Background
This post hoc analysis of the international SINUS‐24/‐52 trials (NCT02912468/NCT02898454) aimed to assess dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal ...polyps (CRSwNP) according to different definitions of type 2 inflammatory signature.
Methods
Six definitions of type 2 inflammation were used: ≥150 eosinophils/μL or total immunoglobulin E (IgE) ≥100 IU/mL with a coexisting type 2 condition; ≥150 eosinophils/μL or total IgE ≥100 IU/mL; ≥150 eosinophils/μL; ≥250 eosinophils/μL or total IgE ≥100 IU/mL; coexisting asthma or ≥300 eosinophils/μL; presence of a coexisting type 2 condition. Odds ratios (ORs; dupilumab vs. placebo) for achieving clinically meaningful improvement (≥1 point) from baseline to week 24 (pooled SINUS‐24/‐52) and week 52 (SINUS‐52) were calculated for nasal polyp score (NPS; range 0–8), nasal congestion/obstruction score (NC; 0−3), and loss of smell score (LoS; 0−3).
Results
At baseline (n = 724), most patients displayed a type 2 inflammatory signature across definitions (64.2%–95.3%). At week 24, ORs for clinically meaningful improvement ranged from 11.9 to 14.9 for NPS across type 2 definitions, 6.5–9.6 for NC, and 12.2–17.8 for LoS (all p < 0.0001). OR ranges were similar or greater at week 52: 19.0–36.6, 7.6–12.1, and 9.2–33.5, respectively (all p < 0.0001).
Conclusion
Most patients with CRSwNP in the SINUS study had type 2 inflammation. Dupilumab demonstrated robust efficacy across definitions of type 2 inflammation, consistent with its profile as an inhibitor of Interleukin‐4 and Interleukin‐13 signaling, key and central drivers of type 2 inflammation in CRSwNP.
Key Points
This study assessed type 2 inflammation prevalence and dupilumab efficacy in chronic rhinosinusitis with nasal polyps according to algorithm‐defined type 2 inflammation
Dupilumab efficacy was similar across all type 2 definitions
To evaluate the variation of hospital rates of delayed epinephrine administration in pediatric patients with nonshockable in-hospital cardiac arrest, and the association of those rates with event, ...24-hour, and overall survival to hospital discharge.
A retrospective evaluation was performed. Delayed epinephrine was defined as greater than 5 minutes between the time the need for chest compressions was identified and epinephrine was administered. The main outcome was the association of hospital rate of delayed epinephrine administration with survival to hospital discharge. Secondary outcomes were event and 24-hour survival. Evaluation used hierarchical logistic regression and included 13 patient/event-level and seven hospital-level factors.
Hospitals with greater than 6 months data in the American Heart Association's Get With the Guidelines-Resuscitation registry (2000-2016) and greater than or equal to five total pediatric cardiac arrests with nonshockable rhythm.
Children less than 18 years old with index nonshockable in-hospital cardiac arrest treated with greater than or equal to one epinephrine dose.
None.
One-thousand four-hundred sixty-two patients at 69 hospitals were included: 218 patients (14.9%) had epinephrine delay rates ranging from 0% to 80% of events (median, 15.6%; interquartile range, 7-25%). The median and interquartile range of hospital level delay was 16% (7-25%). Patient/event-level predictors of delayed epinephrine were asystole (odds ratio, 1.54 95% CI, 1.10-2.16) and insertion of an endotracheal tube (odds ratio, 1.86 95% CI, 1.27-2.73). Hospital size less than 200 compared with greater than or equal to 500 beds (odds ratio, 3.07 95% CI, 1.22-7.73) and ICU location (odds ratio, 0.51 95% CI, 0.36-0.74) were associated with epinephrine delay rates. After adjustment, increasing quartiles of epinephrine delay were associated with lower patient and hospital-level return of spontaneous circulation (p = 0.019, p = 0.006) and 24-hour survival (p = 0.018, p = 0.002) respectively, but not survival to discharge (p = 0.20, p = 0.24).
