Deep Learning-Based Data-Point Precise R-Peak Detection in Single-Lead Electrocardiograms.

Low-cost wearables with capability to record electrocardiograms (ECG) are becoming increasingly available. These wearables typically acquire single-lead ECGs that are mainly used for screening of cardiac arrhythmias such as atrial fibrillation. Most arrhythmias are characteruzed by changes in the RR-interval, hence automatic methods to diagnose arrythmia may utilize R-peak detection. Existing R-peak detection methods are fairly accurate but have limited precision. To enable data-point precise detection of R-peaks, we propose a method that uses a fully convolutional dilated neural network. The network is trained and evaluated with manually annotated R-peaks in a heterogeneous set of ECGs that contain a wide range of cardiac rhythms and acquisition noise. 700 randomly chosen ECGs from the PhysioNet/CinC challenge 2017 were used for training (n=500), validation (n=100) and testing (n=100). The network achieves a precision of 0.910, recall of 0.926, and an F1-score of 0.918 on the test set. Our data-point precise R-peak detector may be important step towards fully automatic cardiac arrhythmia detection.Clinical relevance- This method enables data-point precise detection of R-peaks that provides a basis for detection and characterization of arrhythmias.

Review article: Gastro-oesophageal reflux disease--application of the concept of complete remission.

BACKGROUND: Therapeutic success in the treatment of gastro-oesophageal reflux disease cannot be measured by endoscopic healing or symptomatic relief alone. Assessment of treatment efficacy should be based on symptomatic relief and endoscopic healing. As most questionnaires focus on heartburn, it is important to stress that there is more to gastro-oesophageal reflux disease than just heartburn. The 'complete remission' concept was recently introduced; an approach in which endoscopic appearances and symptomatic relief are integrated, thus allowing the full gastro-oesophageal reflux disease picture and its changes over time to be described in a simple and accurate manner. Complete remission is defined as the absence of both oesophagitis and symptoms. ReQuest, a relatively new questionnaire acceptable as a clinical endpoint in trials, seems to be of use in daily practice. AIM: To review the utility of the ReQuest questionnaire. RESULTS: This questionnaire assesses the gastro-oesophageal reflux disease symptom profile using 67 symptom descriptions adapted from patients' view, doctors' view, clinical trials and from the literature. Individual symptoms are reduced to seven dimensions by factor analysis and expert consensus. This gives insight into multiple symptoms over time as well as individual patient profiles. ReQuest determines symptom relief using a gastro-oesophageal reflux disease symptom threshold. This unique concept allows the doctor to measure the time to first symptom relief and also to sustained symptom relief. CONCLUSIONS: ReQuest makes it possible to evaluate the complete symptom spectrum in patients with non-erosive oesophageal reflux disease and gastro-oesophageal reflux disease. ReQuest is available for daily practice to use for comparability with regard to treatment efficacy.

A double-blind, randomized comparison of omeprazole Multiple Unit Pellet System (MUPS) 20 mg, lansoprazole 30 mg and pantoprazole 40 mg in symptomatic reflux oesophagitis followed by 3 months of omeprazole MUPS maintenance treatment: a Dutch multicentre trial.

BACKGROUND: Proton pump inhibitors (PPIs) have proved to be effective in treating reflux oesophagitis. Until now, no study had compared the PPIs omeprazole Multiple Unit Pellet System (MUPS), lansoprazole and pantoprazole in patients with reflux oesophagitis. AIM: To compare omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg for treatment effect in symptomatic reflux oesophagitis. METHOD: Patients with grade I-IV symptomatic reflux oesophagitis were randomized to double-blind omeprazole 20 mg once morning, lansoprazole 30 mg o.m. or pantoprazole 40 mg o.m. Patient satisfaction and symptoms were evaluated after 4 and 8 weeks. Patients not satisfied after 8 weeks were treated for another 4 weeks with omeprazole 40 mg MUPS (open). Successful treatment was followed by 3 months' maintenance treatment with omeprazole MUPS 20 mg (patients satisfied after 4 or 8 weeks) or omeprazole MUPS 40 mg (patients satisfied after 12 weeks). RESULTS: On intention-to-treat (ITT) analysis (n = 461) at 4 and 8 weeks, respectively, 84% and 87% (omeprazole MUPS), 78% and 81% (lansoprazole), and 84% and 89% (pantoprazole) were free of heartburn. Equivalence was found between omeprazole MUPS and pantoprazole (heartburn relief), but not with lansoprazole. Patient satisfaction after 4 and 8 weeks, respectively, was 79% and 89% (omeprazole MUPS), 76% and 86% (lansoprazole), and 79% and 91% (pantoprazole). Patient satisfaction was similar in all treatment groups. During maintenance, 87% in the omeprazole MUPS 20 mg group and 81% in the omeprazole MUPS 40 mg group were satisfied after 3 months. CONCLUSIONS: Omeprazole MUPS 20 mg and pantoprazole 40 mg have equivalent efficacy in the treatment of reflux oesophagitis. Based on patient satisfaction, omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg are equally effective.

