Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease\u2014secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide\u2014and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future

Cardiac rehabilitation for heart failure: Do older people want to attend and are they referred?

Purpose Uptake of cardiac rehabilitation services by older people is suboptimal. Offering suitable services may increase participation. This study investigated older heart failure patients' preferences between hospital, community and home-based service models and sociodemographic and clinical factors associated with these preferences. Rates of referral were examined. Methods Cross-sectional survey of patients aged 65 years and older consecutively admitted to elderly care, cardiology and general medicine wards in a large UK hospital with confirmed heart failure between March-December 2009. A 57-item interview schedule incorporating open and closed questions and standard measures was developed enabling both quantitative and qualitative analysis. Associations between patients' preferences and characteristics including disease severity (New York Heart Association [NYHA] classification) and comorbidity (Charlson comorbidity score) were analysed using Chi-squared tests and one-way ANOVA. Results One hundred and six interviews were completed (mean age 77.8 ± 7.3, 62% male, 47% lived alone). Most patients had moderate-severe heart failure (55% NYHA class III; 34% class II) and co-morbidities (mean Charlson score 3.3 ± 1.7). Most opted for cardiac rehabilitation (72%), preferring hospital to community classes. Those preferring hospital programmes were younger (mean 5.1 years, 95% CI -10.1 to -0.1, P = 0.043) than those preferring not to participate. Neither disease severity nor comorbidity was associated with preferences. Only 21% were referred to any cardiac rehabilitation service. Conclusion Most of these older heart failure patients wanted to attend cardiac rehabilitation, but few were referred. Age was related to preferring certain cardiac rehabilitation service models but not to an overall preference to attend. Referral processes need urgent improvement and offering choice of service models may increase participation. © 2014 Elsevier Masson SAS and European Union Geriatric Medicine Society

Ten Year Real World Experience with Ultrafiltration for the Management of Acute Decompensated Heart Failure

Background: Randomized controlled trials (RCT) of ultrafiltration (UF) have demonstrated conflicting results regarding its efficacy and safety. Objective: We reviewed 10 years of data for adjustable UF during heart failure hospitalizations in a real world cohort. Methods: We performed a retrospective, single center analysis of 335 consecutive patients treated with adjustable rate UF using the CHF Solutions Aquadex Flex Flo System from 2009 to 2019. Results: Compared to previous RCTs investigating UF, our cohort was older, with worse renal impairment and more antecedent HF hospitalizations in the year preceding therapy. Mean fluid removal with UF was 14.6 l. Mean weight loss with UF was 15.6 lbs (range 0.2–57 lbs) and was sustained at 1–2 week follow-up. Mean creatinine change upon stopping UF, at discharge and follow-up (mean 30 days) was +0.11 mg/dl, +0.07 mg/dl and +0.11 mg/dl, respectively. HF rehospitalizations at 30 days, 90 days and 1 year were 12.4 %, 14.9 % and 27.3 % respectively. On average patients had 1.74 fewer hospitalizations for HF in the year following UF when compared to 12 months preceding UF. Major bleeding defined as requiring discontinuation of anticoagulation occurred in 3.6 % of patients. Conclusions: Compared with previous UF trials, our study demonstrates that UF compares favorably for HF rehospitalizations, renal function response, and weight/volume loss. Importantly, our real world experience allowed for the adjustment of UF rate during therapy and we believe this is a major contributor to our favorable outcomes. In clinical practice, UF can be a safe and effective strategy for decongestion

Prognostic value of discharge heart rate in acute heart failure patients: more relevant in atrial fibrillation?

[Abstract] Aims. The prognostic impact of heart rate (HR) in acute heart failure (AHF) patients is not well known especially in atrial fibrillation (AF) patients. The aim of the study was to evaluate the impact of admission HR, discharge HR, HR difference (admission-discharge) in AHF patients with sinus rhythm (SR) or AF on long- term outcomes. Methods. We included 1398 patients consecutively admitted with AHF between October 2013 and December 2014 from a national multicentre, prospective registry. Logistic regression models were used to estimate the association between admission HR, discharge HR and HR difference and one- year all-cause mortality and HF readmission. Results. The mean age of the study population was 72 ± 12 years. Of these, 594 (42.4%) were female, 655 (77.8%) were hypertensive and 655 (46.8%) had diabetes. Among all included patients, 745 (53.2%) had sinus rhythm and 653 (46.7%) had atrial fibrillation. Only discharge HR was associated with one year all-cause mortality (Relative risk (RR) = 1.182, confidence interval (CI) 95% 1.024–1.366, p = 0.022) in SR. In AF patients discharge HR was associated with one year all cause mortality (RR = 1.276, CI 95% 1.115–1.459, p ≤ 0.001). We did not observe a prognostic effect of admission HR or HRD on long-term outcomes in both groups. This relationship is not dependent on left ventricular ejection fraction. Conclusions. In AHF patients lower discharge HR, neither the admission nor the difference, is associated with better long-term outcomes especially in AF patients

Prognostic value of discharge heart rate in acute heart failure patients: More relevant in atrial fibrillation?