Delayed epinephrine administration following pediatric nonshockable in-hospital cardiac arrest varies significantly between hospitals. Hospitals with higher rates of delayed epinephrine administration had worse patient- and hospital-level outcomes after adjusting for multiple patient- and hospital-level factors. Delayed epinephrine administration may directly contribute to increased mortality risk and/or may be a marker of unmeasured elements of hospital resuscitation performance.
The study aimed to assess the diagnostic properties of electrocardiographic (ECG) criteria for right ventricular hypertrophy (RVH) measured by cardiac magnetic resonance imaging (cMRI) in adults ...without clinical cardiovascular disease.
Current ECG criteria for RVH were based on cadaveric dissection in small studies.
MESA (Multi-Ethnic Study of Atherosclerosis) performed cMRIs with complete right ventricle (RV) interpretation on 4,062 participants without clinical cardiovascular disease. Endocardial margins of the RV were manually contoured on diastolic and systolic images. The ECG screening criteria for RVH from the 2009 American Heart Association Recommendations for Standardization and Interpretation of the ECG were examined in participants with and without left ventricular (LV) hypertrophy or reduced ejection fraction. RVH was defined using sex-specific normative equations based on age, height, and weight.
The study sample with normal LV morphology and function (n = 3,719) was age 61.3 ± 10.0 years, 53.5% female, 39.6% Caucasian, 25.5% African American, 21.9% Hispanic, and 13.0% Asian. The mean body mass index was 27.9 ± 5.0 kg/m(2). A total of 6% had RVH, which was generally mild. Traditional ECG criteria were specific (many >95%) but had low sensitivity for RVH by cMRI. The positive predictive values were not sufficiently high as to be clinically useful (maximum 12%). The results did not differ based on age, sex, race, or smoking status, or with the inclusion of participants with abnormal LV mass or function. Classification and regression tree analysis revealed that no combination of ECG variables was better than the criteria used singly.
The recommended ECG screening criteria for RVH are not sufficiently sensitive or specific for screening for mild RVH in adults without clinical cardiovascular disease.
ABSTRACT
Background
Chronic kidney disease (CKD) is associated with an increased risk of pulmonary hypertension, which may lead to right ventricular (RV) pressure overload and RV dysfunction. ...However, the presence of subclinical changes in RV structure or function in early CKD and the influence of these changes on mortality are not well studied. We hypothesized that early CKD, as indicated by elevated albuminuria or mild reductions in estimated glomerular filtration rate (eGFR), is associated with greater RV dilation and RV mass.
Methods
We included 4063 participants (age 45–84 years) without baseline clinical cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis. The associations of baseline creatinine–cystatin C-based eGFR and albuminuria with cardiac magnetic resonance–derived RV measures (2000–02) were examined cross-sectionally with linear regression models. Cox regression models were used to examine whether RV parameters modified the associations of eGFR and albuminuria with all-cause mortality.
Results
Participants with reductions in eGFR primarily within the 60–89 mL/min/1.73 m2 category had smaller RV end-diastolic and end-systolic volumes and stroke volume (all adjusted P-trends <.001) than those with eGFR ≥90 mL/min/1.73 m2, an association that was predominantly seen in participants with albuminuria below 30 mg/g creatinine. Albuminuria was more strongly associated with death among those with lower RV volumes (P-values for interaction <.03).
Conclusions
Among community-dwelling adults, reductions in eGFR primarily within the normal range were associated with smaller RV volumes and the association of albuminuria with worse survival was stronger among those with smaller RV volumes. Further studies are needed to elucidate the underlying mechanistic pathways that link kidney measures and RV morphology.
Lay Summary
Low glomerular filtration rate (GFR) and increased albuminuria are well-known risk factors associated with all-cause and cardiovascular mortality. However, limited data are available on the independent associations of GFR and albuminuria with cardiac morphology, and prior studies largely focused on the left ventricle and patients with advanced CKD. Furthermore, it is not known whether subclinical changes in right ventricular (RV) morphology are present in early CKD or the impact of these changes on mortality. In a large, diverse population-based cohort without cardiovascular disease and predominantly no CKD at baseline, reductions in eGFR primarily within the normal range were associated with discrete smaller RV volumes. Higher albuminuria and smaller RV volumes were associated with increased all-cause mortality risk independent of eGFR, traditional risk factors and left ventricular parameters. Our data highlight the need for further studies to examine the mechanistic link between kidney disease and RV morphology.