Evidence for genetic heterogeneity in inflammatory bowel disease (IBD); HLA genes in the predisposition to suffer from ulcerative colitis (UC) and Crohn's disease (CD).

Family and epidemiological studies support a genetic susceptibility to UC and CD. Conflicting reports regarding associations between UC and HLA-DR2 and between CD and various HLA alleles have been published. The aim of this study was to determine whether molecularly defined HLA-DR genes are associated with these diseases in a Dutch group of patients. Fifty-nine unrelated Dutch UC patients and 89 CD patients were typed using DNA-based methods. A total of 2400 healthy local blood donors served as controls. The phenotype frequency of the HLA-DRB1*15 allele was increased in UC patients compared with controls (42% versus 26% in controls; P = 0.006; odds ratio (OR) = 2.1), and was predominantly found in female patients (53% versus 24%; P = 0.001; OR = 3.5). The DRB1*15 allele was increased in UC patients having a positive family history (P = 0.01; OR = 5.8). Among the 16 patients who showed an increase in extent of disease during follow up, 10 were DRB1*15+ (P = 0.002; OR = 4.8). The frequency of the DRB1*13 allele was decreased in patients with UC (15% versus 28% in controls; P = 0.04; OR = 0.5). In CD, no association was observed between disease or particular clinical subgroups and any allele tested. The present study provides additional evidence for the genetic association between UC and HLA-DRB1*15, and supports recent findings that the susceptibility gene(s) for CD is not located in the HLA class II region.

Ranitidine bismuth citrate with clarithromycin versus omeprazole with amoxycillin in the cure of Helicobacter pylori infection.

AIM: To compare the efficacy of ranitidine bismuth citrate plus clarithromycin (RBC-C) vs. omeprazole plus amoxycillin (OME-AMO) in the cure of Helicobacter pylori infection. METHODS: In this double-blind, multicentre, parallel-group study 122 H. pylori-positive patients with active duodenal ulcer or gastritis, with confirmed history of duodenal ulcer, were randomized to treatment with ranitidine bismuth citrate 400 mg b.d. plus clarithromycin 500 mg b.d. or omeprazole 20 mg b.d. plus amoxycillin 1000 mg b.d. for 14 days, followed by 14 days of ranitidine bismuth citrate 400 mg b.d. or omeprazole 20 mg once daily, respectively, to facilitate ulcer healing. Endoscopy was carried out at the start of the study and 28 days after the end of treatment. At each endoscopy four biopsies were obtained from the antrum and four biopsies from the corpus, for rapid urease test, histology and culture. H. pylori infection was defined as a positive urease test, confirmed by histology or culture. Cure of H. pylori infection was defined as negative urease test, histology or culture from both sites. RESULTS: Per-protocol, all-patients-treated and intention-to-treat cure rates (95% confidence interval) were, respectively, 90% (81-89%), 90% (82-89%) and 84% (74-93%) for ranitidine bismuth citrate plus clarithromycin, and 39% (27-54%), 44% (31-57%) and 41% (29-53%) for omeprazole plus amoxycillin, P < 0.00001. Both regimens were well tolerated. Eight patients were lost to follow-up, for lack of efficacy (one patient), adverse events (three patients) or refusal of second endoscopy (four patients). CONCLUSION: Ranitidine bismuth citrate 400 mg b.d. with clarithromycin 500 mg b.d. is superior to omeprazole 20 mg b.d. with amoxycillin 1000 mg b.d. Ranitidine bismuth citrate with clarithromycin is the first dual therapy with high cure rates and good tolerance, and is easy to take. It may therefore prove a suitable first-line treatment in H. pylori infection.

Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease.

The genes for tumour necrosis factor alpha (TNF alpha) and lymphotoxin alpha (LT alpha; TNF beta) are tandemly arranged in the central region of the MHC. They may, therefore, be of importance for the aetiology of MHC-associated diseases. The authors have prospectively studied the secretion of TNF alpha and LT alpha in relation to polymorphisms at positions -308 and -238 in the TNF alpha gene (TNFA), and two polymorphisms in the first intron of the LT alpha gene (LTA), as well as HLA-DR in 30 patients with chronic inflammatory bowel diseases (IBD) and 12 healthy controls. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF-haplotypes: TNF-C, -E, -H, -I, and -P. Significant associations between TNF haplotypes and TNF alpha and LT alpha secretion were found when PBMC were cultured with T-cell activators, irrespective of disease. Mean TNF alpha secretion of individuals carrying the HLA-DR3 associated TNF-E haplotype was significantly higher, as compared to individuals without this haplotype (26 441 pg/ml versus 19 629 pg/ml; P = 0.014). Individuals carrying the TNF-C haplotype produced the lowest amount of TNF alpha (17 408 pg/ml; P=0.022). The TNF-C and TNF-E haplotypes differ only at position -308 in the promoter of TNFA. Individuals carrying the HLA-DR1 associated TNF-I haplotype produced significantly less LT alpha when compared to those who lack this haplotype (1979 pg/ml versus 3462 pg/ml; P = 0.006). As the TNF-I haplotype is also associated with low TNF alpha secretion, this haplotype thus defines a 'low secretor phenotype'. In conclusion, this is the first study to show associations between TNF haplotypes and TNF alpha and LT alpha secretion when T-cell stimulators are used. These findings will contribute to define disease heterogeneity in IBD and may be of relevance for understanding the pathogenesis of autoimmune diseases.

Differences in the intrinsic capacity of peripheral blood mononuclear cells to produce tumor necrosis factor alpha and beta in patients with inflammatory bowel disease and healthy controls.

BACKGROUND: Tumor necrosis factor alpha (TNF alpha) and beta (TNF beta) appear to play an important role in the regulation of the inflammatory response. The aim of the present study was to investigate the intrinsic capacity of peripheral blood mononuclear cells (PBMC) to produce these cytokines. METHODS: PBMC from 41 patients with Crohn's disease (CD), with ulcerative colitis (UC), and 23 healthy controls (HC) were cultured for 48 h in the presence of the T-cell activators anti-CD3 and anti-CD28. Biologically active total TNF (TNF alpha and beta), TNF alpha, and TNF beta production were measured using a bioassay for biologically active TNF and specific TNF alpha and TNF beta enzyme-linked immunosorbent assays. RESULTS: Large interindividual differences in TNF production were observed. Production of biologically active TNF after T-cell stimulation was significantly decreased in UC patients as compared with HC and CD patients (median, 337 U/ml, 800 U/ml, and 1050 U/ml, respectively). Stimulated TNF alpha production in UC patients (median, 432 U/ml) and in CD patients (median, 537 U/ml) did not differ statistically significantly from HC (median, 730 U/ml) as compared with HC and UC patients(median, 800 U/ml and 837 U/ml, respectively). CONCLUSIONS: These findings support the concept that UC and CD are homogeneous, clearly distinguishable disease entities but rather a heterogeneous group of diseases. Studies directed to assess the immunogenetic background of these different disease manifestations in IBD are underway.

Serum nitrate levels in ulcerative colitis and Crohn's disease.

