Testing for ocean acidification during the Early Toarcian using δ44/40Ca and δ88/86Sr

During the Early Toarcian, volcanic gases released by the Karoo-Ferrar large igneous province are widely believed to have caused severe environmental disturbances, including ocean acidification. Here we show records of δ Ca and δ Sr through the Early Toarcian, as recorded in three groups of biogenic calcite: Megateuthididae belemnites, Passaloteuthididae belemnites, and brachiopods of the species Soaresirhynchia bouchardi. We evaluate the data to eliminate the influence on isotopic composition of varying temperature, calcification rate, and salinity, through the section that may mask the environmental signals. Neither δ Ca nor δ Sr show negative isotope excursions across the suggested acidification interval as would be expected had acidification occurred. A profile of δ B, re-interpreted from a published study, shows no variation through the interval. Taken together, these data provide little support for ocean acidification at this time. In our belemnites, values of δ Sr are independent of temperature or Sr/Ca. For brachiopods, too few data are available to determine whether such dependences exist. Values of δ Ca show a weak temperature control of magnitude +0.020 ± 0.004 ‰/°C (2 s.d.). In belemnites, δ Ca also correlates positively with Mg/Ca and Sr/Ca. 44/40 88/86 44/40 88/86 11 88/86 44/40 44/4

Effect of disease-modifying agents and their association with mortality in multi-morbid patients with heart failure with reduced ejection fraction

Aims An increasing proportion of patients with heart failure with reduced ejection fraction (HFrEF) have co‐morbidities. The effect of these co‐morbidities on modes of death and the effect of disease‐modifying agents in multi‐morbid patients is unknown. Methods and results We performed a prospective cohort study of ambulatory patients with HFrEF to assess predictors of outcomes. We identified four key co‐morbidities—ischaemic aetiology of heart failure, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and chronic kidney disease (CKD)—that were highly prevalent and associated with an increased risk of all‐cause mortality. We used these data to explore modes of death and the utilization of disease‐modifying agents in patients with and without these co‐morbidities. The cohort included 1789 consecutively recruited patients who had an average age of 69.6 ± 12.5 years, and 1307 (73%) were male. Ischaemic aetiology of heart failure was the most common co‐morbidity, occurring in 1061 (59%) patients; 503 (28%) patients had diabetes mellitus, 283 (16%) had COPD, and 140 (8%) had CKD stage IV/V. During mean follow‐up of 3.8 ± 1.6 years, 737 (41.5%) patients died, classified as progressive heart failure (n = 227, 32%), sudden (n = 112, 16%), and non‐cardiovascular deaths (n = 314, 44%). Multi‐morbid patients were older (P 2.5‐fold and 1.5‐fold increased risk of sudden death, whilst higher doses of beta‐adrenoceptor antagonists were protective (hazard ratio per milligram 0.92, 95% confidence interval 0.86–0.98, P = 0.009). Each milligram of bisoprolol‐equivalent beta‐adrenoceptor antagonist was associated with 9% (P = 0.001) and 11% (P = 0.023) reduction of sudden deaths in patients with <2 and ≥2 co‐morbidities, respectively. Conclusions Higher doses of beta‐adrenoceptor antagonist are associated with greater protection from sudden death, most evident in multi‐morbid patients. Patients with COPD who appear to be at the highest risk of sudden death are prescribed the lowest doses and less likely to be implanted with implantable cardioverter defibrillators, which might represent a missed opportunity to optimize safe and proven therapies for these patients

Effect of antiandrogen flutamide on measures of hepatic regeneration in rats

Male rat liver undergoes a process of demasculinization during hepatic regeneration following partial hepatectomy. The possibility that antiandrogens might potentiate this demasculinization process and in so doing augment the hepatic regenerative response was investigated. Adult male Wistar rats were treated with the antiandrogen flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for three days prior to and daily after a 70% partial hepatectomy. At various times after hepatectomy, the liver remnants were removed and weighed. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. Hepatic estrogen receptor status and the activity of alcohol dehydrogenase, an androgen-sensitive protein, were measured. Prior to surgery, the administration of 5 mg/day flutamide reduced the hepatic cytosolic androgen receptor activity by 98% and hepatic cytosolic estrogen receptor content by 92% compared to that present in vehicle-treated controls. After hepatectomy, however, all differences in sex hormone receptor activity between the treatment groups were abolished. The rate of liver growth after partial hepatectomy in the three groups was identical. Moreover, hepatectomy-induced increases in ornithine decarboxylase activity and thymidine kinase activity were comparable. These data demonstrate that, although flutamide administration initially alters the sex hormone receptor status of the liver, these affects have no effect on the hepatic regenerative response following a partial hepatectomy. © 1989 Plenum Publishing Corporation

Epidermoid cyst of the floor of the mouth: two case reports

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Rate-Response Programming Tailored to the Force-Frequency Relationship Improves Exercise Tolerance in Chronic Heart Failure