Aims: The prognostic impact of heart rate (HR) in acute heart failure (AHF) patients is not well known especially in atrial fibrillation (AF) patients. The aim of the study was to evaluate the impact of admission HR, discharge HR, HR difference (admission-discharge) in AHF patients with sinus rhythm (SR) or AF on long- term outcomes. Methods: We included 1398 patients consecutively admitted with AHF between October 2013 and December 2014 from a national multicentre, prospective registry. Logistic regression models were used to estimate the association between admission HR, discharge HR and HR difference and one- year all-cause mortality and HF readmission. Results: The mean age of the study population was 72+/-12years. Of these, 594 (42.4%) were female, 655 (77.8%) were hypertensive and 655 (46.8%) had diabetes. Among all included patients, 745 (53.2%) had sinus rhythm and 653 (46.7%) had atrial fibrillation. Only discharge HR was associated with one year all-cause mortality (Relative risk (RR)=1.182, confidence interval (CI) 95% 1.024-1.366, p=0.022) in SR. In AF patients discharge HR was associated with one year all cause mortality (RR=1.276, CI 95% 1.115-1.459, p</=0.001). We did not observe a prognostic effect of admission HR or HRD on long-term outcomes in both groups. This relationship is not dependent on left ventricular ejection fraction. Conclusions: In AHF patients lower discharge HR, neither the admission nor the difference, is associated with better long-term outcomes especially in AF patients

Angiotensin receptor-neprilysin inhibitors: a new paradigm in heart failure with reduced ejection fraction

Despite significant advances in the last 30 years in reducing morbidity and mortality from heart failure with reduced ejection fraction (HFrEF) with pharmacological and device-based therapies, patients remain at a high risk of adverse cardiovascular outcomes. Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitors (ARNI), has been shown to reduce the risk of cardiovascular death or heart failure hospitalisation and improve symptoms in patients with chronic, ambulatory, symptomatic HFrEF in a large, phase 3, multicentre, international, randomised controlled trial, PARADIGM-HF, when compared to the gold-standard angiotensin converting enzyme inhibitor, enalapril. This article will review the development of sacubitril/valsartan, the evidence for its use and its current and future role in the management of HFrEF

Evolution of renal function and predictive value of serial renal assessments among patients with acute coronary syndrome: BIOMArCS study

Background: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. Methods: F

Evolution of renal function and predictive value of serial renal assessments among patients with acute coronary syndrome:BIOMArCS study

Background: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. Methods: From 844 ACS patients included in the BIOMArCS study, we analysed patient-specific longitudinal marker trajectories from the case-cohort of 187 patients to determine the risk of the endpoint (cardiovascular death or hospitalization for recurrent non-fatal ACS) during 1-year follow-up. Study included only patients with eGFRCr ≥ 30 ml/min/1.73 m2. Survival analyses were adjusted for GRACE risk score and based on data >30 days after the index ACS (mean of 8 sample per patient). Results: Mean age was 63 years, 79% were men, 43% had STEMI, and 67% were in eGFR stages 2–3. During hospitalization for index ACS (median [IQR] duration: 5 (3–7) days), CysC levels indicated deterioration of renal function earlier than creatinine did (CysC peaked on day 3, versus day 6 for creatinine), and both stabilized after two weeks. Higher CysC levels, but not creatinine, predicted the endpoint independently of the GRACE score within the first year after index ACS (adjusted HR [95% CI] per 1SD increase: 1.68 [1.03–2.74]). Conclusion: Immediately following index ACS, plasma CysC levels deteriorate earlier than creatinine-based indices do, but neither marker stabilizes during hospitalization but on average two weeks after ACS. Serially measured CysC levels predict mortality or recurrence of ACS during 1-year follow-up independently of patients' GRACE risk score

Inpatient versus outpatient intravenous diuresis for the acute exacerbation of chronic heart failure

BACKGROUND: We established an IV outpatient diuresis (IVOiD) clinic and conducted a quality improvement project to evaluate safety, effectiveness and costs associated with outpatient versus inpatient diuresis for patients presenting with acute decompensated heart failure (ADHF) to the emergency department (ED). METHODS: Patients who were clinically diagnosed with ADHF in the ED, but did not have high-risk features, were either diuresed in the hospital or in the outpatient IVOiD clinic. The dose of IV diuretic was based on their home maintenance diuretic dose. The outcomes measured were the effects of diuresis (urine output, weight, hemodynamic and laboratory abnormalities), 30-90 day readmissions, 30-90 day death and costs. RESULTS: In total, 36 patients (22 inpatients and 14 outpatients) were studied. There were no significant differences in the baseline demographics between groups. The average inpatient stay was six days and the average IVOiD clinic days were 1.2. There was no significant difference in diuresis per day of treatment (1159 vs. 944 ml, p = 0.46). There was no significant difference in adverse outcomes, 30-90 day readmissions or 30-90 day deaths. There was a significantly lower cost in the IVOiD group compared to the inpatient group ($839.4 vs.$9895.7, p=\u3c0.001). CONCLUSIONS: Outpatient IVOiD clinic diuresis may be a viable alternative to accepted clinical practice of inpatient diuresis for ADHF. Further studies are needed to validate this in a larger cohort and in different sites