Circulating proteins to predict COVID-19 severity.

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care.

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity.

Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10-10). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.

The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals.

INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

Association between access to primary care and unplanned emergency department return visits among patients 75 years and older.

OBJECTIVE: To identify factors associated with unplanned return visits to the emergency department (ED) among the population aged 75 years and older. Moreover, it aims to determine the association between patients' access to primary care and unplanned return visits. DESIGN: Data were collected from structured interviews, administrative databases, and medical charts at the index visits, and follow-up telephone calls were made at 3 months. SETTING: Emergency departments of the 3 tertiary care hospitals in Montréal, Que. PARTICIPANTS: Community-dwelling patients aged 75 years and older. MAIN OUTCOME MEASURES: Zero-inflated negative binomial regression analysis was conducted of unplanned return visits within 3 months. Rate ratios (RRs) and odds ratios (ORs) with 95% CIs are presented. RESULTS: During the study period, 4577 patients were identified, 2303 were recruited, and 1998 were retained for the analysis. Among the analysis sample, 33% were 85 and older, 34% lived alone, and 91% had a family physician. Before their ED visits, 16% of patients attempted to contact their family physicians. More than half of the patients reported having difficulty seeing their physicians for urgent problems, more than 40% had difficulty speaking with their family physicians by telephone, and more than one-third had difficulty booking appointments for new health problems. Within 3 months, 562 patients (28%) had made 894 return visits. Factors associated with a lower return visit rate included age 85 years and older (RR=0.80; 95% CI 0.67 to 0.96), less severe triage score (RR=0.83; 95% CI 0.74 to 0.92), and hospitalization at the index visit (RR=0.76; 95% CI 0.64 to 0.90). Factors that resulted in a higher return visit rate were difficulty booking appointments for new problems with their family physicians (RR=1.19; 95% CI 1.01 to 1.41), having had ED visits within the previous 6 months (RR=1.47; 95% CI 1.28 to 1.68), and higher Charlson comorbidity index scores (RR=1.06; 95% CI 1.01 to 1.11). Having had ED visits within the previous 6 months (OR=2.11; 95% CI 1.27 to 3.49), having a higher Charlson comorbidity index score (OR=1.41; 95% CI 1.19 to 1.68), and having received community care services (OR=3.00; 95% CI 0.95 to 9.53) also increased the odds of return visits. CONCLUSION: Although most people 75 years and older have a family physician, problems still exist in terms of timely access. Unplanned return visits to the ED are associated with having more comorbidities, having had previous ED visits, having already received community services, and having difficulty booking appointments with family physicians for new problems.

"Emergency Room Evaluation and Recommendations" and Incident Hospital Admissions in Older People with Major Neurocognitive Disorders Visiting Emergency Department: Results of an Experimental Study.

INTRODUCTION: Older people with major neurocognitive disorders (MNCDs) visiting the emergency department (ED) are at high risk of hospital admissions. The "Emergency Room Evaluation and Recommendations" (ER2) tool decreases the length of stay (LOS) in the hospital when older people visiting ED are hospitalized after an index ED visit, regardless of their cognitive status. Its effect on hospital admissions has not yet been examined in older people with MNCD visiting ED. This study aimed to examine whether ER2 recommendations were associated with incident hospital admissions and LOS in ED in older people with MNCD visiting ED. METHODS: A total of 356 older people with MNCD visiting ED of the Jewish General Hospital (Montreal, Quebec, Canada) were recruited in this non-randomized, pre-post-intervention, single arm, prospective and longitudinal open label trial. ED staff and patients were blinded of the ER2 score, and patients received usual ED care during the observation period, whereas ED staff were informed about the ER2 score, and patients had ER2 tailor-made recommendations in addition to usual care during the intervention period. Hospital admissions and the LOS in ED were the outcomes. RESULTS: There were less incident hospital admissions (odds ratio ≤ 0.61 with p ≤ 0.022) and longer LOS in ED (coefficient beta ≥4.28 with p ≤ 0.008) during the intervention period compared to the observation period. DISCUSSION/CONCLUSION: ER2 recommendations have mixed effects in people with MNCD visiting ED. They were associated with reduced incident hospital admissions and increased LOS in ED, suggesting that they may have benefits in addition to usual ED care.