Objectives: This study sought to examine whether the heart rate (HR) at which the force-frequency relationship (FFR) slope peaks (critical HR) could be used to tailor HR response in chronic heart failure (CHF) patients with cardiac pacemakers and whether this favorably influences exercise capacity. Background: CHF secondary to left ventricular (LV) systolic dysfunction is characterized by blunting of the positive relationship between HR and LV contractility known as the FFR. Methods: This observational study was carried out in patients with CHF and healthy subjects with pacemaker devices. The study assessed the 3 important features of the FFR (critical HR, peak contractility, and the FFR slope), and their reproducibility was measured noninvasively using echocardiography. The investigators then undertook a double-blind, randomized, controlled crossover study comparing the effects of tailored pacemaker rate-response programming on the basis of the FFR with conventional rate-response programming on exercise time and maximal oxygen consumption. Results: The study enrolled 90 patients with CHF into the observational cohort study: mean age, 73.6 ± 8.9 years; mean left ventricular ejection fraction (LVEF), 33.5 ± 10.9%. The study investigated 15 control subjects with normal LV function (LVEF, 55.6 ± 5.3%). The critical HR (103 ± 22 beats/min vs. 126 ± 15 beats/min; p = 0.0002), peak contractility (3.8 ± 3.7 SBP/LVESVI vs. 9.8 ± 4.1 SBP/LVESVI; p = 0.0001), and the slope of the FFR (p < 10−15) were lower in patients with CHF than in control subjects. A total of 52 patients, with a mean LVEF of 32 ± 11% on optimal therapy, took part in the crossover study. Rate-response settings limiting HR rise to below the critical HR led to greater exercise time (475 ± 189 s vs. 425 ± 196 s; p = 0.003) and higher peak oxygen consumption (17.3 ± 4.6 ml/kg/min vs. 16.6 ± 4.7 ml/kg/min; p = 0.01). Conclusions: A personalized approach to rate-response programming, determined using a reproducible noninvasive method for assessing the FFR, improves exercise time in patients with CHF and pacemaker devices. (Bowditch Revisited: Defining the Optimum Heart Rate Range in Chronic Heart Failure; NCT02563873

Vitamin D deficiency is an independent predictor of mortality in patients with chronic heart failure

Purpose: Low 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with adverse outcomes in selected populations with established chronic heart failure (CHF). However, it remains unclear whether 25[OH]D deficiency is associated with mortality and hospitalisation in unselected patients receiving contemporary medical and device therapy for CHF. Methods: We prospectively examined the prevalence and correlates of 25[OH]D deficiency in 1802 ambulatory patients with CHF due to left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 45%) attending heart failure clinics in the north of England. Results: 73% of patients were deficient in 25[OH]D (< 50 nmol/L). 25[OH]D deficiency was associated with male sex, diabetes, lower serum sodium, higher heart rate, and greater diuretic requirement. During a mean follow-up period of 4 years, each 2.72-fold increment in 25[OH]D concentration (for example from 32 to 87 nmol/L) is associated with 14% lower all-cause mortality (95% confidence interval (CI) 1, 26%; p = 0.04), after accounting for potential confounding factors. Conclusions: Low 25-hydroxyvitamin D deficiency is associated with increased mortality in patients with chronic heart failure due to left ventricular systolic dysfunction. Whether vitamin D supplementation will improve outcomes is, as yet, unproven

Personalised reprogramming to prevent progressive pacemaker-related left ventricular dysfunction: A phase II randomised, controlled clinical trial

Background Pacemakers are widely utilised to treat bradycardia, but right ventricular (RV) pacing is associated with heightened risk of left ventricular (LV) systolic dysfunction and heart failure. We aimed to compare personalised pacemaker reprogramming to avoid RV pacing with usual care on echocardiographic and patient-orientated outcomes. Methods A prospective phase II randomised, double-blind, parallel-group trial in 100 patients with a pacemaker implanted for indications other than third degree heart block for ≥2 years. Personalised pacemaker reprogramming was guided by a published protocol. Primary outcome was change in LV ejection fraction on echocardiography after 6 months. Secondary outcomes included LV remodeling, quality of life, and battery longevity. Results Clinical and pacemaker variables were similar between groups. The mean age (SD) of participants was 76 (+/-9) years and 71% were male. Nine patients withdrew due to concurrent illness, leaving 91 patients in the intention-to-treat analysis. At 6 months, personalised programming compared to usual care, reduced RV pacing (-6.5±1.8% versus -0.21±1.7%; p<0.01), improved LV function (LV ejection fraction +3.09% [95% confidence interval (CI) 0.48 to 5.70%; p = 0.02]) and LV dimensions (LV end systolic volume indexed to body surface area -2.99mL/m2 [95% CI -5.69 to -0.29; p = 0.03]). Intervention also preserved battery longevity by approximately 5 months (+0.38 years [95% CI 0.14 to 0.62; p<0.01)) with no evidence of an effect on quality of life (+0.19, [95% CI -0.25 to 0.62; p = 0.402]). Conclusions Personalised programming in patients with pacemakers for bradycardia can improve LV function and size, extend battery longevity, and is safe and acceptable to patients. Trial registration ClinicalTrials.gov identifier: NCT03627585

