Early prediction of cardiac resynchronization therapy response by non-invasive electrocardiogram markers

[EN] Cardiac resynchronization therapy (CRT) is an effective treatment for those patients with severe heart failure. Regrettably, there are about one third of CRT "non-responders", i.e. patients who have undergone this form of device therapy but do not respond to it, which adversely affects the utility and cost-effectiveness of CRT. In this paper, we assess the ability of a novel surface ECG marker to predict CRT response. We performed a retrospective exploratory study of the ECG previous to CRT implantation in 43 consecutive patients with ischemic (17) or non-ischemic (26) cardiomyopathy. We extracted the QRST complexes (consisting of the QRS complex, the S-T segment, and the T wave) and obtained a measure of their energy by means of spectral analysis. This ECG marker showed statistically significant lower values for non-responder patients and, joint with the duration of QRS complexes (the current gold-standard to predict CRT response), the following performances: 86% accuracy, 88% sensitivity, and 80% specificity. In this manner, the proposed ECG marker may help clinicians to predict positive response to CRT in a non-invasive way, in order to minimize unsuccessful procedures.This work was supported by MINECO under grants MTM2013-43540-P and MTM2016-76647-P.Ortigosa, N.; Pérez-Roselló, V.; Donoso, V.; Osca Asensi, J.; Martínez-Dolz, L.; Fernández Rosell, C.; Galbis Verdu, A. (2018). Early prediction of cardiac resynchronization therapy response by non-invasive electrocardiogram markers. Medical & Biological Engineering & Computing. 56(4):611-621. https://doi.org/10.1007/s11517-017-1711-1S611621564Boggiatto P, Fernández C, Galbis A (2009) A group representation related to the stockwell transform. Indiana University Mathematics Journal 58(5):2277–2296Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G et al (2013) 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy. Europace 15:1070–1118Brown RA, Lauzon ML, Frayne R (2010) A general description of linear time-frequency transforms and formulation of a fast, invertible transform that samples the continuous s-transform spectrum nonredundantly. IEEE Trans Signal Process 58(1): 281–290Carità P, Corrado E, Pontone G, Curnis A, Bontempi L et al (2016) Non-responders to cardiac resynchronization therapy: insights from multimodality imaging and electrocardiography. A brief review. Int J Cardiol 225:402–407Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C et al (2001) Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 344:873–880Chang CC, Lin CJ (2011) LIBSVM: a library for support vector machines. ACM Trans Intell Syst Technol 2(3):27:1–27:27Chawla NV, Bowyer KW, Hall LO, Kegelmeyer WP (2002) SMOTE: synthetic minority over-sampling technique. J Artif Intell Res 16(1):321–357Cleland JGF, Abraham WT, Linde C, Gold MR, Young J et al (2013) An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resyn- chronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart Journal 34(46):3547–3556Cleland JGF, Calvert MJ, Verboven Y, Freemantle N (2009) Effects of cardiac resynchronization therapy on long-term quality of life: an analysis from the Cardiac Resynchronisation-Heart Failure (CARE-HF) study. Am Heart J 157:457–466Cleland JGF, Freemantle N, Erdmann E, Gras D, Kappenberger L et al (2012) Long-term mortality with cardiac resynchronization therapy in the Cardiac Resynchronization-Heart Failure (CARE-HF) trial. Eur J Heart Fail 14:628–634Egoavil CA, Ho RT, Greenspon AJ, Pavri BB (2005) Cardiac resynchronization therapy in patients with right bundle branch block: analysis of pooled data from the MIRACLE and Contak CD trials. Heart Rhythm 2(6):611–615Engels EB, Mafi-Rad M, van Stipdonk AM, Vernooy K, Prinzen FW (2016) Why QRS duration should be replaced by better measures of electrical activation to improve patient selection for cardiac resynchronization therapy. J Cardiovasc