A randomized controlled trial of renin-angiotensin-aldosterone system inhibitor management in patients admitted in hospital with COVID-19.

BACKGROUND: Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection coronavirus disease 2019 (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes. METHODS: The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-to-treat principle. RESULTS: Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients' mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); P = .60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06-2.62]; P = .027); RAASi discontinuation increased brain natriuretic peptide levels (% change from baseline: +16.7% vs -27.5%; P = .024) and the incidence of acute heart failure (33% vs 4.2%, P = .016). CONCLUSION: RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased brain natriuretic peptide levels and may increase risk of acute heart failure; where possible, RAASi should be continued.

Risk for short-term undesirable outcomes in older emergency department users: Results of the ER2 observational cohort study.

BACKGROUND: The "Emergency Room Evaluation and Recommendations" (ER2) is a clinical tool designed to determine prognosis for the short-term Emergency Department (ED) undesirable outcomes including long length of stay (LOS) in ED and in hospital, as well as the likelihood of hospital admission during an index ED visit. It is also designed to guide appropriate and timely tailor-made geriatric interventions. This study aimed to examine whether ER2 assessment part was: 1) usable by ED healthcare workers (e.g. nurses) and 2) scoring system associated with long LOS in ED and in hospital, as well as hospital admission in older ED users on stretchers. METHODS: Based on an observational, prospective and longitudinal cohort study 1,800 participants visiting the ED of the Jewish General Hospital (Montreal, Quebec, Canada) were recruited between September and December 2017. ER2 assessment determined three risk-levels (i.e., low, medium and high) for short-term ED undesirable outcomes. The rate of ER2 digital form completed, the time to fill ER2 items and obtain ER2 risk-levels, the LOS in ED and in hospital, and hospital admission were used as outcomes. RESULTS: ER2 was usable by ED nurses in charge of older ED users. High-risk group was associated with both increased ED stay (coefficient of regression ß = 3.81 with P≤0.001) and hospital stay (coefficient of regression ß = 4.60 with P = 0.002) as well as with hospital admission (HR = 1.32 with P≤0.001) when low ER2 risk level was used as referent level. Kaplan-Meier distributions showed that the three risk groups of participants differed significantly (P = 0.001). Those with high-risk level (P≤0.001) were discharged later from hospital to a non-hospital location compared to those with low risk. There was no significant difference between those classified in low-risk and in medium-risk groups (P = 0.985) and those in medium and high-risk groups (P = 0.096). CONCLUSION: The ER2 assessment part is usable in daily practice of ED care and its risk stratifications may be used to predict adverse outcomes including prolonged LOS in ED and in hospital as well as hospital admission. TRIAL REGISTRATION: NCT03964311.

Emergency room evaluation and recommendations for older emergency department users: results of the ER2 experimental study.

PURPOSE: The study aims to examine whether the use of "emergency room evaluation and recommendations" (ER2) tool in daily ED practice reduces the length of stay in ED and hospital, and hospital admission in older patients visiting ED on stretcher. METHODS: A total of 3931 older patients visiting ED of the Jewish General Hospital (Montreal, Quebec, Canada) on stretcher were recruited in this non-randomized, pre-post intervention, single arm, prospective and longitudinal open-label trial. ED staff and patients were blinded of the ER2 score and patients received usual ED care over the observational phase, whereas ED staff were informed about the ER2 score and patients had usual care plus interventions based on tailor-made geriatric recommendations during the interventional phase. The length of stay in ED and in hospital, and hospital admission were the outcomes. RESULTS: The ER2 recommendations were associated with increased length of stay in ED (ß = 2.94 with P ≤ 0.001) and decreased length of stay in hospital (ß = - 2.07 with P = 0.011). No effect was found for hospital admission (Odd Ratio (OR) = 0.92 with P = 0.182). CONCLUSION: Emergency room evaluation and recommendations (ER2) tool had mixed effects. Shorter hospital stay has been reported for older ED users hospitalized, but increased ED stay and no effects on hospital admission were found.

