Statistical analysis of actigraphy data with generalised additive models.

There is a growing interest in the use of physical activity data in clinical studies, particularly in diseases that limit mobility in patients. High-frequency data collected with digital sensors are typically summarised into actigraphy features aggregated at epoch level (e.g., by minute). The statistical analysis of such volume of data is not straightforward. The general trend is to derive metrics, capturing specific aspects of physical activity, that condense (say) a week worth of data into a single numerical value. Here we propose to analyse the entire time-series data using Generalised Additive Models (GAMs). GAMs are semi-parametric models that allow inclusion of both parametric and non-parametric terms in the linear predictor. The latter are smooth terms (e.g., splines) and, in the context of actigraphy minute-by-minute data analysis, they can be used to assess daily patterns of physical activity. This in turn can be used to better understand changes over time in longitudinal studies as well as to compare treatment groups. We illustrate the application of GAMs in two clinical studies where actigraphy data was collected: a non-drug, single-arm study in patients with amyotrophic lateral sclerosis, and a physical-activity sub-study included in a phase 2b clinical trial in patients with chronic obstructive pulmonary disease.

The Role of Urinary Calcium and Chitotriosidase in a Cohort of Chronic Sarcoidosis Patients.

BACKGROUND: Calcium metabolism alterations are quite common in sarcoidosis and have been correlated with disease activity. OBJECTIVES: The aim of the study was to investigate the clinical significance of calcium metabolism alterations in patients with chronic sarcoidosis. We paid particular attention to associations with specific disease phenotypes and chitotriosidase (CTO) expression. METHODS: 212 chronic sarcoidosis patients (mean age 56.07 ± 12 years; 97 males) were retrospectively recruited. Demographic, clinical, functional, and radiological data, and serum-urinary calcium metabolism were entered into an electronical database for analysis. Levels of CTO and angiotensin-converting enzyme (ACE) were measured and bone mineral density and lung function tests were conducted. RESULTS: Hypercalciuria and hypercalcemia were observed in 18.8 and 1.8% of patients, respectively. Urinary calcium levels correlated with CTO activity (r = 0.33, p = 0.0042). Patients with worsening persistent disease showed the highest levels of urinary calcium. Diffusing capacity of the lung for carbon monoxide (DLCO) percentage correlated inversely with urinary calcium (r = 0.1482; p = 0.0397). CONCLUSIONS: Calcium metabolism alteration, particularly hypercalciuria, was observed in a significant percentage of patients of sarcoidosis. Urinary calcium was correlated with clinical status, DLCO, and serum CTO activity, suggesting its potential role as a biomarker of the activity and severity of sarcoidosis.

Relationship between pruritus and sleep in participants with primary biliary cholangitis in the Phase 2b GLIMMER trial.

BACKGROUND: Cholestatic pruritus and fatigue are debilitating conditions associated with primary biliary cholangitis (PBC) and can significantly impact patients' quality of life. Pruritus in PBC often worsens at night and patients frequently report sleep disturbance, which contributes to cognitive symptoms and fatigue. Linerixibat is an ileal bile acid transporter inhibitor in clinical development for the treatment of pruritus associated with PBC and was recently assessed versus placebo in the Phase 2b GLIMMER trial. This post-hoc analysis assesses the relationship between pruritus severity and sleep disturbance in participants of GLIMMER regardless of treatment group. METHODS: GLIMMER (NCT02966834), a multicenter, double-blind, randomized, placebo-controlled trial, recruited 147 patients with PBC and moderate-to-severe pruritus. Following 4 weeks single-blind placebo, patients (randomized 3:1) received linerixibat or placebo for 12 weeks (to Week 16). Participants graded their itch (twice daily) and its interference with sleep (once daily) in an electronic diary using a 0-10 numerical rating scale (NRS). Weekly and monthly itch scores were calculated as the mean of the worst daily itch score over the respective time period. At study visits, participants completed the 5-D itch scale and the PBC-40 quality of life questionnaire, both of which contain an item specific to itch-related sleep disturbance. The impact of pruritus on sleep was assessed post hoc through correlations between the changes in NRS, 5-D itch, and PBC-40. RESULTS: Strong correlations were found between change from baseline in weekly itch and sleep NRS scores (r = 0.88 [95% confidence interval (CI): 0.83; 0.91]) at the end of treatment (Week 16), as well as in monthly itch and sleep NRS scores (r = 0.84 [95% CI: 0.80; 0.87]). Patients with improved weekly pruritus score severity category demonstrated reduced perceived sleep interference on average. Itch responders (≥2-point improvement in weekly itch score from baseline) displayed larger improvements in weekly sleep NRS score, 5-D itch, and PBC-40 sleep items, than itch non-responders (<2-point improvement). CONCLUSIONS: A strong correlation exists between changes in pruritus severity and sleep interference in patients with PBC; pruritus reduction could generate concomitant improvement in sleep.

