/day and placebo, respectively. The groups were fairly balanced at baseline regarding demographics, clinical symptoms or imaging characteristics. Treatment with SrRan 2 g/day significantly decreased CVL on the plateaus at 12 (p=0.002) and 36 (p=0.003) months compared with placebo. Of note, in the medial femur and plateau, SrRan 1 g/day, but not SrRan 2 g/day, had more CVL than placebo. In patients with BML in the medial compartment at baseline, the BML score at 36 months was decreased in both treatment groups compared with the placebo group (SrRan 1 g/day, p=0.002 and SrRan 2 g/day p=0.001, respectively), and CVL significantly decreased with SrRan 2 g/day (p=0.023) in the plateau compared with placebo. CONCLUSIONS: In knee OA patients, treatment with SrRan 2 g/day was found to have beneficial effects on structural changes by significantly reducing CVL in the plateau and BML progression in the medial compartment.