Deep learning-based NT-proBNP prediction from the ECG for risk assessment in the community.

OBJECTIVES: The biomarker N-terminal pro B-type natriuretic peptide (NT-proBNP) has predictive value for identifying individuals at risk for cardiovascular disease (CVD). However, it is not widely used for screening in the general population, potentially due to financial and operational reasons. This study aims to develop a deep-learning model as an efficient means to reliably identify individuals at risk for CVD by predicting serum levels of NT-proBNP from the ECG. METHODS: A deep convolutional neural network was developed using the population-based cohort study Hamburg City Health Study (HCHS, n=8,253, 50.9 % women). External validation was performed in two independent population-based cohorts (SHIP-START, n=3,002, 52.1 % women, and SHIP-TREND, n=3,819, 51.2 % women). Assessment of model performance was conducted using Pearson correlation (R) and area under the receiver operating characteristics curve (AUROC). RESULTS: NT-proBNP was predictable from the ECG (R, 0.566 [HCHS], 0.642 [SHIP-START-0], 0.655 [SHIP-TREND-0]). Across cohorts, predicted NT-proBNP (pNT-proBNP) showed good discriminatory ability for prevalent and incident heart failure (HF) (baseline: AUROC 0.795 [HCHS], 0.816 [SHIP-START-0], 0.783 [SHIP-TREND-0]; first follow-up: 0.669 [SHIP-START-1, 5 years], 0.689 [SHIP-TREND-1, 7.3 years]), comparable to the discriminatory value of measured NT-proBNP. pNT-proBNP also demonstrated comparable results for other incident CVD, including atrial fibrillation, stroke, myocardial infarction, and cardiovascular death. CONCLUSIONS: Deep learning ECG algorithms can predict NT-proBNP concentrations with high diagnostic and predictive value for HF and other major CVD and may be used in the community to identify individuals at risk. Long-standing experience with NT-proBNP can increase acceptance of such deep learning models in clinical practice.

Pragmatic screening for heart failure in the general population using an electrocardiogram-based neural network.

AIMS: We aim to develop a pragmatic screening tool for heart failure at the general population level. METHODS AND RESULTS: This study was conducted within the Hamburg-City-Health-Study, an ongoing, prospective, observational study enrolling randomly selected inhabitants of the city of Hamburg aged 45-75 years. Heart failure was diagnosed per current guidelines. Using only digital electrocardiograms (ECGs), a convolutional neural network (CNN) was built to discriminate participants with and without heart failure. As comparisons, known risk variables for heart failure were fitted into a logistic regression model and a random forest classifier. Of the 5299 individuals included into this study, 318 individuals (6.0%) had heart failure. Using only the digital ECGs instead of several risk variables as an input, the CNN provided a comparable predictive accuracy for heart failure versus the logistic regression model and the random forest classifier [area under the curve (AUC) of 0.75, a sensitivity of 0.67 and a specificity of 0.69 for the CNN; AUC 0.77, a sensitivity of 0.63 and a specificity of 0.76 for the logistic regression; AUC 0.79, a sensitivity of 0.67 and a specificity of 0.72 for the random forest classifier]. CONCLUSIONS: Using a CNN build on digital ECGs only and requiring no additional input, we derived a screening tool for heart failure in the general population. This could be perfectly embedded into clinical routine of general practitioners, as it builds on an already established diagnostic tool and does not require additional, time-consuming input. This could help to alleviate the underdiagnosis of heart failure.

Intra- and inter-rater reliability of endonasal activity estimation in granulomatosis with polyangiitis (Wegener´s).