A randomised, double-blind, placebo-controlled study of the LAG-3-depleting monoclonal antibody GSK2831781 in patients with active ulcerative colitis.

BACKGROUND: Selective depletion of T cells expressing LAG-3, an immune checkpoint receptor that is upregulated on activated T cells, has been investigated in pre-clinical models as a potential therapeutic approach in inflammatory and autoimmune diseases where activated T cells are implicated. AIMS: GSK2831781, a depleting monoclonal antibody that specifically binds LAG-3 proteins, may deplete activated LAG-3+ cells in ulcerative colitis (UC). METHODS: Patients with moderate to severe UC were randomised to GSK2831781 or placebo. Safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of GSK2831781 were evaluated. RESULTS: One hundred four participants across all dose levels were randomised prior to an interim analysis indicating efficacy futility criteria had been met. Efficacy results focus on the double-blind induction phase of the study (GSK2831781 450 mg intravenously [IV], N = 48; placebo, N = 27). Median change from baseline (95% credible interval [CrI]) in complete Mayo score was similar between groups (GSK2831781 450 mg IV: -1.4 [-2.2, -0.7]; placebo: -1.4 [-2.4, -0.5]). Response rates for endoscopic improvement favoured placebo. Clinical remission rates were similar between groups. In the 450-mg IV group, 14 (29%) participants had an adverse event of UC versus 1 (4%) with placebo. LAG-3+ cells were depleted to 51% of baseline in blood; however, there was no reduction in LAG-3+ cells in the colonic mucosa. Transcriptomic analysis of colon biopsies showed no difference between groups. CONCLUSION: Despite evidence of target cell depletion in blood, GSK2831781 failed to reduce inflammation in the colonic mucosa suggesting no pharmacological effect. The study was terminated early (NCT03893565).

Randomized Trial of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2831781 in Healthy Japanese and White Participants.

This study investigated ethnic differences in the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK2831781, an anti-lymphocyte activation gene 3 (LAG3) monoclonal antibody, in healthy participants, and determined local tolerability and bioavailability following subcutaneous (SC) administration. A double-blind, randomized study of (A) single intravenous (IV) doses of GSK2831781 450 mg or placebo in Japanese and White participants; and (B) single SC doses of GSK2831781 150 or 450 mg, or placebo in White participants, was conducted. Blood samples for analyses were collected before dosing and over 112 days after dosing. GSK2831781 was well tolerated in Japanese and White participants after both IV and SC doses, with the adverse event profile in Japanese being consistent with other populations. There were no injection site adverse events. There was no evidence of differences in systemic exposure among Japanese and White participants. Systemic exposure did not vary with body weight. SC bioavailability was 76.5%, as estimated using population pharmacokinetic modeling. Full and sustained target engagement and evidence of LAG3+ cell depletion (≈53%-66%) were observed in both populations and after both administration routes. No evidence of reduced circulating regulatory T cells (CD4+ CD25+ CD127low FoxP3+ ) was observed. Following IV and SC administration, GSK2831781 depleted circulating LAG3+ T cells with no interethnic difference observed. There were no major impacts on circulating regulatory T cells.