Transl Res 9(4):257–265Engels EB, Végh EM, Van Deursen CJ, Vernooy K, Singh JP, Prinzen FW (2015) T-wave area predicts response to cardiac resynchronization therapy in patients with left bundle branch block. J Cardiovasc Electrophysiol 26(2):176–183Eschalier R, Ploux S, Ritter P, Haïssaguerre M, Ellenbogen K, Bordachar P (2015) Nonspecific intraventricular conduction delay: definitions, prognosis, and implications for cardiac resynchronization therapy. Heart Rhythm 12(5):1071–1079Goldenberg I, Kutyifa V, Klein HU, Cannom DS, Brown MW et al (2014) Survival with cardiac-resynchronization therapy in mild heart failure. N Engl J Med 370:1694–1701He H, Bai Y, Garcia EA, Li S (2008) ADASYN: adaptive synthetic sampling approach for imbalanced learning. In: International joint conference on neural networks, pp 1322–1328Jacobsson J, Borgguist R, Reitan C, Ghafoori E, Chatterjee NA et al (2016) Usefulness of the sum absolute QRST integral to predict outcomes in patients receiving cardiac resynchronization therapy. J Cardiovasc Electrophysiol 118(3):389–395McMurray JJ (2010) Clinical practice. Systolic heart failure. N Engl J Med 3623:228–238Meyer CR, Keiser HN (1977) Electrocardiogram baseline noise estimation and removal using cubic splines and state-space computation techniques. Comput Biomed Res 10:459–470Ortigosa N, Giménez VM (2014) Raw data extraction from electrocardiograms with portable document format. Comput Meth Programs Biomed 113(1):284–289Ortigosa N, Osca J, Jiménez R, Rodríguez Y, Fernández C, Galbis A (2016) Predictive analysis of cardiac resynchronization therapy response by means of the ECG. 2016 Comput Cardio 43:753–756. https://doi.org/10.22489/CinC.2016.218-415Ponikowski P, Voors AA, Anker S, Bueno H, Cleland JG, Coats AJ et al (2016) 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 18(8):891–975Rad MM, Wijntjens GW, Engels EB, Blaauw Y, Luermans JG et al (2016) Vectorcardiographic QRS area identifies delayed left ventricular lateral wall activation determined by electroanatomic mapping in candidates for cardiac resynchronization therapy. Heart Rhythm 13(1):217–225Shanks M, Delgado V, Bax JJ (2016) Cardiac resynchronization therapy in non-ischemic cardiomyopathy. Journal of Atrial Fibrillation 8(5):47–52Singh JP, Fan D, Heist EK, Alabiad CR, Taub C et al (2006) Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy. Heart Rhythm 3(11):1285–1292Sohaib SM, Finegold JA, Nijjer SS, Hossain R, Linde C et al (2015) Opportunity to increase life span in narrow QRS cardiac resynchronization therapy recipients by deactivating ventricular pacing: evidence from randomized controlled trials. JACC Heart Fail 3:327–336Stockwell RG, Mansinha L, Lowe RP (1996) Localization of the complex spectrum: the S transform. IEEE Trans Signal Process 44(4):998–1001Tang ASL, Wells GA, Talajic M, Arnold MO, Sheldon R et al (2010) Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 363:2385–2395Tereshchenko LG, Cheng A, Park J, Wold N, Meyer TE, Gold MR et al (2015) Novel measure of electrical dyssynchrony predicts response in cardiac resynchronization therapy: results from the SMART-AV trial. Heart Rhythm 12(2):2402–2410van Deursen CJ, Vernooy K, Dudink E, Bergfeldt L, Crijns HJ et al (2015) Vectorcardiographic QRS area as a novel predictor of response to cardiac resynchronization therapy. J Electrocardiol 48(1):45–52Wang TJ (2003) Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation 108:977–982Woods B, Hawkins N, Mealing S, Sutton A, Abraham WT et al (2015) Individual patient data network meta-analysis of mortality effects of implantable cardiac devices. Heart 101:1800–1806Ypenburg C, van Bommel RJ, Borleffs CJ, Bleeker GB, Boersma E et al (2009) Long-term prognosis after cardiac resynchronization therapy is related to the extent of left ventricular reverse remodeling at midterm follow-up. J Am Coll Cardiol 53(6):483–490Yu CM, Hayes DL (2013) Cardiac resynchronization therapy: state of the art 2013. Eur Heart J 34:1396–140