Ischemic Heart Disease Modifies the Association of Atrial Fibrillation With Mortality in Heart Failure With Reduced Ejection Fraction

Background: The CASTLE‐AF (Catheter Ablation versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation) trial recently reported that catheter ablation of atrial fibrillation (AF) improves survival in heart failure (HF) with reduced ejection fraction (HFrEF). However, established AF was not associated with mortality in trials of contemporary HFrEF pharmacotherapies. We investigated whether HFrEF pathogenesis may influence the conclusions of studies evaluating the prognostic impact of AF. Methods and Results: Using a prospective cohort study of 791 patients with HFrEF, with AF determined using 24‐hour ambulatory ECG monitoring, univariable and multivariable Cox regression analyses were used to define the association between AF and mode‐specific mortality (mean follow‐up of 5.4 years). One‐year HF‐related hospitalization was assessed with binary logistic regression analysis. One‐year cardiac remodeling was assessed in a subgroup (n=378) using echocardiography. AF was present in 28.2% of patients, with 9.4% of these being paroxysmal. While AF was associated with increased risk of all‐cause mortality (hazard ratio, 1.27; 95% confidence interval 1.03–1.57), with diverging survival curves after 1 year of follow‐up, this association was lost in age‐sex–adjusted analyses. However, AF was associated with increased risk of age‐sex–adjusted all‐cause mortality in people with ischemic pathogenesis, with a statistically significant interaction between pathogenesis and AF. This was predominantly attributed to progressive HF deaths. After 1 year, HF hospitalization and cardiac remodeling were not associated with AF, even in people with ischemic pathogenesis. Conclusions: AF is associated with increased risk of death in HFrEF of ischemic pathogenesis, predominantly due to progressive HF deaths during long‐term follow‐up. HFrEF pathogenesis should be considered in trial design and interpretation

Impact of QRS duration on left ventricular remodelling and survival in patients with heart failure

Aims In patients with chronic heart failure, QRS duration is a consistent predictor of poor outcomes. It has been suggested that for indicated patients, cardiac resynchronization therapy (CRT) could come sooner in the treatment algorithm, perhaps in parallel with the attainment of optimal guideline-directed medical therapy (GDMT). We aimed to investigate differences in left ventricular (LV) remodelling in those with narrow QRS (NQRS) compared with wide QRS (WQRS) in the absence of CRT, whether an early CRT strategy resulted in unnecessary implants and the effect of early CRT on outcomes. Methods Our cohort consisted of 214 consecutive patients with LV ejection fraction (LVEF) of 35% or less who underwent repeat echocardiography 1 year after enrolment. Of these, 116 patients had NQRS, and 98 had WQRS of whom 40 received CRT within 1 year and 58 did not. Results In the absence of CRT, patients with WQRS had less LV reverse remodelling compared with those with NQRS, with differences in ΔLVEF (+2 vs. +9%, P < 0.001) ΔLV end-diastolic diameter (−1 vs. −2 mm, P = 0.095), ΔLV end-systolic diameter (−2 vs. −4.5 mm, P = 0.038), LV end-systolic volume (−12.6 vs. −25.0 ml, P = 0.054) and LV end-diastolic volume (−7.3 vs. −12.2 ml, P = 0.071). LVEF was more likely to improve by at least 10% if patients had NQRS or received CRT (P = 0.08). Thirteen (24%) patients with WQRS achieved an LVEF greater than 35% in the absence of CRT; however, none achieved greater than 50%. Conclusion A strictly linear approach to heart failure therapy might lead to delays to optimal treatment in those patients with the most to gain from CRT and the least to gain from GDMT

Optimising pacemaker therapy and medical therapy in pacemaker patients for heart failure: protocol for the OPT-PACE randomised controlled trial

Introduction: Permanent artificial pacemaker implantation is a safe and effective treatment for bradycardia and is associated with extended longevity and improved quality of life. However, the most common long-term complication of standard pacemaker therapy is pacemaker-associated heart failure. Pacemaker follow-up is potentially an opportunity to screen for heart failure to assess and optimise patient devices and medical therapy. Methods and analysis: The study is a multicentre, phase-3 randomised trial. The 1200 participants will be people who have a permanent pacemaker for bradycardia for at least 12 months, randomly assigned to undergo a transthoracic echocardiogram with their pacemaker check, thereby tailoring their management directed by left ventricular function or the pacemaker check alone, continuing with routine follow-up. The primary outcome measure is time to all-cause mortality or heart failure hospitalisation. Secondary outcomes include external validation of our risk stratification model to predict onset of heart failure and quality of life assessment. Ethics and Dissemination: The trial design and protocol have received national ethical approval (12/YH/0487). The results of this randomised trial will be published in international peer-reviewed journals, communicated to healthcare professionals and patient involvement groups and highlighted using social media campaigns. Trial registration number: NCT01819662