OBJECTIVES: Granulomatosis with polyangiitis (GPA) frequently starts with an affection of the nasal and paranasal mucosa. Localised GPA of the nasal mucosa or persistent disease activity ('grumbling disease') is often encountered even under immunosuppressive therapy. Necessity for reconstructive surgery is common and careful scheduling to prevent failure and minimise revision rates is crucial. Therefore, reliable estimation of GPA activity in the upper airways using a score is mandatory for diagnosis, follow-up and scheduling reconstructive surgery. METHODS: Fifty endoscopic, endonasal images of 45 patients with GPA were used. Twelve (4 German, 8 Mexican) experienced (n=7) and inexperienced (n=5) physicians assessed GPA-activity at two times (T1/T2) in dichotomy and in a grading approach (none, mild, moderate and high activity) using the novel ENT Activity Score (ENTAS). All documents were written in English. RESULTS: Estimation of activity in dichotomy (none vs. mild/moderate/high): Cohen's Kappa (κ) for intra-rater reliability T1/T2 in inexperienced and experienced physicians was κ=0.58 (agreement 85%) and κ=0.72 (agreement 91%). The inter-rater reliability (Fleiss's κ) T1/T2 for inexperienced and experienced physicians was κ=0.62/κ=0.59 and κ=0.50/κ=0.58 respectively. Estimation of activity in grading approach (none, mild, moderate, high): for inexperienced physicians the intra-rater reliability T1/T2 was κ=0.67 (agreement 56%) and the inter-rater reliability at T1/T2 was κ=0.29 (intraclass correlation coefficient, ICC=0.69) and κ=0.27 (ICC=0.59). For experienced physicians the intra-rater reliability T1/T2 was κ=0.80 (agreement 67%) and the inter-rater reliability at T1 and T2 was κ=0.41 (ICC=0.77) and κ=0.39 (ICC=0.75) respectively. CONCLUSIONS: Intra-rater reliability is high in decision in dichotomy and even in grading activity. There is no difference for experienced or inexperienced physicians. Inter-rater reliability is high in dichotomy, but low for activity grading. Thus, the ENTAS provides a reliable instrument for assessing, documenting and following GPA-related disease activity in the upper respiratory tract. The relationship of activity and following damage needs to be investigated in further studies.

Contrasting association of a non-synonymous leptin receptor gene polymorphism with Wegener's granulomatosis and Churg-Strauss syndrome.

OBJECTIVE: There is evidence that the leptin/ghrelin system is involved in T-cell regulation and plays a role in (auto)immune disorders such as SLE, RA and ANCA-associated vasculitides (AAVs). Here, we evaluate the genetic background of this system in WG. METHODS: We screened variations in the genes encoding leptin, ghrelin and their receptors, the leptin receptor (LEPR) and the growth hormone secretagogue receptor (GHSR). Three single nucleotide polymorphisms (SNPs) in each gene region were analysed in 460 German WG cases and 878 ethnically matched healthy controls. RESULTS: A three-SNP haplotype of GHSR was significantly associated with WG [P = 0.0067; corrected P-value (P(c)) = 0.026; odds ratio (OR) = 1.30; 95% CI 1.08, 1.57], as was one non-synonymous SNP in LEPR (Lys656Asn, P = 0.0034; P(c) = 0.013; OR = 0.72; 95% CI 0.58, 0.90). These four SNPs were re-analysed in independent cohorts of 226 German WG cases and 519 controls. While the GHSR association was not confirmed, allele frequencies of the LEPR SNP were virtually identical to those from the initial cohorts. Analysis of this SNP in the combined WG and control panels revealed a significant association of the LEPR 656Lys allele with WG (P = 0.00032; P(c) = 0.0013; OR = 0.72; 95% CI 0.60, 0.86). Remarkably, the Lys656Asn SNP showed contrasting allele distribution in two cohorts of 108 and 88 German cases diagnosed with Churg-Strauss syndrome (CSS, combined P = 0.0067; OR = 1.41; 95% CI 1.10, 1.81), whereas identical allele frequencies were revealed when comparing British WG and microscopic polyangiitis cases. CONCLUSIONS: While GHSR has to be further evaluated, these data provide profound evidence for an association of the LEPR Lys656Asn SNP with AAV, resulting in opposing effects in WG and CSS.

Methotrexate plus leflunomide for the treatment of relapsingWegener's granulomatosis. A retrospective uncontrolled study.