Patterns of Schistosoma haematobium infection, impact of praziquantel treatment and re-infection after treatment in a cohort of schoolchildren from rural KwaZulu-Natal/South Africa

BACKGROUND: Schistosomiasis is one of the major health problems in tropical and sub-tropical countries, with school age children usually being the most affected group. In 1998 the Department of Health of the province of KwaZulu-Natal established a pilot programme for helminth control that aimed at regularly treating primary school children for schistosome and intestinal helminth infections. This article describes the baseline situation and the impact of treatment on S. haematobium infection in a cohort of schoolchildren attending grade 3 in a rural part of the province. METHODS: Primary schoolchildren from Maputaland in northern KwaZulu-Natal were examined for Schistosoma haematobium infection, treated with praziquantel and re-examined four times over one year after treatment in order to assess the impact of treatment and patterns of infection and re-infection. RESULTS: Praziquantel treatment was highly efficacious at three weeks after treatment when judged by egg reduction rate (95.3%) and cure rate of heavy infections (94.1%). The apparent overall cure rate three weeks after treatment (57.9%) was much lower but improved to 80.7% at 41 weeks after treatment. Re-infection with S. haematobium was low and appeared to be limited to the hot and rainy summer. Analysis of only one urine specimen per child considerably underestimated prevalence when compared to the analysis of two specimens, but both approaches provided similar estimates of the proportion of heavy infections and of average infection intensity in the population. CONCLUSION: According to WHO guidelines the high prevalence and intensity of S. haematobium infection necessitate regular treatment of schoolchildren in the area. The seasonal transmission pattern together with the slow pace of re-infection suggest that one treatment per year, applied after the end of summer, is sufficient to keep S. haematobium infection in the area at low levels

The breadth of primary care: a systematic literature review of its core dimensions

Background: Even though there is general agreement that primary care is the linchpin of effective health care delivery, to date no efforts have been made to systematically review the scientific evidence supporting this supposition. The aim of this study was to examine the breadth of primary care by identifying its core dimensions and to assess the evidence for their interrelations and their relevance to outcomes at (primary) health system level. Methods: A systematic review of the primary care literature was carried out, restricted to English language journals reporting original research or systematic reviews. Studies published between 2003 and July 2008 were searched in MEDLINE, Embase, Cochrane Library, CINAHL, King's Fund Database, IDEAS Database, and EconLit. Results: Eighty-five studies were identified. This review was able to provide insight in the complexity of primary care as a multidimensional system, by identifying ten core dimensions that constitute a primary care system. The structure of a primary care system consists of three dimensions: 1. governance; 2. economic conditions; and 3. workforce development. The primary care process is determined by four dimensions: 4. access; 5. continuity of care; 6. coordination of care; and 7. comprehensiveness of care. The outcome of a primary care system includes three dimensions: 8. quality of care; 9. efficiency care; and 10. equity in health. There is a considerable evidence base showing that primary care contributes through its dimensions to overall health system performance and health. Conclusions: A primary care system can be defined and approached as a multidimensional system contributing to overall health system performance and health

Exploration of tumour-infiltrating lymphocytes as a predictive biomarker for adjuvant endocrine therapy in early breast cancer.

PURPOSE:Tumour-infiltrating lymphocytes (TILs) have been shown to be prognostic for disease-free survival and predictive for the benefit of chemotherapy in patients with early breast cancer, but have not been studied for endocrine therapy. EXPERIMENTAL DESIGN:The number of CD8-positive TILs was assessed in a subcohort of 236 patients in the Intergroup Exemestane Study. AQ After 2-3 years of adjuvant tamoxifen, AQpatients were randomized between the schemes of continuation for 5 years on tamoxifen and switching to exemestane. The numbers of CD8-positive TILs were analysed for correlations with disease-free survival (DFS) and overall survival (OS). A similar analysis was performed on 2596 patients in the TEAM trial who were randomized between the sequential scheme and the exemestane monotherapy. RESULTS:In the first cohort, patients with low (below median) numbers of CD8-positive TILs had a univariate hazard ratio (HR) for DFS of 0.27 (95% CI 0.13-0.55) in favour of treatment with exemestane, whereas this benefit was not observed in patients with high numbers of CD8-positive TILs (HR 1.34, 95% CI 0.71-2.50, HR for interaction 5.02, p = 0.001). In the second cohort, patients with low numbers of CD8-positive TILs showed a benefit of exemestane treatment on recurrence-free survival (RFS HR 0.67, 95% CI 0.45-0.99), and not with above-median numbers of CD8-positive TILs (HR 0.86, 95% CI 0.59-1.26, HR for interaction 1.29, p = 0.36). CONCLUSIONS:This study is the first to propose the number of CD8-positive TILs as potential predictive markers for endocrine therapy, with the low presence of CD8-positive TILs associated to benefit for exemestane-inclusive therapy. However, treatment-by-marker interactions were only significant in one cohort, indicating the need for further validation