Left atrial strain by speckle tracking predicts atrial fibrosis in patients undergoing heart transplantation.

AIMS: In patients with heart failure (HF), chronically raised left ventricular (LV) filling pressures lead to progressive left atrial (LA) dysfunction and fibrosis. We aimed to assess the correlation of LA reservoir strain (peak atrial longitudinal strain, PALS) by speckle tracking echocardiography (STE) and LA fibrosis assessed by myocardial biopsy in patients undergoing heart transplantation (HTx). METHODS AND RESULTS: Forty-eight patients with advanced HF [mean age 51.2 ± 8.1 years, 29% females; LV ejection fraction ≤25% and New York Heart Association (NYHA) class III-IV] referred for HTx were enrolled and underwent pre-operative echocardiographic evaluation, right heart catheterization, and cardiopulmonary exercise testing. Exclusion criteria were non-sinus rhythm, mechanical ventilation, severe mitral/tricuspid regurgitation, or other valvular disease and poor acoustic window. After HTx, LA bioptic samples were collected and analysed to determine the extent of myocardial fibrosis (%). LA fibrosis showed correlation with PALS (R = -0.88, P < 0.0001), VO2max (R = -0.68, P < 0.0001), NYHA class (R = 0.66, P < 0.0001), LA stiffness (R = 0.58, P = 0.0002), and E/e' (R = 0.44, P = 0.005), while poorly correlated with E/A ratio (R = 0.23, P = 0.21). PALS had a good correlation with NYHA class (R = -0.64, P < 0.0001), PAoP (R = -0.61, P = 0.03) and VO2max (R = 0.57, P = 0.0001). Multivariate regression analysis identified PALS (beta = -0.91, P < 0.001) and LA Volume (beta = -0.19, P = 0.03) as predictors of LA Fibrosis, while E/e' was not a significant predictor (beta = 0.15, P = 0.08). CONCLUSION: Emerging as a possible index of myocardial fibrosis in patients with advanced HF, PALS could help to optimize the management and the selection of those patients with irreversible LA structural damage for advanced therapeutic strategies.

Modelling and forecasting art movements with CGANs.

Conditional generative adversarial networks (CGANs) are a recent and popular method for generating samples from a probability distribution conditioned on latent information. The latent information often comes in the form of a discrete label from a small set. We propose a novel method for training CGANs which allows us to condition on a sequence of continuous latent distributions f (1), …, f (K). This training allows CGANs to generate samples from a sequence of distributions. We apply our method to paintings from a sequence of artistic movements, where each movement is considered to be its own distribution. Exploiting the temporal aspect of the data, a vector autoregressive (VAR) model is fitted to the means of the latent distributions that we learn, and used for one-step-ahead forecasting, to predict the latent distribution of a future art movement f (K+1). Realizations from this distribution can be used by the CGAN to generate 'future' paintings. In experiments, this novel methodology generates accurate predictions of the evolution of art. The training set consists of a large dataset of past paintings. While there is no agreement on exactly what current art period we find ourselves in, we test on plausible candidate sets of present art, and show that the mean distance to our predictions is small.

Left Atrial Fractional Shortening: A Simple and Practical "Strain" for Everyone.