A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity.

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10-8), hospitalization (OR = 0.61, P = 8 × 10-8) and susceptibility (OR = 0.78, P = 8 × 10-6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.

Muscle Mass and Direct Oral Anticoagulant Activity in Older Adults With Atrial Fibrillation.

BACKGROUND: Direct oral anticoagulants (DOAC) are hydrophilic drugs with plasma levels inversely proportional to lean body mass. Sarcopenic patients with low muscle mass may be at risk for supra-therapeutic DOAC levels and bleeding complications. We therefore sought to examine the influence of lean body mass on DOAC levels in older adults with atrial fibrillation (AF). METHODS: A prospective cohort study was conducted with patients 65 years of age or more receiving rivaroxaban or apixaban for AF. Appendicular lean mass (ALM) was measured using a bioimpedance device and a dual X-ray absorptiometry scanner. DOAC levels were measured using a standardized anti-Xa assay 4 hours after (peak) and 1 hour before (trough) ingestion. RESULTS: The cohort consisted of 62 patients (47% female, 77.0 ± 6.1 years). The prescribed DOACs were apixaban 2.5 mg (21%), apixaban 5 mg (53%), and rivaroxaban 20 mg (26%). Overall, 16% had supra-therapeutic DOAC levels at trough and 25% at peak. In the multivariable logistic regression model, lower ALM was independently associated with supra-therapeutic DOAC levels at trough (odds ratio per ↓ 1-kg 1.23, 95% confidence interval 1.02 to 1.49) and peak (odds ratio per ↓ 1-kg 1.18, 95% confidence interval 1.02 to 1.37). Addition of ALM to a model consisting of age, total body weight, and renal function resulted in improved discrimination for supra-therapeutic DOAC levels. CONCLUSION: Our proof-of-concept study has identified an association between ALM and DOAC levels in older adults with AF. Further research is needed to determine the impact of ALM on bleeding complications and the potential role of ALM-guided dosing for sarcopenic patients.

Prognosis tools for short-term adverse events in older emergency department users: result of a Québec observational prospective cohort.

BACKGROUND: The "Program of Research on the Integration of Services for the Maintenance of Autonomy" (PRISMA-7) and "Emergency room evaluation and recommendations" (ER2) are both clinical tools used in Québec Emergency Departments (EDs) for screening of older ED users at higher risk of poor outcomes, such as prolonged length of stay (LOS) in EDs and in hospital. The study aimed to: 1) examine whether the PRISMA-7 and ER2 risk levels were associated with length of stays in ED and hospital, as well as hospital admission; and 2) compare the criteria performance (i.e., sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratios and area under receiver operating characteristic curve) of the PRISMA-7 and ER2 high-risk levels for these three ED adverse events in Québec older patients visiting ED on a stretcher. METHODS: A total of 1905 older patients who visited the ED of the Jewish General Hospital (Montreal, Québec, Canada) on stretchers were recruited in this prospective observational cohort. Upon their ED arrival, PRISMA-7 and ER2 were performed. The outcomes were LOS in ED and in hospital, and hospital admission. RESULTS: The PRISMA-7 and ER2 risk levels were associated with length of stay in ED and hospital as well as with hospital admission. Prolonged stays and higher hospitalization rates were associated with high-risk levels, whereas those in low-risk level groups had significantly shorter LOS and a lower rate of hospital admission (P < 0.006). While performance measures were poor for both assessment tools, ER2 had a greater prognostic testing accuracy compared with PRISMA-7. CONCLUSION: PRISMA-7 and ER2 were both associated with incidental short-term ED adverse events but their overall prognostic testing accuracy was low, suggesting that they cannot be used as prognostic tools for this purpose.