Implementation of the external cephalic version in breech delivery. Dutch national implementation study of external cephalic version

<p>Abstract</p> <p>Background</p> <p>Breech presentation occurs in 3 to 4% of all term pregnancies. External cephalic version (ECV) is proven effective to prevent vaginal breech deliveries and therefore it is recommended by clinical guidelines of the Royal Dutch Organisation for Midwives (KNOV) and the Dutch Society for Obstetrics and Gynaecology (NVOG). Implementation of ECV does not exceed 50 to 60% and probably less.</p> <p>We aim to improve the implementation of ECV to decrease maternal and neonatal morbidity and mortality due to breech presentations. This will be done by defining barriers and facilitators of implementation of ECV in the Netherlands. An innovative implementation strategy will be developed based on improved patient counselling and thorough instructions of health care providers for counselling.</p> <p>Method/design</p> <p>The ultimate purpose of this implementation study is to improve counselling of pregnant women and information of clinicians to realize a better implementation of ECV.</p> <p>The first phase of the project is to detect the barriers and facilitators of ECV. The next step is to develop an implementation strategy to inform and counsel pregnant women with a breech presentation, and to inform and educate care providers. In the third phase, the effectiveness of the developed implementation strategy will be evaluated in a randomised trial. The study population is a random selection of midwives and gynaecologists from 60 to 100 hospitals and practices. Primary endpoints are number of counselled women. Secondary endpoints are process indicators, the amount of fetes in cephalic presentation at birth, complications due to ECV, the number of caesarean sections and perinatal condition of mother and child. Cost effectiveness of the implementation strategy will be measured.</p> <p>Discussion</p> <p>This study will provide evidence for the cost effectiveness of a structural implementation of external cephalic versions to reduce the number of breech presentations at term.</p> <p>Trial Registration</p> <p>Dutch Trial Register (NTR): 1878</p

Diffractive Dijet Production at sqrt(s)=630 and 1800 GeV at the Fermilab Tevatron

We report a measurement of the diffractive structure function $F_{jj}^D$ of the antiproton obtained from a study of dijet events produced in association with a leading antiproton in $\bar pp$ collisions at $\sqrt s=630$ GeV at the Fermilab Tevatron. The ratio of $F_{jj}^D$ at $\sqrt s=630$ GeV to $F_{jj}^D$ obtained from a similar measurement at $\sqrt s=1800$ GeV is compared with expectations from QCD factorization and with theoretical predictions. We also report a measurement of the $\xi$ ($x$-Pomeron) and $\beta$ ($x$ of parton in Pomeron) dependence of $F_{jj}^D$ at $\sqrt s=1800$ GeV. In the region $0.035<\xi<0.095$, $|t|<1$ GeV$^2$ and $\beta<0.5$, $F_{jj}^D(\beta,\xi)$ is found to be of the form $\beta^{-1.0\pm 0.1} \xi^{-0.9\pm 0.1}$, which obeys $\beta$-$\xi$ factorization.Comment: LaTeX, 9 pages, Submitted to Phys. Rev. Letter

A Study of B0 -> J/psi K(*)0 pi+ pi- Decays with the Collider Detector at Fermilab