BACKGROUND: The function of the left atrium (LA) is reduced in many cardiac diseases even with normal size. The assessment of its compliance could represent an added value in an echocardiographic report in case the gold standard technique (speckle-tracking echocardiography [STE]) is not available. We sought to test a simple and quick method as surrogate of STE: the dynamic measurement of the LA anteroposterior diameter (APD) that we called LA fractional shortening (LAFS). MATERIALS AND METHODS: A total of 153 consecutive patients underwent a transthoracic echocardiography in our echo laboratory between January and June 2017. The only inclusion criteria were the presence of an acoustic window and the informed consent. We chose to not apply exclusion criteria to assess LAFS feasibility. The LAFS was calculated as (maxAPD-minAPD)/(maxAPD) × 100 in parasternal long-axis view. We evaluated the correlation of its value with the peak atrial longitudinal strain (PALS) and the LA emptying fraction (EF). RESULTS: Mean execution time was 32.1 ± 5 s for LAFS, 2.3 ± 0.7 min for LAEF, and 2 ± 1 min for PALS. LAFS, with a feasibility of about 97%, was moderately correlated with PALS and LAEF (R between 0.20 and 0.30, P < 0.05). LAFS fractional shortening also emerged as surrogate for PALS via the relationship PALS = 21.07 + 0.364x (LAFS). CONCLUSIONS: LAFS demonstrated a correlation with PALS, a short execution time, a high feasibility, and the possibility to be used as a surrogate of PALS, applying a specific formula.

ACUTE HF score, a multiparametric prognostic tool for acute heart failure: A real-life study.

BACKGROUND: Acute heart failure (AHF) is the first cause of hospitalization for over-65 individuals, associated with high mortality and readmission rate. The aim of this study was to assess the prognostic value of a multiparametric score combining clinical, biochemical and echocardiographic indexes in AHF for clinical practice. METHODS: 830 patients hospitalized for AHF were enrolled. Exclusion criteria were: active neoplasms; previous heart transplantation or left ventricular assist device implantation. Different variables were analyzed: etiology of AHF, clinical and biochemical data, lung congestion on chest-X ray, echocardiographic parameters and administered therapy. The endpoints were: all-cause mortality at 30 days, 6 months and 5 years and the duration of hospitalization. RESULTS: 771 patients met eligibility criteria. Using the univariate and multivariate analysis the indexes with the best correlation with outcome were discretized and used to create the ACUTE HF score, computed as: 1.4*[serum creatinine>2 mg/dl] + 0.8*[ejection fraction<30] + 0.7*[age > 76] + 0.7*[prior hospitalization for AHF] + 0.9*[prior stroke/transient ischemic attack] + 0.5*[more than moderate mitral regurgitation] + 0.8*[use of non-invasive ventilation] and used to divide patients into 3 groups according to the risk of 6-months mortality. With the receiver operating curves and Kaplan-Meier analysis, this score proved to have a high predictive power for mortality at 30 days, 6 months and 5 years from hospitalization, and for event-free survival rates, providing a risk stratification capability superior to that of single variables. CONCLUSIONS: The ACUTE HF score could be a complete and useful tool for assessing prognosis of AHF patients. It could represent a step in the long standardization pathway of prognostic protocols for AHF.

Prognosis and Risk Stratification of Patients With Advanced Heart Failure (from PROBE).

In recent years, many prognostic scores have been developed for advanced chronic heart failure (CHF), but none of them is comprised of first- and second level echocardiographic indexes. The aim was to create a new prognostic echocardiographic score for patients with advanced CHF. Patients with advanced CHF were analyzed by standard, 3D, and speckle tracking echocardiography and followed prospectively for 2 ± 0.7 years recording major adverse cardiac events (MACE): cardiovascular death, hospitalization for HF, emergency heart transplantation, and left ventricular assist device or intra-aortic balloon pump implantation. A total of 110 patients were enrolled. The best predictors of MACE were selected on the basis of area under the curve by receiver operating characteristic analysis >0.70: left atrial volume index (no MACE vs MACE groups, 51.3 ± 20 ml/m2 vs 67 ± 20 ml/m2, p = 0.0003), right ventricular sphericity index (0.53 ± 0.09 vs 0.61 ± 0.10, p = 0.0002), right ventricular fractional area change (41 ± 9% vs 33 ± 9.5, p <0.0001), free-wall right ventricular longitudinal strain (-20 ± 4.5% vs -16 ± 6%, p = 0.0013). A prognostic score formula was calculated as: PROBE score = 1(if left atrial volume index >65 ml/m2) + 1(if right ventricular sphericity index >0.53) + 0.5(if right ventricular fractional area change <36.5%) + 1(if free-wall right ventricular longitudinal strain >-14%). It presented an area under the curve by receiver operating characteristic analysis of 0.90 and classified patients at low (PROBE ≤1), intermediate (PROBE = 1 to 2), or high (PROBE >2) risk of MACE. The Kaplan-Meier analysis revealed a strong correlation between the event-free survival rate and the 3 groups. In conclusion, the PROBE score, with first- and second level echocardiographic parameters, demonstrated a good predictive value for MACE. It represents a useful tool for a noninvasive, individualized, and accurate evaluation and stratification of prognosis in patients with advanced CHF.

