Thromboelastography (TEG (R)) demonstrates that tinzaparin 4500 international units has no detectable anticoagulant activity after caesarean section

Background Low molecular weight heparin is routinely used for thromboprophylaxis in pregnancy and the puerperium. Consensus guidelines recommend waiting 10–12 h after administration of a thromboprophylactic dose of low molecular weight heparin before performing a neuraxial block or removing an epidural catheter. Thromboelastography (TEG®) has been reported to be sensitive to the effects of enoxaparin 4 h after administration. The purpose of this study was to use TEG to examine coagulation changes in the first 10 h after a thromboprophylactic dose of tinzaparin in an attempt to ratify the current consensus guidelines about timing of neuraxial blockade and epidural catheter removal. Methods Twenty-four women who had undergone caesarean delivery and were classified as low or intermediate risk of thrombosis were recruited. Blood samples were taken before subcutaneous administration of tinzaparin 4500 IU, and at 4, 8 and 10 h post-dose. Standard TEG analyses were performed using plain and heparinase cuvettes and samples were also sent for laboratory anti-Xa assay. Thromboelastograph profiles were analysed for a low molecular weight heparin effect. Results Analysis revealed no significant differences in R time, K time, alpha angle or maximum amplitude between plain and heparinase samples at any time point. Apart from a small statistically significant (P=0.033) decrease in maximum amplitude of 2.8% (95% CI 0.3 to 5.4%) at 4 h, there were no significant changes in coagulation for any TEG parameter. Anti-Xa levels were virtually undetectable in all patients over the 10 h period (median 0.00 U/mL; range 0.00–0.13 U/mL). Conclusion A thromboprophylactic dose of tinzaparin 4500 IU had little detectable effect on coagulation as assessed by TEG and anti-Xa assay. These findings support consensus guidelines which state that it is acceptable to perform neuraxial blockade or remove an epidural catheter 10–12 h after a thromboprophylactic dose of tinzaparin. Rather than suggesting a lack of anticoagulant activity, the findings indicate that TEG may not have the sensitivity to detect a tinzaparin effect when this dose is used in this patient group

DPD Quantification in Cardiac Amyloidosis A Novel Imaging Biomarker

OBJECTIVES: To assess whether single-photon emission computed tomography (SPECT/CT) quantification of bone scintigraphy would improve diagnostic accuracy and offer a means of quantifying amyloid burden. BACKGROUND: Transthyretin-related cardiac amyloidosis is common and can be diagnosed noninvasively using bone scintigraphy; interpretation, however, relies on planar images. SPECT/CT imaging offers 3-dimensional visualization. METHODS: This was a single-center, retrospective analysis of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scans reported using the Perugini grading system (0 = negative; 1 to 3 = increasingly positive). Conventional planar quantification techniques (heart/contralateral lung, and heart/whole-body retention ratios) were performed. Heart, adjacent vertebra, paraspinal muscle and liver peak standardized uptake values (SUVpeak) were recorded from SPECT/CT acquisitions. An SUV retention index was also calculated: (cardiac SUVpeak/vertebral SUVpeak) × paraspinal muscle SUVpeak. In a subgroup of patients, SPECT/CT quantification was compared with myocardial extracellular volume quantification by CT imaging (ECVCT). RESULTS: A total of 100 DPD scans were analyzed (patient age 84 ± 9 years; 52% male): 40 were Perugini grade 0, 12 were grade 1, 41 were grade 2, and 7 were grade 3. Cardiac SUVpeak increased from grade 0 to grade 2; however, it plateaued between grades 2 and 3 (p < 0.001). Paraspinal muscle SUVpeak increased with grade (p < 0.001), whereas vertebral SUVpeak decreased (p < 0.001). The composite parameter of SUV retention index overcame the plateauing of the cardiac SUVpeak and increased across all grades (p < 0.001). Cardiac SUVpeak correlated well (r2 = 0.73; p < 0.001) with ECVCT. Both the cardiac SUVpeak and SUV retention index had excellent diagnostic accuracy (area under the curve [AUC]: 0.999). The heart to contralateral lung ratio performed the best of the planar quantification techniques (AUC: 0.987). CONCLUSIONS: SPECT/CT quantification in DPD scintigraphy is possible and outperforms planar quantification techniques. Differentiation of Perugini grade 2 or 3 is confounded by soft tissue uptake, which can be overcome by a composite SUV retention index. This index can help in the diagnosis of cardiac amyloidosis and may offer a means of monitoring response to therapy

Real-world performance and accuracy of stress echocardiography: The EVAREST observational multi-centre study

