A critique of models for body composition and energy-balance components in childhood and adolescence

It is well known that, in Western countries, people of all ages and both sexes are becoming ‘fatter’ in general. In a ‘healthy’ population, we arbitrarily consider cut-offs to be that 10% of people should be ‘overweight’ and 5% ‘obese’, as there is limited evidence that these cut-off points are related to ill-health. However, we are seeing a dramatic rise in the numbers of people in each of these categories. The mechanism behind weight gain is energy-imbalance. At energy-balance for adults - i.e. where weight is expected to remain stable over time, we know that: energy intake (EI) = energy expenditure (EE) This equation is far less straightforward than it first appears. The first important issue is that EE has several different components (e.g. resting EE). The second issue is to do with measurement - how do we measure energy intake and energy expenditure? Another is down to physiological differences between people - how do things vary between individuals and do they differ systematically between males and females, adults and children? The above equation applies to adults, but we know that children and adolescents actually require a positive imbalance for healthy growth - what is not known is what degree of positive imbalance is healthy. This thesis is particularly concerned with energy-balance and imbalance during puberty, at which time the human body goes through extreme changes. We investigate how these changes are measured, and how energy-imbalance and the modelling thereof must change across this time. We will show that the proportions of children who are overweight and obese are higher than we would expect; commonly used models for body composition are not in agreement; commonly used models for resting energy expenditure are not in agreement; children do not need a high energy-imbalance for normal growth; and those girls with early menarche are more likely to become overweight than their counterparts

Circumferential strain predicts major adverse cardiovascular events following an acute ST-segment-elevation myocardial infarction

Purpose: To investigate the prognostic value of circumferential left ventricular (LV) strain measured by using cardiac MRI for prediction of major adverse cardiac events (MACE) following an acute ST-segment–elevation myocardial infarction (STEMI). Materials and Methods: Participants with acute STEMI were prospectively enrolled from May 11, 2011, to November 22, 2012. Cardiac MRI was performed at 1.5 T during the index hospitalization. Displacement encoding with stimulated echoes (DENSE) and feature tracking of cine cardiac MRI was used to assess circumferential LV strain. MACE that occurred after discharge were independently assessed by cardiologists blinded to the baseline observations. Results: A total of 259 participants (mean age, 58 years ± 11 [standard deviation]; 198 men [mean age, 58 years ± 11] and 61 women [mean age, 58 years ± 12]) underwent cardiac MRI 2.2 days ± 1.9 after STEMI. Average infarct size was 18% ± 13 of LV mass and circumferential strain was −13% ± 3 (DENSE method) and −24% ± 7 (feature- tracking method). Fifty-one percent (131 of 259 participants) had presence of microvascular obstruction. During a median follow-up period of 4 years, 8% (21 of 259) experienced MACE. Area under the curve (AUC) for DENSE was different from that of feature tracking (AUC, 0.76 vs 0.62; P = .03). AUC for DENSE was similar to that of initial infarct size (P = .06) and extent of microvascular obstruction (P = .08). DENSE-derived strain provided incremental prognostic benefit over infarct size for prediction of MACE (hazard ratio, 1.3; P < .01). Conclusion: Circumferential strain has independent prognostic importance in study participants with acute ST-segment–elevation myocardial infarction

Predictors of segmental myocardial functional recovery in patients after an acute ST-elevation myocardial infarction

Objective: We hypothesized that Displacement Encoding with Stimulated Echoes (DENSE) and feature-tracking derived circumferential strain would provide incremental prognostic value over the extent of infarction for recovery of segmental myocardial function. Methods: Two hundred and sixty-one patients (mean age 59 years, 73% male) underwent MRI 2 days post-ST elevation myocardial infarction (STEMI) and 241 (92%) underwent repeat imaging 6 months later. The MRI protocol included cine, 2D-cine DENSE, T2 mapping and late enhancement. Wall motion scoring was assessed by 2-blinded observers and adjudicated by a third. (WMS: 1=normal, 2=hypokinetic, 3=akinetic, 4=dyskinetic). WMS improvement was defined as a decrease in WMS ≥ 1, and normalization where WMS = 1 on follow-up. Segmental circumferential strain was derived utilizing DENSE and feature-tracking. A generalized linear mixed model with random effect of subject was constructed and used to account for repeated sampling when investigating predictors of segmental myocardial improvement or normalization Results: At baseline and follow-up, 1416 segments had evaluable data for all parameters. Circumferential strain by DENSE (p < 0.001) and feature-tracking (p < 0.001), extent of oedema (p < 0.001), infarct size (p < 0.001), and microvascular obstruction (p < 0.001) were associates of both improvement and normalization of WMS. Circumferential strain provided incremental predictive value even after accounting for infarct size, extent of oedema and microvascular obstruction, for segmental improvement (DENSE: odds ratio, 95% confidence intervals: 1.08 per −1% peak strain, 1.05–1.12, p < 0.001, feature-tracking: odds ratio, 95% confidence intervals: 1.05 per −1% peak strain, 1.03–1.07, p < 0.001) and segmental normalization (DENSE: 1.08 per −1% peak strain, 1.04–1.12, p < 0.001, feature-tracking: 1.06 per −1% peak strain, 1.04–1.08, p < 0.001). Conclusions: Circumferential strain provides incremental prognostic value over segmental infarct size in patients post STEMI for predicting segmental improvement or normalization by wall-motion scoring