Left atrial, ventricular and atrio-ventricular strain in patients with subclinical heart dysfunction.

Arterial hypertension (AH) and diabetes mellitus (DM) are the most common causes of heart deterioration because of their high prevalence in the population. The aim of this study was to evaluate peak left atrial (LA), longitudinal strain (PALS), left ventricular (LV), longitudinal  strain (LS) and global atrial-ventricular strain (GAVS), by speckle-tracking echocardiography (STE), in asymptomatic patients with AH or/and DM and normal LA, LV size and ejection fraction (EF), to analyze their capability to detect early subclinical dysfunction. We enrolled 162 patients affected by AH and/or DM with normal indexed LA volume, LV end-diastolic diameter and a LVEF > 52% (females) or > 54% (males) (60 hypertensives, 52 diabetics and 50 both) and 60 healthy controls. All subjects underwent standard and advanced STE. PALS, LS and GAVS were measured. GAVS was calculated as the algebraic sum of absolute PALS and LS values in four- and two-chambers views. LS, although with lower values in hypertensives, diabetics and both, did not show significant differences between groups. PALS and GAVS were significantly reduced in AH (31.9 ± 10.3% and 49.7 ± 11.2%, respectively) and DM (26.2 ± 7.1% and 42.6 ± 9.8%) compared to controls, and even more if the two coexisted (20.4 ± 6.5% and 37.1 ± 8.4%). PALS had the highest statistical significance and was able to identify subclinical damage independently from LS value. PALS was reduced in patients with AH and/or DM without alteration of standard echo indexes. The value of PALS was independent from LS and was sufficient to identify heart dysfunction in an earlier stage.

Left heart longitudinal deformation analysis in mitral regurgitation.

In mitral regurgitation (MR), left atrium (LA) and left ventricle (LV) undergo remodeling even if the patient is asymptomatic. The aim of our study was to identify the best echo index that correlates with MR severity in asymptomatic patients affected by MR. We enrolled 150 MR patients (50: mild, 50: moderate, 50: severe), asymptomatic for exertional dyspnea and 50 healthy controls. MR was graded using Doppler quantitative method. All underwent standard and Speckle Tracking Echocardiography (STE) with analysis of global peak atrial longitudinal strain (PALS), LV longitudinal strain (LS) and global atrio-ventricular strain (GAVS). LA dimensions showed significant differences between the groups while LV end-diastolic diameter did not significantly differ, although having a slight increase. PALS was slightly higher in patients with mild MR, while decreased in moderate and, mainly, in severe MR (controls 37.4 ± 12.2%, mild MR 38.2 ± 9%, moderate MR 29.1 ± 9%, severe MR 19.8 ± 10.6%, p < 0.0001 by ANOVA); the same was found for GAVS (56.1 ± 13%, 57.6 ± 9.7%, 48.2 ± 9% 39 ± 9.4%, p < 0.0001 by ANOVA). LV LS showed a tendency for gradual reduction in the three groups. In multivariate analysis, PALS and GAVS were far superior than GLS as predictors of MR groups. PALS emerged as an added value to the LA indexed volumes as predictor of MR severity. STE-derived PALS and GAVS emerged as promising tools to investigate heart longitudinal function in patients with chronic MR and no symptoms. PALS can represent a surplus in the prediction of severity of MR, in addition to the assessment of LA volumes.