Graphical Abstract
Graphical Abstract
Introduction
In rheumatoid arthritis, time spent using ineffective medications may lead to irreversible disease progression. Despite availability of targeted treatments, only a minority of patients ...achieve sustained remission, and little evidence exists to direct the choice of biologic disease-modifying antirheumatic drugs in individual patients. Machine learning was used to identify a rule to predict the response to sarilumab and discriminate between responses to sarilumab versus adalimumab, with a focus on clinically feasible blood biomarkers.
Methods
The decision tree model GUIDE was trained using a data subset from the sarilumab trial with the most biomarker data, MOBILITY, to identify a rule to predict disease activity after sarilumab 200 mg. The training set comprised 18 categorical and 24 continuous baseline variables; some data were omitted from training and used for validation by the algorithm (cross-validation). The rule was tested using full datasets from four trials (MOBILITY, MONARCH, TARGET, and ASCERTAIN), focusing on the recommended sarilumab dose of 200 mg.
Results
In the training set, the presence of anti-cyclic citrullinated peptide antibodies, combined with C-reactive protein > 12.3 mg/l, was identified as the “rule” that predicts American College of Rheumatology 20% response (ACR20) to sarilumab. In testing, the rule reliably predicted response to sarilumab in MOBILITY, MONARCH, and ASCERTAIN for many efficacy parameters (e.g., ACR70 and the 28-joint disease activity score using CRP DAS28-CRP remission). The rule applied less to TARGET, which recruited individuals refractory to tumor necrosis factor inhibitors. The potential clinical benefit of the rule was highlighted in a clinical scenario based on MONARCH data, which found that increased ACR70 rates could be achieved by treating either rule-positive patients with sarilumab or rule-negative patients with adalimumab.
Conclusions
Well-established and clinically feasible blood biomarkers can guide individual treatment choice. Real-world validation of the rule identified in this post hoc analysis is merited.
Clinical Trial Registration
NCT01061736, NCT02332590, NCT01709578, NCT01768572.
Reply Whitman, Isaac R., MD; Kawut, Steven M., MD, MS; Praestgaard, Amy, PhD
Journal of the American College of Cardiology,
2014, Letnik:
64, Številka:
7
Journal Article
Right ventricular (RV) morphology has been associated with drivers of atrial fibrillation (AF) risk, including left ventricular and pulmonary pathology, systemic inflammation, and neurohormonal ...activation. The aim of this study was to investigate the association between RV morphology and risk of incident AF.
We interpreted cardiac magnetic resonance imaging in 4204 participants free of clinical cardiovascular disease in the MESA (Multi-Ethnic Study of Atherosclerosis). Incident AF was determined using hospital discharge records, study electrocardiograms, and Medicare claims data. The study sample (n=3819) was 61±10 years old and 47% male with 47.2% current/former smokers. After adjustment for demographics and clinical factors, including incident heart failure, higher RV ejection fraction (hazard ratio, 1.16 per SD; 95% confidence interval, 1.03-1.32; P=0.02) and greater RV mass (hazard ratio, 1.25 per SD; 95% confidence interval, 1.08-1.44; P=0.002) were significantly associated with incident AF. After additional adjustment for the respective left ventricular parameter, higher RV ejection fraction remained significantly associated with incident AF (hazard ratio, 1.15 per SD; 95% confidence interval, 1.01-1.32; P=0.04), whereas the association was attenuated for RV mass (hazard ratio, 1.16 per SD; 95% confidence interval, 0.99-1.35; P=0.07). In a subset of patients with available spirometry (n=2540), higher RV ejection fraction and mass remained significantly associated with incident AF after additional adjustment for lung function (P=0.02 for both).
Higher RV ejection fraction and greater RV mass were associated with an increased risk of AF in a multiethnic population free of clinical cardiovascular disease at baseline.
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