"Emergency Room Evaluation and Recommendations" (ER2) Tool for the Screening of Older Emergency Department Visitors With Major Neurocognitive Disorders: Results From the ER2 Database.

Purpose: The Emergency Room Evaluation and Recommendation (ER2) is an application in the electronic medical file of patients visiting the Emergency Department (ED) of the Jewish General Hospital (JGH; Montreal, Quebec, Canada). It screens for older ED visitors at high risk of undesirable events. The aim of this study is to examine the performance criteria (i.e., sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV], positive likelihood ratio [LR+], negative likelihood ratio [LR-] and area under the receiver operating characteristic curve [AUROC]) of the ER2 high-risk level and its "temporal disorientation" item alone to screen for major neurocognitive disorders in older ED visitors at the JGH. Methods: Based on a cross-sectional design, 999 older adults (age 84.9 ± 5.6, 65.1% female) visiting the ED of the JGH were selected from the ER2 database. ER2 was completed upon the patients' arrival at the ED. The outcomes were ER2's high-risk level, the answer to ER2's temporal disorientation item (present vs. absent), and the diagnosis of major neurocognitive disorders (yes vs. no) which was confirmed when it was present in a letter or other files signed by a physician. Results: The sensitivities of both ER2's high-risk level and temporal disorientation item were high (≥0.91). Specificity, the PPV, LR+, and AROC were higher for the temporal disorientation item compared to ER2's high-risk level, whereas a highest sensitivity, LR-, and NPV were obtained with the ER2 high-risk level. Both area under the receiver operating characteristic curves were high (0.71 for ER2's high-risk level and 0.82 for ER2 temporal disorientation item). The odds ratios (OR) of ER2's high-risk level and of temporal disorientation item for the diagnosis of major neurocognitive disorders were positive and significant with all OR above 18, the highest OR being reported for the temporal disorientation item in the unadjusted model [OR = 26.4 with 95% confidence interval (CI) = 17.7-39.3]. Conclusion: Our results suggest that ER2 and especially its temporal disorientation item may be used to screen for major neurocognitive disorders in older ED users.

Racial Disparities in Acute Coronary Syndrome Management Within a Universal Healthcare Context: Insights From the AMI-OPTIMA Trial.

BACKGROUND: Although prior studies have demonstrated racial disparities regarding acute coronary syndrome (ACS) care within private or mixed healthcare systems, few researchers have explored such disparities within universal healthcare systems. We aimed to evaluate the quality and outcomes of in-hospital ACS management for White patients vs patients of colour, within a universal healthcare context. METHODS: We performed a post hoc analysis of the Acute Myocardial Infarction - Knowledge Translation to Optimize Adherence to Evidence-Based Therapy study, a cluster-randomized trial evaluating a knowledge-translation intervention at 24 hospitals in Quebec, Canada (years: 2009 and 2012). The primary endpoint was coronary catheterization. The secondary endpoints included in-hospital mortality, percutaneous and surgical coronary revascularization, major bleeding, total stroke, and discharge prescription of evidence-based medical therapy. RESULTS: Of 3444 included patients, 2738 were White, and 706 were people of colour. The mean age was 68.2 years (33.3% women) among White patients and 69.5 years (36.0% women) among patients of colour. Patients of colour were less likely to undergo in-hospital coronary catheterization than were White patients (74.5% vs 80.3%, P = 0.001). This difference was attenuated after adjusting for patient-level characteristics (odds ratio 0.89; 95% confidence interval 0.73-1.09), and it was eliminated after adjusting for hospital-level characteristics (odds ratio 1.04; 95% confidence interval 0.73-1.49). CONCLUSIONS: Racial disparity in coronary catheterization for ACS persists within a universal healthcare context. Patients' comorbidities and hospital-level factors may be partially responsible for this inequality. Future research on cardiovascular healthcare in patients with diverse racial/ethnic backgrounds in universal healthcare systems is needed to remediate racial inequality in ACS management.