Aims - Stress echocardiography is widely used to identify obstructive coronary artery disease. High accuracy is reported in expert hands but is dependent on operator training and image quality. The EVAREST study provides UK-wide data to evaluate real-world performance and accuracy of stress echocardiography. Methods and Results - Participants undergoing stress echocardiography for coronary artery disease were recruited from 31 hospitals. Participants were followed up through health records which underwent expert adjudication. Cardiac outcome was defined as anatomically or functionally-significant stenosis on angiography, revascularisation, medical management of ischaemia, acute coronary syndrome or cardiac-related death within six months. 5131 patients (55% male) participated with a median age of 65 years (IQR 57 – 74). 72.9% of studies used dobutamine and 68.5% were contrast studies. Inducible ischaemia was present in 19.3% of scans. Sensitivity and specificity for prediction of a cardiac outcome were 95.4% and 96.0%, respectively, with an accuracy of 95.9%. Sub-group analysis revealed high levels of predictive accuracy across a wide range of patient and protocol sub-groups, with the presence of a resting regional wall motion abnormalitiy significantly reducing the performance of both dobutamine (p<0.01) and exercise (p<0.05) stress echocardiography (p<0.05). Overall accuracy remained consistently high across all participating hospitals. Conclusion – Stress echocardiography has high accuracy across UK-based hospitals and thus indicates stress echocardiography is being delivered effectively in real-world practice, reinforcing its role as a first-line investigation in the assessment of patients with stable chest pain

Prevalence and Outcomes of Concomitant Aortic Stenosis and Cardiac Amyloidosis

Background: Older patients with severe aortic stenosis (AS) are increasingly identified to have cardiac amyloidosis (CA). It is unknown whether dual AS-CA has worse outcomes or results in futility of transcatheter aortic valve replacement (TAVR). / Objective: To identify clinical characteristics and outcomes of AS-CA compared to lone AS. / Methods: TAVR referrals at three international sites underwent blinded research-corelab 99mTc-DPD bone scintigraphy (Perugini Grade-0 negative, 1–3 increasingly positive) prior to intervention. Transthyretin-CA (ATTR) was diagnosed by DPD and absence of a clonal immunoglobulin, and light-chain-CA (AL) via tissue biopsy. National registries captured all-cause mortality. / Results: 407 patients (83.4±6.5 years, 49.8% male) were recruited. DPD was positive in n=48 (11.8%, Grade-1 3.9%[n=16] Grade-2/3 7.9%[n=32]); AL was diagnosed in one Grade-1. Grade-2/3 patients had worse functional capacity, biomarkers (NT-proBNP/hsTnT), and bi-ventricular remodeling. A clinical score (RAISE) using left-ventricular Remodeling (hypertrophy/diastolic dysfunction), Age, Injury (hsTnT), Systemic involvement, and Electrical abnormalities (RBBB/low-voltages) was developed to predict AS-CA presence (AUC 0.86, 95%CI 0.78-0.94, p<0.001). Heart Team decision (DPD-blinded) resulted in TAVR (333[81.6%]), surgical-AVR (10[2.5%]), or medical management (65[15.9%]). After median 1.7 years, 23% of patients had died. 1-year mortality was worse in all-comers AS-CA (Grade-1-3) than lone AS (24.5 vs 13.9%, p=0.05). TAVR improved survival versus medical management with AS-CA survival post-TAVR no different to lone AS (p=0.36). / Conclusion: Dual pathology of AS-CA is common in older AS patients and can be predicted clinically. AS-CA has worse clinical presentation and a trend towards worse prognosis, unless treated. TAVR should therefore not be withheld in AS-CA

Numerical loop quantum cosmology: an overview

A brief review of various numerical techniques used in loop quantum cosmology and results is presented. These include the way extensive numerical simulations shed insights on the resolution of classical singularities, resulting in the key prediction of the bounce at the Planck scale in different models, and the numerical methods used to analyze the properties of the quantum difference operator and the von Neumann stability issues. Using the quantization of a massless scalar field in an isotropic spacetime as a template, an attempt is made to highlight the complementarity of different methods to gain understanding of the new physics emerging from the quantum theory. Open directions which need to be explored with more refined numerical methods are discussed.Comment: 33 Pages, 4 figures. Invited contribution to appear in Classical and Quantum Gravity special issue on Non-Astrophysical Numerical Relativit

Prevalence and Outcomes of Concomitant Aortic Stenosis and Cardiac Amyloidosis

BACKGROUND: Older patients with severe aortic stenosis (AS) are increasingly identified as having cardiac amyloidosis (CA). It is unknown whether concomitant AS-CA has worse outcomes or results in futility of transcatheter aortic valve replacement (TAVR). OBJECTIVES: This study identified clinical characteristics and outcomes of AS-CA compared with lone AS. METHODS: Patients who were referred for TAVR at 3 international sites underwent blinded research core laboratory 99mtechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) bone scintigraphy (Perugini grade 0: negative; grades 1 to 3: increasingly positive) before intervention. Transthyretin-CA (ATTR) was diagnosed by DPD and absence of a clonal immunoglobulin, and light-chain CA (AL) was diagnosed via tissue biopsy. National registries captured all-cause mortality. RESULTS: A total of 407 patients (age 83.4 6.5 years; 49.8% men) were recruited. DPD was positive in 48 patients (11.8%; grade 1: 3.9% [n ¼ 16]; grade 2/3: 7.9% [n ¼ 32]). AL was diagnosed in 1 patient with grade 1. Patients with grade 2/3 had worse functional capacity, biomarkers (N-terminal pro-brain natriuretic peptide and/or high-sensitivity troponin T), and biventricular remodeling. A clinical score (RAISE) that used left ventricular remodeling (hypertrophy/diastolic dysfunction), age, injury (high-sensitivity troponin T), systemic involvement, and electrical abnormalities (right bundle branch block/low voltages) was developed to predict the presence of AS-CA (area under the curve: 0.86; 95% confidence interval: 0.78 to 0.94; p < 0.001). Decisions by the heart team (DPD-blinded) resulted in TAVR (333 [81.6%]), surgical AVR (10 [2.5%]), or medical management (65 [15.9%]). After a median of 1.7 years, 23% of patients died. One-year mortality was worse in all patients with AS-CA (grade: 1 to 3) than those with lone AS (24.5% vs. 13.9%; p ¼ 0.05). TAVR improved survival versus medical management; AS-CA survival post-TAVR did not differ from lone AS (p ¼ 0.36). CONCLUSIONS: Concomitant pathology of AS-CA is common in older patients with AS and can be predicted clinically. AS-CA has worse clinical presentation and a trend toward worse prognosis, unless treated. Therefore, TAVR should not be withheld in AS-CA. (J Am Coll Cardiol 2021;77:128–39) © 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The aetiology of rickets-like lower limb deformities in Malawian children