BACKGROUND: Nitric oxide is an important mediator in inflammatory and autoimmune-mediated tissue destruction and may be of pathophysiologic importance in inflammatory bowel disease. We studied whether serum levels of nitrate, the stable end-product of nitric oxide, are increased in active Crohn's disease or ulcerative colitis, in comparison with quiescent disease and healthy controls. The setting was the gastroenterology unit of the Free University Hospital, Amsterdam. METHODS: In 146 patients--75 with ulcerative colitis and 71 with Crohn's disease--and 33 controls serum nitrate was measured by the Griess reaction after enzymatic conversion of nitrate to nitrite with nitrate reductase. RESULTS: Median serum nitrate concentrations did not differ statistically significantly between ulcerative colitis (median, 34.2 mumol/l; range, 15.6-229.4 mumol/l), Crohn's disease (median 32.3 mumol; range 13.2-143.2 mumol/l), and healthy controls (median, 28.7 mumol/l; range, 13.0-108.4 mumol/l). However, when active ulcerative colitis patients (median, 44 mumol/l; range, 29.1-229.4 mumol/l were compared with inactive ulcerative colitis patients (median, 31.2 mumol/l; range, 15.6-59.7 mumol/l), a significant difference in nitrate concentration was found (p < 0.0001). A significant positive correlation was found between serum nitrate levels in ulcerative colitis and erythrocyte sedimentation rate (ESR) (r = 0.30, p - 0.01), leucocyte count (r = 0.27, p = 0.02), and thrombocyte count (r = 0.24, p = 0.04). Comparing active Crohn's disease patients (median, 37.5 mumol/l; range, 13.2-143.2 mumol/l) with inactive Crohn's disease patients (median, 31.3 mumol/l; range, 14.5-92.3 mumol/l) also showed a significant difference in serum nitrate concentration (p < 0.009). Serum nitrate levels correlated with the ESR (r = 0.26, p = 0.028) and serum albumin (r = 0.38, p = 0.004) as well. CONCLUSION: Nitric oxide production is increased in both active ulcerative colitis and Crohn's disease and may be implicated in the pathogenesis of inflammatory bowel disease.

Serological markers to differentiate between ulcerative colitis and Crohn's disease.

AIM: To assess prospectively the value of three serological tests for differentiating between ulcerative colitis and Crohn's disease, used either alone or combined. METHODS: Coded serum samples from 63 patients with ulcerative colitis and 67 patients with Crohn's disease were analysed. Detection assays for the presence of perinuclear antineutrophil cytoplasmic antibodies (pANCA), serum agglutinating antibodies to anaerobic coccoid rods, and specific IgG antibodies against a Kd-45/48 immunological crossreactive mycobacterial antigen complex (ImCrAC) were studied. Sensitivity, specificity, pre- and post-test probabilities, likelihood ratios, and predictive values of each of these serological tests were determined. RESULTS: The sensitivity and specificity of the pANCA test for the diagnosis of ulcerative colitis were 61 and 79%, respectively. The serum agglutination test for anaerobic coccoid rods had a sensitivity of 42% and a specificity of 89% for a diagnosis of Crohn's disease. The sensitivity of specific IgG antibodies against Kd-45/48 ImCrAC in diagnosing Crohn's disease was 70% and specificity 60%. Although 100% specificity was achieved by combining all three tests in a small group of patients with Crohn's disease (n = 20), combining two or more tests had no additive clinical value. No correlation was found between the presence of any one of these antibodies and disease activity, duration, or localisation of disease. Surgery or medical treatment did not influence the presence of antibodies or the antibody titre. CONCLUSIONS: The value of these tests in the differential diagnosis between ulcerative colitis and Crohn's disease is limited, but the high predictive values and specificities of different tests for both diseases suggest that these tests may be of help in studying disease heterogeneity and in defining different subgroups of patients with different pathogenesis.

Neutrophil cytoplasmic antibodies (p-ANCA) in ulcerative colitis.