CONTEXTE: Bien que des études antérieures aient démontré l'existence de disparités raciales dans la prise en charge du syndrome coronarien aigu (SCA) au sein de systèmes de santé privés ou mixtes, peu de chercheurs ont étudié ces disparités au sein de systèmes universels de soins de santé. Nous avons cherché à évaluer la qualité et les résultats de la prise en charge du SCA à l'hôpital pour les patients blancs par rapport aux patients de couleur, dans un contexte de soins de santé universels. MÉTHODOLOGIE: Nous avons effectué une analyse a posteriori de l'étude AMI-OPTIMA, un essai sur échantillon en grappes aléatoire évaluant une intervention d'application des connaissances dans 24 hôpitaux du Québec, au Canada (années : 2009 et 2012). Le paramètre d'évaluation principal était le cathétérisme coronaire. Les paramètres d'évaluation secondaires comprenaient la mortalité à l'hôpital, la revascularisation coronaire percutanée et chirurgicale, l'hémorragie majeure, l'accident vasculaire cérébral et la prescription au congé d'un traitement médical fondé sur des données probantes. RÉSULTATS: Sur les 3444 patients étudiés, 2738 étaient blancs et 706 étaient des personnes de couleur. L'âge moyen était de 68,2 ans (33,3 % de femmes) chez les patients blancs, et de 69,5 ans (36,0 % de femmes) chez les patients de couleur. Les patients de couleur étaient moins susceptibles de subir un cathétérisme coronaire à l'hôpital que les patients blancs (74,5 % contre 80,3 %, p = 0,001). Cette différence a été atténuée après ajustement pour tenir compte des caractéristiques des patients (rapport de cotes : 0,89; intervalle de confiance [IC] à 95 % : 0,73-1,09), et éliminée après ajustement pour tenir compte des caractéristiques des hôpitaux (rapport de cotes : 1,04; IC à 95 % : 0,73-1,49). CONCLUSIONS: La disparité raciale en ce qui a trait au cathétérisme coronaire pour un SCA persiste dans un contexte de soins de santé universels. Les comorbidités des patients et des facteurs liés à l'hôpital peuvent être partiellement responsables de cette inégalité. De plus amples recherches sur les soins cardiovasculaires chez les patients de diverses origines raciales ou ethniques dans les systèmes universels de soins de santé sont nécessaires pour remédier aux inégalités raciales dans la prise en charge du SCA.

Diagnostic and Prognostic Utilities of Insulin-Like Growth Factor Binding Protein-7 in Patients With Dyspnea.

OBJECTIVES: This study examined whether insulin-like growth factor binding protein-7 (IGFBP7) would aid in the diagnosis and prognosis of acute heart failure (HF) beyond N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration. BACKGROUND: IGFBP7 is associated with impaired ventricular relaxation and worse prognosis. METHODS: The ICON-RELOADED (International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial that enrolled subjects presenting with dyspnea. Six-month prognosis for death or repeat hospitalization was obtained. RESULTS: Among 1,449 patients, 274 (18.9%) were diagnosed with acute HF. Those with IGFBP7 concentrations in the highest quartile were older, male, had hypertension and HF, had lower estimated glomerular filtration rate (eGFR) and lowest ejection fraction (41 ± 20%; all p < 0.001). Independent predictors of IGFBP7 were age, male sex, history of diabetes, history of HF, and eGFR. Median concentrations of NT-proBNP (2,844 ng/ml vs. 99 ng/ml) and IGFBP7 (146.1 ng/ml vs. 86.1 ng/ml) were higher in those with acute HF (both; p < 0.001). Addition of IGFBP7 to NT-proBNP concentrations improved discrimination, therefore increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p < 0.001 for differences). Addition of IGFBP7 to a complete model of independent predictors of acute HF improved model calibration. IGFBP7 significantly reclassified acute HF diagnosis beyond NT-proBNP (net reclassification index: +0.25). Higher log2-IGFBP7 concentrations in patients with acute HF predicted death or rehospitalization at 6 months (hazard ratio: 1.84 per log2-SD; 95% confidence interval: 1.30 to 2.61; p = 0.001). In Kaplan-Meier analyses, supramedian concentrations of IGFBP7 were associated with shorter event-free survival (log-rank: p < 0.001). CONCLUSIONS: Among patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk.