Summary: Debilitating rickets-like lower limb deformities are common in children throughout the world, particularly in Malawi, Africa where the causes are unknown. We have identified that Blount disease and calcium deficiency rickets are the likely causes of these deformities and propose calcium supplementation as a potential treatment of Malawian rickets. Introduction: Surgical correction of rickets-like lower limb deformities is the most common paediatric operation performed at Beit Cure Orthopaedic Hospital, Malawi. The aim of this study was to investigate the aetiology of these deformities. Methods: Children with a tibio-femoral angle of deformity >20° were enrolled (n = 42, 3.0–15.0 years). Anthropometric and early life and well-being data were collected. Early morning serum and urine samples were collected on the morning of the operation for markers of calcium and phosphate homeostasis. Knee radiographs were obtained, and the children were diagnosed with either Blount (BD, n = 22) or evidence of rickets disease (RD, n = 20). As BD is a mechanical rather than metabolic disease, BD were assumed to be biochemically representative of the local population and thus used as a local reference for RD. Results: There were no differences in anthropometry or early life experiences between BD and RD. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, total alkaline phosphatase and urinary phosphate were significantly higher and serum phosphate, 25-hydroxyvitamin D (25OHD) and tubular maximal reabsorption of phosphate significantly lower in RD than BD. There was no difference in serum calcium, fibroblast growth factor 23 or markers of iron status between groups. All children had 25OHD > 25 nmol/L. Conclusions: Vitamin D deficiency is not implicated in the aetiology of RD or BD in Malawian children. The cause of RD in Malawi is likely to be dietary calcium deficiency leading to elevated PTH resulting in increased losses of phosphate from the bone and glomerular filtrate. The causes of BD remain unclear; there was no evidence in support of previously suggested risk factors such as being overweight or starting to walk early. Prior to surgical intervention, supplementation with calcium should be considered for children with RD

Identifying Cardiac Amyloid in Aortic Stenosis: ECV Quantification by CT in TAVR Patients

OBJECTIVES: To validate computed tomography measured ECV (ECVCT) as part of routine evaluation for the detection of cardiac amyloid in patients with aortic stenosis (AS)-amyloid. BACKGROUND: AS-amyloid affects 1 in 7 elderly patients referred for transcatheter aortic valve replacement (TAVR). Bone scintigraphy with exclusion of a plasma cell dyscrasia can diagnose transthyretin-related cardiac amyloid noninvasively, for which novel treatments are emerging. Amyloid interstitial expansion increases the myocardial extracellular volume (ECV). METHODS: Patients with severe AS underwent bone scintigraphy (Perugini grade 0, negative; Perugini grades 1 to 3, increasingly positive) and routine TAVR evaluation CT imaging with ECVCT using 3- and 5-min post-contrast acquisitions. Twenty non-AS control patients also had ECVCT performed using the 5-min post-contrast acquisition. RESULTS: A total of 109 patients (43% male; mean age 86 ± 5 years) with severe AS and 20 control subjects were recruited. Sixteen (15%) had AS-amyloid on bone scintigraphy (grade 1, n = 5; grade 2, n = 11). ECVCT was 32 ± 3%, 34 ± 4%, and 43 ± 6% in Perugini grades 0, 1, and 2, respectively (p < 0.001 for trend) with control subjects lower than lone AS (28 ± 2%; p < 0.001). ECVCT accuracy for AS-amyloid detection versus lone AS was 0.87 (0.95 for 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid Perugini grade 2 only), outperforming conventional electrocardiogram and echocardiography parameters. One composite parameter, the voltage/mass ratio, had utility (similar AUC of 0.87 for any cardiac amyloid detection), although in one-third of patients, this could not be calculated due to bundle branch block or ventricular paced rhythm. CONCLUSIONS: ECVCT during routine CT TAVR evaluation can reliably detect AS-amyloid, and the measured ECVCT tracks the degree of infiltration. Another measure of interstitial expansion, the voltage/mass ratio, also performed well