OBJECTIVES: While remission is achieved in the majority of Wegener's granulomatosis (WG)-patients with cyclophosphamide, maintenance of remission remains a challenge due to the high rate of relapses. The purpose of this study was to evaluate the safety and efficacy of the combination of methotrexate (MTX) plus leflunomide (LEF) for the treatment of minor relapsing WG not warranting cyclophosphamide. METHODS: Retrospective chart analyses of 51 WG-patients with non-life-threatening relapses under MTX or LEF maintenance monotherapy. Relapsing patients were subsequently treated with a combination therapy of MTX+LEF. RESULTS: Fifty-one WG patients with relapses under MTX (n=36) or LEF (n=15) maintenance monotherapy were identified. They were subsequently treated with MTX+LEF to reintroduce remission. Mean follow-up was 26.0 (3-93) months. MTX+LEF controlled relapsing WG in 43/51 (84%) patients: 28/51 achieved a Birmingham Vasculitis activity index (BVAS)=0 and 15/51 a response (BVAS reduction of > = or). 8/51 patients did not respond to MTX+LEF (<50% BVAS reduction) and were switched to cyclophosphamide and/or a biological for ongoing disease activity. Follow up showed a sustained remission (BVAS=0 >3 months) in 14/51 patients, a minor relapse in 27/51, and a major relapse in 2/51 (subsequently switched to cyclophosphamide). Fifty adverse effects were observed. MTX+LEF therapy was discontinued in 18/51 patients because of adverse effects (main causes: gastro-intestinal complaints, hypertension, infections). CONCLUSIONS: Although side effects limited the overall performance of MTX+LEF, this combination, if tolerated well, remains an effective treatment in patients not warranting cyclophosphamide.

Accuracy of Magnetic Resonance Imaging for Grading of Subglottic Stenosis in Patients With Granulomatosis With Polyangiitis: Correlation With Pulmonary Function Tests and Laryngoscopy.

OBJECTIVE: To compare magnetic resonance imaging (MRI)-based and laryngoscopy-based subglottic stenosis (SGS) grading with pulmonary function testing (PFT) in patients with granulomatosis with polyangiitis (GPA). METHODS: In this retrospective study, we included 118 examinations of 44 patients with GPA and suspected SGS. All patients underwent MRI, laryngoscopy, and PFT. Stenosis was graded on a 4-point scale by endoscopy and MRI using the Meyer-Cotton (MC) score (score 1: ≤50%, 2: 51-70%, 3: 71-99%, and 4: 100%) and as percentage by MRI. Results were compared with peak expiratory flow (PEF) and maximum inspiratory flow (MIF) from PFT, serving as objective functional reference. RESULTS: In MRI, 112 of 118 examinations (95%) were rated positive for SGS (grade 1 [n = 82], grade 2 [n = 26], and grade 3 [n = 4]), whereas in laryngoscopy 105 of 118 examinations (89%) were rated positive for SGS (grade 1 [n = 73], grade 2 [n = 24], and grade 3 [n = 8]). MRI and laryngoscopy agreed in 75 of 118 examinations (64%). MRI determined higher scores in 20 examinations (17%) and lower scores in 23 examinations (19%) compared to laryngoscopy. MC scores as determined by both MRI and laryngoscopy showed comparable correlations with PEF (r = -0.363, P = 0.016, and r = -0.376, P = 0.012, respectively) and MIF (r = -0.340, P = 0.024, and r = -0.320, P = 0.034, respectively). The highest correlation was found between MRI-based stenosis grading in percentage with PEF (r = -0.441, P = 0.003) and MIF (r = -0.413, P = 0.005). CONCLUSION: MRI and laryngoscopy provide comparable results for grading of SGS in GPA and correlate well with PFT. MRI is an attractive noninvasive and radiation-free alternative for monitoring the severity of SGS in patients with GPA.

Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (ANCA)-Positive Granulomatosis With Polyangiitis (Wegener's) Is a Clinically Distinct Subset of ANCA-Associated Vasculitis: A Retrospective Analysis of 315 Patients From a German Vasculitis Referral Center.

OBJECTIVE: To compare the phenotype, clinical course, and outcome of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (Wegener's) (GPA) to proteinase 3 (PR3)-ANCA-positive GPA and to MPO-ANCA-positive microscopic polyangiitis (MPA). METHODS: We characterized all MPO-ANCA-positive patients classified as having GPA by the European Medicines Agency algorithm who attended our center, in a retrospective chart review. A second cohort of patients with PR3-ANCA-positive GPA matched for age and sex was characterized. Patients with MPO-ANCA-positive MPA from a recently published cohort were also included in the analysis. All patients were diagnosed and treated according to a standardized interdisciplinary approach at a vasculitis referral center. RESULTS: Comprehensive data were available for 59 patients with MPO-ANCA-positive GPA, and they were compared to 118 patients with PR3-ANCA-positive GPA and 138 patients with MPO-ANCA-positive MPA. We observed a distinct phenotype in MPO-ANCA-positive GPA as compared to the other 2 cohorts. Patients with MPO-ANCA-positive GPA frequently had limited disease without severe organ involvement, had a high prevalence of subglottic stenosis, and had less need for aggressive immunosuppressive therapy (cyclophosphamide/rituximab). The patients with MPO-ANCA-positive GPA were also younger than the MPA patients and were predominantly female (significantly different than the MPA cohort). While GPA patients had higher survival rates compared to MPA patients (due to a high prevalence of pulmonary fibrosis in MPA), patients with MPO-ANCA had significantly lower relapse rates than those with PR3-ANCA. CONCLUSION: Patients with MPO-ANCA-positive GPA show significantly different clinical courses compared to those with PR3-ANCA-positive GPA or MPO-ANCA-positive MPA, which should be considered in their clinical management. Classification according to ANCA specificity may improve the evaluation of relapse risk.