Perfusion by Arterial Spin Labelling following Single Dose Tadalafil in Small Vessel Disease (PASTIS): study protocol for a randomized controlled trial

Background Cerebral small vessel disease is a common cause of vascular cognitive impairment in older people, with no licensed treatment. Cerebral blood flow is reduced in small vessel disease. Tadalafil is a widely prescribed phosphodiesterase-5 inhibitor that increases blood flow in other vascular territories. The aim of this trial is to test the hypothesis that tadalafil increases cerebral blood flow in older people with small vessel disease. Methods/design Perfusion by Arterial Spin labelling following Single dose Tadalafil In Small vessel disease (PASTIS) is a phase II randomised double-blind crossover trial. In two visits, 7-30 days apart, participants undergo arterial spin labelling to measure cerebral blood flow and a battery of cognitive tests, pre- and post-dosing with oral tadalafil (20 mg) or placebo. Sample size: 54 participants are required to detect a 15% increase in cerebral blood flow in subcortical white matter (p < 0.05, 90% power). Primary outcomes are cerebral blood flow in subcortical white matter and deep grey nuclei. Secondary outcomes are cortical grey matter cerebral blood flow and performance on cognitive tests (reaction time, information processing speed, digit span forwards and backwards, semantic fluency). Discussion Recruitment started on 4th September 2015 and 36 participants have completed to date (19th April 2017). No serious adverse events have occurred. All participants have been recruited from one centre, St George’s University Hospitals NHS Foundation Trust. Trial registration European Union Clinical Trials Register: EudraCT number 2015-001235-20. Registered on 13 May 2015

Combined free light chains are novel predictors of prognosis in heart failure

Objectives: This study investigated the prevalence and potential incremental prognostic value of combined free light chains (cFLCs) in patients recently hospitalized with decompensated heart failure (HF). Background: Inflammatory pathways are recognized in the pathogenesis and progression of HF. Free light chain (FLC) elevation is conventionally associated with monoclonal gammopathies, including multiple myeloma. Polyclonal increases in both kappa and lambda FLCs occur in autoimmune and other chronic inflammatory conditions. Recently, a novel assay for measuring kappa and lambda immunoglobulin FLCs together, known as combined free light chain (cFLC) has been developed. Methods: Six hundred twenty-eight patients recently hospitalized with decompensated HF were studied. cFLCs were measured by turbidimetry using an immunoassay. The incremental prognostic value of cFLCs for mortality was evaluated using Cox proportional hazard models including 22 established predictors of outcome in HF. Results: Of 628 patients, 290 (46%) died during a follow-up of 3.2 ± 1.5 years. Two hundred seventy patients (43%) had elevated cFLCs. There was a clear gradient in the risk of death according to cFLC quartile, with those in the top quartile having an unadjusted risk of mortality more than twice that of those in the lowest quartile (hazard ratio: 2.38; p &lt; 0.0001). After multivariable analysis, cFLC remained an independent predictor of mortality, with an almost 50% higher adjusted risk for those in the top compared with bottom quartile. Older age, lower body mass index, New York Heart Association classification III/IV, previous myocardial infarction, current smoking and B-type natriuretic peptide, bilirubin, high-sensitivity C-reactive protein, glycated hemoglobin, and lymphocyte concentrations were also independent predictors of mortality. Conclusions: cFLCs are an independent predictor of mortality in patients recently hospitalized with decompensated HF. Further work is required to assess the effects of HF therapies on cFLC concentrations and whether or not directly targeting this marker of inflammation improves prognosis for patients with HF