We report a study of the decays B0 -> J/psi K(*)0 pi+ pi-, which involve the creation of a u u-bar or d d-bar quark pair in addition to a b-bar -> c-bar(c s-bar) decay. The data sample consists of 110 1/pb of p p-bar collisions at sqrt{s} = 1.8 TeV collected by the CDF detector at the Fermilab Tevatron collider during 1992-1995. We measure the branching ratios to be BR(B0 -> J/psi K*0 pi+ pi-) = (8.0 +- 2.2 +- 1.5) * 10^{-4} and BR(B0 -> J/psi K0 pi+ pi-) = (1.1 +- 0.4 +- 0.2) * 10^{-3}. Contributions to these decays are seen from psi(2S) K(*)0, J/psi K0 rho0, J/psi K*+ pi-, and J/psi K1(1270)

Risks of myeloid malignancies in patients with autoimmune conditions

Autoimmune conditions are associated with an elevated risk of lymphoproliferative malignancies, but few studies have investigated the risk of myeloid malignancies. From the US Surveillance Epidemiology and End Results (SEER)-Medicare database, 13 486 myeloid malignancy patients (aged 67+ years) and 160 086 population-based controls were selected. Logistic regression models adjusted for gender, age, race, calendar year and number of physician claims were used to estimate odds ratios (ORs) for myeloid malignancies in relation to autoimmune conditions. Multiple comparisons were controlled for using the Bonferroni correction (P<0.0005). Autoimmune conditions, overall, were associated with an increased risk of acute myeloid leukaemia (AML) (OR 1.29) and myelodysplastic syndrome (MDS, OR 1.50). Specifically, AML was associated with rheumatoid arthritis (OR 1.28), systemic lupus erythematosus (OR 1.92), polymyalgia rheumatica (OR 1.73), autoimmune haemolytic anaemia (OR 3.74), systemic vasculitis (OR 6.23), ulcerative colitis (OR 1.72) and pernicious anaemia (OR 1.57). Myelodysplastic syndrome was associated with rheumatoid arthritis (OR1.52) and pernicious anaemia (OR 2.38). Overall, autoimmune conditions were not associated with chronic myeloid leukaemia (OR 1.09) or chronic myeloproliferative disorders (OR 1.15). Medications used to treat autoimmune conditions, shared genetic predisposition and/or direct infiltration of bone marrow by autoimmune conditions, could explain these excess risks of myeloid malignancies

Pharmacological development of target-specific delocalized lipophilic cation-functionalized carboranes for cancer therapy

PURPOSE: Tumor cell heterogeneity and microenvironment represent major hindering factors in the clinical setting toward achieving the desired selectivity and specificity to malignant tissues for molecularly targeted cancer therapeutics. In this study, the cellular and molecular evaluation of several delocalized lipophilic cation (DLC)-functionalized carborane compounds as innovative anticancer agents is presented. METHODS: The anticancer potential assessment of the DLC-carboranes was performed in established normal (MRC-5, Vero), cancer (U-87 MG, HSC-3) and primary glioblastoma cancer stem (EGFRpos, EGFRneg) cultures. Moreover, the molecular mechanism of action underlying their pharmacological response is also analyzed. RESULTS: The pharmacological anticancer profile of DLC-functionalized carboranes is characterized by: a) a marked in vitro selectivity, due to lower concentration range needed (ca. 10 fold) to exert their cell growth-arrest effect on U-87 MG and HSC-3, as compared with that on MRC-5 and Vero; b) a similar selective growth inhibition behavior towards EGFRpos and EGFRneg cultures (>10 fold difference in potency) without, however, the activation of apoptosis in cultures; c) notably, in marked contrast to cancer cells, normal cells are capable of recapitulating their full proliferation potential following exposure to DLC-carboranes; and, d) such pharmacological effects of DLC-carboranes has been unveiled to be elicited at the molecular level through activation of the p53/p21 axis. CONCLUSIONS: Overall, the data presented in this work indicates the potential of the DLC-functionalized carboranes to act as new selective anticancer therapeutics that may be used autonomously or in therapies involving radiation with thermal neutrons. Importantly, such bifunctional capacity may be beneficial in cancer therapy