Risk factors for development of hemolytic uremic syndrome in a cohort of adult patients with STEC 0104:H4 infection.

The outbreak of Shiga toxin producing E.coli O104:H4 in northern Germany in 2011 was one of the largest worldwide and involved mainly adults. Post-diarrheal hemolytic uremic syndrome (HUS) occurred in 22% of STEC positive patients. This study's aim was to assess risk factors for HUS in STEC-infected patients and to develop a score from routine hospital parameters to estimate patient risks for developing HUS. In a cohort analysis, adult patients with STEC infection were included in five participating hospitals in northern Germany between May and July 2011. Clinical data were obtained from questionnaires and medical records, laboratory data were extracted from hospitals' electronic data systems. HUS was defined as thrombocytopenia, hemolytic anemia and acute renal dysfunction. Random forests and multivariate logistic regression were used to identify risk factors for HUS and develop a score using the estimated coefficients as weights. Among 259 adults with STEC infection, vomiting (OR 3.48,95%CI 1.88-6.53), visible blood in stools (OR 3.91,95%CI1.20-16.01), age above 75 years (OR 3.27, 95%CI 1.12-9.70) and elevated leukocyte counts (OR 1.20, 95%CI 1.10-1.31, per 1000 cells/mm(3)) were identified as independent risk factors for HUS. A score using these variables has an area under the ROC curve of 0.74 (95%CI 0.68-0.80). Vomiting, visible blood in stools, higher leukocyte counts, and higher age indicate increased risk for developing HUS. A score using these variables might help to identify high risk patients who potentially benefit from aggressive pre-emptive treatment to prevent or mitigate the devastating consequences of HUS.

Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study.

OBJECTIVE: To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome. DESIGN: Multicentre retrospective case-control study. SETTING: 23 hospitals in northern Germany. PARTICIPANTS: 298 adults with enterohaemorrhagic E coli induced haemolytic uraemic syndrome. MAIN OUTCOME MEASURES: Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death. RESULTS: 160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% v 15%, P = 0.03), fewer deaths (0% v 5%, p = 0.029), required no abdominal surgery, and excreted E coli for a shorter duration. CONCLUSIONS: Enterohaemorrhagic E coli induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial.

Hypoglycemia unawareness in older compared with middle-aged patients with type 2 diabetes.

OBJECTIVE Older patients with type 2 diabetes are at a particularly high risk for severe hypoglycemic episodes, and experimental studies in healthy subjects hint at a reduced awareness of hypoglycemia in aged humans. However, subjective responses to hypoglycemia have rarely been assessed in older type 2 diabetic patients. RESEARCH DESIGN AND METHODS We tested hormonal, subjective, and cognitive responses (reaction time) to 30-min steady-state hypoglycemia at a level of 2.8 mmol/l in 13 older (> or =65 years) and 13 middle-aged (39-64 years) type 2 diabetic patients. RESULTS Hormonal counterregulatory responses to hypoglycemia did not differ between older and middle-aged patients. In contrast, middle-aged patients showed a pronounced increase in autonomic and neuroglycopenic symptom scores at the end of the hypoglycemic plateau that was not observed in older patients (both P < 0.01). Also, seven middle-aged patients, but only one older participant, correctly estimated their blood glucose concentration to be <3.3 mmol/l during hypoglycemia (P = 0.011). A profound prolongation of reaction times induced by hypoglycemia in both groups persisted even after 30 min of subsequent euglycemia. CONCLUSIONS Our data indicate marked subjective unawareness of hypoglycemia in older type 2 diabetic patients that does not depend on altered neuroendocrine counterregulation and may contribute to the increased probability of severe hypoglycemia frequently reported in these patients. The joint occurrence of hypoglycemia unawareness and deteriorated cognitive function is a critical factor to be carefully considered in the treatment of older patients.