Frailty and adverse outcomes in older adults being discharged from the emergency department: A prospective cohort study.

BACKGROUND: A growing number of frail older adults are treated in the emergency department (ED) and discharged home. There is an unmet need to identify older adults that are predisposed to functional decline and repeat ED visits so as to target them with proactive interventions. METHODS: A prospective cohort study was conducted in patients 75 years or older who were being discharged from the ED. The objective was to test the value of frailty screening tests, namely 5-meter gait speed and handgrip strength, to predict repeat ED visits at 1 and 6 months and functional decline at 1 month using multivariable logistic regression. RESULTS: After excluding 7 patients lost to follow-up, 150 patients were available for analysis. The mean age was 81.1 ± 4.9 years with 51% females, 13% arriving by ambulance, and 67% having at least two comorbid conditions. At ED discharge, 41% of patients were found to have slow gait speed, whereas 23% had weak handgrip strength. After adjustment, only slow gait speed was independently associated with functional decline at 1 month (odds ratio [OR] 1.39 per 0.1 meters/second decrement, 95% confidence interval [CI], 1.12 to 1.72) and repeat ED visits at 6 months (OR 1.20 per 0.1 meters/second decrement, 95% CI, 1.01 to 1.42). CONCLUSIONS: Gait speed can be feasibly measured at the time of ED discharge to identify frail older adults at risk for early functional decline and subsequent return to the ED. Conversely, grip strength was not found to be associated with functional decline or ED visits.

Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability.

BACKGROUND: Retrospective analyses suggest that pulmonary embolism is ruled out by a d-dimer level of less than 1000 ng per milliliter in patients with a low clinical pretest probability (C-PTP) and by a d-dimer level of less than 500 ng per milliliter in patients with a moderate C-PTP. METHODS: We performed a prospective study in which pulmonary embolism was considered to be ruled out without further testing in outpatients with a low C-PTP and a d-dimer level of less than 1000 ng per milliliter or with a moderate C-PTP and a d-dimer level of less than 500 ng per milliliter. All other patients underwent chest imaging (usually computed tomographic pulmonary angiography). If pulmonary embolism was not diagnosed, patients did not receive anticoagulant therapy. All patients were followed for 3 months to detect venous thromboembolism. RESULTS: A total of 2017 patients were enrolled and evaluated, of whom 7.4% had pulmonary embolism on initial diagnostic testing. Of the 1325 patients who had a low C-PTP (1285 patients) or moderate C-PTP (40 patients) and a negative d-dimer test (i.e., <1000 or <500 ng per milliliter, respectively), none had venous thromboembolism during follow-up (95% confidence interval [CI], 0.00 to 0.29%). These included 315 patients who had a low C-PTP and a d-dimer level of 500 to 999 ng per milliliter (95% CI, 0.00 to 1.20%). Of all 1863 patients who did not receive a diagnosis of pulmonary embolism initially and did not receive anticoagulant therapy, 1 patient (0.05%; 95% CI, 0.01 to 0.30) had venous thromboembolism. Our diagnostic strategy resulted in the use of chest imaging in 34.3% of patients, whereas a strategy in which pulmonary embolism is considered to be ruled out with a low C-PTP and a d-dimer level of less than 500 ng per milliliter would result in the use of chest imaging in 51.9% (difference, -17.6 percentage points; 95% CI, -19.2 to -15.9). CONCLUSIONS: A combination of a low C-PTP and a d-dimer level of less than 1000 ng per milliliter identified a group of patients at low risk for pulmonary embolism during follow-up. (Funded by the Canadian Institutes of Health Research and others; PEGeD ClinicalTrials.gov number, NCT02483442.).