AIMS: To study ulcerative colitis associated neutrophil cytoplasmic antibodies (p-ANCA) in respect of class and subclass distribution, antigen specificity, and (sub)cellular localisation of the antigen(s) to which these antibodies are directed. METHODS: p-ANCA positivity was determined using the standard indirect immunofluorescence test (IIFT). The immunoglobulin (Ig) subclass distribution of p-ANCA was investigated using monoclonal antibodies directed against IgG1, IgG2, IgG3, and IgG4. Intracellular antigen localisation studies were performed on (fractionated) neutrophils using antigen-specific antibodies. RESULTS: In contrast to vasculitis associated ANCA, ulcerative colitis p-ANCA are mainly of IgG1 and IgG3 subclass and lack IgG4. Ulcerative colitis p-ANCA are myeloid specific. IIFT data indicate that the related antigen(s) seem(s) to be located not in the cytosol, but in the granules (most likely the azurophil granules) of the neutrophil. CONCLUSIONS: p-ANCA in ulcerative colitis have a different immunoglobulin subclass distribution than the ANCA of systemic necrotising vasculitis and necrotising and crescentic glomerulonephritis. This may point to differences in immune regulation between these diseases. Both cathepsin G and lactoferrin are recognised by a subpopulation of ulcerative colitis p-ANCA. In our series, eight out of 36 (22%) of ulcerative colitis associated p-ANCA react with lactoferrin and seven (19.5%) other sera with cathepsin G. None of them recognised both antigens. The main target antigen(s) of ulcerative colitis p-ANCA still remain(s) to be identified.

Serum antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease are mainly associated with ulcerative colitis. A correlation study between perinuclear antineutrophil cytoplasmic autoantibodies and clinical parameters, medical, and surgical treatment.

Perinuclear antineutrophil cytoplasmic antibodies have recently been demonstrated in the sera of patients with inflammatory bowel disease. Three hundred and sixty six sera obtained from 120 patients with ulcerative colitis, 105 patients suffering from Crohn's disease and 49 non-inflammatory bowel disease controls were tested in two laboratories, using an indirect immunofluorescence assay. In addition, a fixed-neutrophil enzyme linked immunoadsorbent assay (ELISA) was evaluated in one of the two laboratories. The results in the immunofluorescence test showed a high degree of correlation between the two laboratories (Kappa coefficient = 0.8). Ninety five of the 120 (79%) ulcerative colitis patients had a positive test whereas only 14 of the 105 (13%) patients with Crohn's disease were positive. Sera from four patients suffering from primary sclerosing cholangitis were positive as well as four of the 45 control sera (9%). The sensitivity of the perinuclear antineutrophil cytoplasmic antibody immunofluorescence test for the diagnosis of ulcerative colitis was 0.75 with a specificity of 0.88 and a positive predictive value of 0.88 (all sera). In the ELISA technique 37 of 94 ulcerative colitis sera and one of the 68 Crohn's disease sera were positive. In the control group only one of the patients suffering from primary sclerosing cholangitis reacted positively (32 non-inflammatory bowel disease sera tested). The ELISA technique had a high specificity (0.97), but a low sensitivity (0.39). There was no relation of perinuclear antineutrophil cytoplasmic antibodies in ulcerative colitis patients or in Crohn's disease patients with disease activity, duration of illness, localisation, extent of disease, previous bowel operations or medical treatment. The clinical significance of perinuclear antineutrophil cytoplasmic antibody positive and negative subsets in both groups of patients thus remains unexplained. Our study confirms that determination of serum antineutrophil cytoplasmatic antibodies in patients with inflammatory bowel disease may differentiate ulcerative colitis from Crohn's disease. Further immunological studies are needed to explain the absence of these antibodies in a subset of ulcerative colitis patients and their role in the pathogenesis of the disease.

[Effect of short-term use of omega-3-type polyunsaturated fatty acids in subjects with hypertriglyceridemia]. / Effecten van kortdurend gebruik van meervoudig onverzadigde vetzuren van het omega-3-type bij personen met hypertriglyceridemie.

OBJECTIVE: To study the effect of omega-3 polyunsaturated fatty acid supplementation on lipid profile in hypertriglyceridaemic patients. SETTING: General practice. DESIGN: Prospective, double blind study of 12 weeks' duration. PATIENTS AND METHODS: Eight patients received fish oil (1800 mg C20: 5 omega-3 eicosapentaenoic acid (EPA) and 1200 mg C22:6 omega-3 docosahexaenoic acid (DHA). Nine patients received corn oil (3000 mg C18: 2 omega-6 linoleic acid daily). RESULTS: Lipid profile analysis showed a decrease in triglyceride levels after fish oil supplementation. An unexpected and unexplained finding was the rise in total cholesterol and LDH cholesterol with corn oil supplementation. CONCLUSION: Fish oil causes a decrease in triglyceride levels in hypertriglyceridaemic patients.