The incremental prognostic and clinical value of multiple novel biomarkers in heart failure

Aims: In recent years there has been an increase in the number of biomarkers in heart failure(HF). The clinical role for these novel biomarkers in combination is not clear. Methods: The following novel biomarkers were measured from 628 patients recently hospitalised with decompensated HF; mid regional pro-adrenomedullin(MR-proADM), mid regional pro-atrial natriuretic peptide(MR-proANP), copeptin, high sensitivity cardiac troponin T(hs-cTnT), ST2, galectin-3, cystatin C, combined free light chains(cFLC) and high sensitivity C-reactive protein(hsCRP). The incremental prognostic value of these novel biomarkers was evaluated within an extensive model containing established predictors of mortality. Results: During a mean(SD) follow-up of 3.2(1.5) years, 290(46%) patients died. Elevated concentrations of all of the novel biomarkers were associated with an increased unadjusted risk of mortality but only two-thirds were independent predictors following multivariable analysis. Using dichotomized cut-points from ROC analysis, MR-proADM, hs-cTnT, cFLC, hsCRP and ST2 remained independent predictors of mortality. Further dichotomization into low(0-2 elevated biomarkers) or high(at least 3 of the 5 biomarkers elevated) risk groups provided greatest incremental prognostic value(HR 2.20; 95%CI, 1.37 to 3.54; p=0.001) and improved the predictive power of the model(C-statistic 0.730 from 0.721, NRI 32.5%). Conclusion: The novel biomarkers included in this study added little, if any, incremental prognostic value on their own to an extensive model containing established predictors of mortality. However, following dichotomization, 5 of the novel biomarkers provided incremental prognostic value. There was a clear gradient in the risk of death with increasing numbers of elevated novel biomarkers; the presence of at least 3 identifying patients at greatest mortality risk

Perfusion by arterial spin labelling following single dose tadalafil in small vessel disease (PASTIS): study protocol for a randomised controlled trial

Background: Cerebral small vessel disease is a common cause of vascular cognitive impairment in older people, with no licensed treatment. Cerebral blood flow is reduced in small vessel disease. Tadalafil is a widely prescribed phosphodiesterase-5 inhibitor that increases blood flow in other vascular territories. The aim of this trial is to test the hypothesis that tadalafil increases cerebral blood flow in older people with small vessel disease. Methods/design: Perfusion by Arterial Spin labelling following Single dose Tadalafil In Small vessel disease (PASTIS) is a phase II randomised double-blind crossover trial. In two visits, 7-30 days apart, participants undergo arterial spin labelling to measure cerebral blood flow and a battery of cognitive tests, pre- and post-dosing with oral tadalafil (20 mg) or placebo. Sample size: 54 participants are required to detect a 15% increase in cerebral blood flow in subcortical white matter (p Discussion: Recruitment started on 4th September 2015 and 36 participants have completed to date (19th April 2017). No serious adverse events have occurred. All participants have been recruited from one centre, St George's University Hospitals NHS Foundation Trust. Trial registration: European Union Clinical Trials Register: EudraCT number 2015-001235-20 . Registered on 13 May 2015.</p

Evaluation of SARS-CoV-2 serology assays reveals a range of test performance.

Appropriate use and interpretation of serological tests for assessments of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, infection and potential immunity require accurate data on assay performance. We conducted a head-to-head evaluation of ten point-of-care-style lateral flow assays (LFAs) and two laboratory-based enzyme-linked immunosorbent assays to detect anti-SARS-CoV-2 IgM and IgG antibodies in 5-d time intervals from symptom onset and studied the specificity of each assay in pre-coronavirus disease 2019 specimens. The percent of seropositive individuals increased with time, peaking in the latest time interval tested (&gt;20 d after symptom onset). Test specificity ranged from 84.3% to 100.0% and was predominantly affected by variability in IgM results. LFA specificity could be increased by considering weak bands as negative, but this decreased detection of antibodies (sensitivity) in a subset of SARS-CoV-2 real-time PCR-positive cases. Our results underline the importance of seropositivity threshold determination and reader training for reliable LFA deployment. Although there was no standout serological assay, four tests achieved more than 80% positivity at later time points tested and more than 95% specificity