Screening for older inpatients at risk for long length of stay: which clinical tool to use?

BACKGROUND: Screening for inpatients at risk for long length of stay (LOS) is the first step of an effective hospital care plan for older inpatients. This study aims, in older adults admitted to a geriatric acute care ward, to examine and compare the 6-item brief geriatric assessment (BGA) and the "Programme de Recherche sur l'Intégration des Services pour le Maintien de l'Autonomie" (PRISMA-7) risk levels with long LOS, and to establish their performance criteria (i.e., sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratios) for LOS. METHODS: Based on an observational, retrospective, cohort design, 166 inpatients aged ≥75 admitted to a geriatric acute care ward of a McGill University-affiliated hospital (Montreal, Quebec, Canada) were recruited. The risk levels of the 6-item BGA (low, moderate and high) and the PRISMA-7 (low versus high) were calculated from a baseline assessment. The LOS was subsequently calculated in number of days. RESULTS: Only the 6-item BGA high risk level was associated with a long LOS (Odds ratio = 1.1 with P = 0.028 and Hazard ratio = 2.1 with P = 0.004). Kaplan-Meier distributions showed that there was no significant difference in the delay of hospital discharge between the low and high-risk level reported by the PRISMA-7 (P = 0.381), whereas the 6-item BGA three risk levels differed significantly (P = 0.008), with individuals at high risk levels being discharged later when compared to those with low (P = 0.001) and moderate (P = 0.019) risk levels. Both tools' performance criteria were poor (i.e., < 0.70), except for PRISMA-7's sensitivity which was 100%. CONCLUSION: The 6-item BGA risk levels were associated with LOS, low risk-level being associated with short LOS and high-risk level with long LOS, but no association was reported with the PRISMA-7 risk levels. Both tools had poor performance criteria for long LOS, suggesting that they cannot be used as prognostic tools with current scientific knowledge.

Impact of an invasive strategy in the elderly hospitalized with acute coronary syndrome with emphasis on the nonagenarians.

BACKGROUND: Published data about nonagenarians with acute coronary syndrome (ACS) were mainly descriptive and limited by small sample sizes and unadjusted outcomes. We aim to describe the characteristics, management, and the impact of an invasive strategy on major adverse events in elderly patients hospitalized with ACS with focus on the nonagerians. METHODS AND RESULTS: We analyzed data collected as part of the AMI-OPTIMA study, a cluster-randomized study of knowledge translation intervention versus usual care on optimal discharge medications in patients admitted with ACS at 24 Canadian hospitals. To determine whether an invasive strategy improved outcomes in the elderly, we used inverse probability weighting to adjust for confounders between patients who underwent invasive versus conservative strategies. Of 4,569 consecutive patients: 2,395 (52%) were <70 years old, 1,031 (23%) were septuagenarians, 941 (21%) were octogenarians, and 202 (4.4%) were nonagenarians. An invasive strategy was associated with reduced in-hospital all-cause mortality in all age groups: 1.1% versus 3.8% in patients <70 years old (P < 0.001), 2.9% versus 7.4% in septuagenarians (P < 0.001), 5.1% versus 14.7% in octogenarians (P < 0.001), and 12.0% versus 25.1% in nonagenarians (P = 0.001). An invasive strategy was also associated with higher thrombolysis in myocardial infarction major bleeds in the nonagenarians (9.0% vs. 2.0%; P = 0.003). CONCLUSIONS: The reduction in in-hospital mortality associated with an invasive strategy in elderly and nonagenarians presented with ACS is generating hypothesis and merits further studies to confirm these benefits and to guide clinicians in the management of these high-risk patients.

Predicting a long hospital stay after admission to a geriatric assessment unit: Results from an observational retrospective cohort study.

OBJECTIVE: Morbidities and related disabilities often lead to older inpatients having a long hospital stay. The aim of this study was to examine whether the 6-item brief geriatric assessment (BGA), developed and validated in France to determine a priori levels of risk of a long hospital stay (i.e.; low, moderate, high), could be successfully used with patients admitted to a geriatric assessment unit (GAU) in Quebec. STUDY DESIGN: Observational retrospective cohort design. SETTING: A GAU of a McGill University affiliated hospital (Montreal, Quebec, Canada). PARTICIPANTS: 499 inpatients (84.7 ±â€¯7.2 years; 73.3% female) recruited upon their admission. MAIN OUTCOME MEASURES: The BGA comprises 6 items: age > 85 years, male gender, ≥ 5 drugs per day, use of home-help support, history of falls and temporal disorientation. It was administered at baseline and a priori levels of risk of a long hospital stay (i.e., low, moderate, high) were determined. Length of hospital stay (LHS, in days) was calculated using the hospital registry. The association between a priori levels of risk from the BGA and LSH was examined using regression models and Kaplan-Meier curves. RESULTS: The LHS increased with the 6-item BGA a priori level of risk (P = 0.010). High-risk (Hazard ratio (HR) = 1.68 with P < 0.001) and moderate-risk (HR = 1.24 with P = 0.039) of a long hospital stay successfully predicted a long stay. Kaplan-Meier distributions of time to discharge showed that inpatients classified as having high and moderate risk levels for a long hospital stay were discharged later than those with a low risk level (P < 0.001 and P = 0.013). CONCLUSION: The 6-item BGA a priori levels of risk for a long hospital stay successfully predicted a long stay among patients admitted to a GAU in Quebec.

Recurrent Cardiovascular Events in Survivors of Myocardial Infarction With ST-Segment Elevation (from the AMI-QUEBEC Study).

The characteristics and predictors of long-term recurrent ischemic cardiovascular events (RICEs) after myocardial infarction with ST-segment elevation (STEMI) have not yet been clarified. We aimed to characterize the 10-year incidence, types, and predictors of RICE. We obtained 10-year follow-up of STEMI survivors at 17 Quebec hospitals in Canada (the AMI-QUEBEC Study) in 2003. There were 858 patients; mean age was 60 years and 73% were male. The majority of patients receive reperfusion therapy; 53.3% and 39.2% of patients received primary percutaneous coronary intervention (PCI) and fibrinolytic therapy, respectively. Seventy-five percent of patients underwent in-hospital PCI (elective, rescue, and primary). At 10 years, 42% of patients suffered a RICE, with most RICEs (88%) caused by recurrent cardiac ischemia. The risk of RICE was the highest during the first year (23.5 per patient-year). At 10 years, the all-cause mortality was 19.3%, with 1/3 of deaths being RICE-related. Previous cardiovascular event, heart failure during the index STEMI hospitalization, discharge prescription of calcium blocker increased the risk of RICE by almost twofold. Each point increase in TIMI (Thrombolysis In Myocardial Infarction) score augmented the risk of RICE by 6%, whereas discharge prescription of dual antiplatelets reduced the risk of RICE by 23%. Our findings suggested that survivors of STEMI remain at high long-term risk of RICE despite high rate of reperfusion therapy and in-hospital PCI. Patients with previous cardiovascular event, in-hospital heart failure, and high TIMI score were particularly susceptible to RICE. Future studies are needed to confirm the impacts of calcium blocker and dual antiplatelets on long-term risk of RICE.