Quantitative Assessment of Whole-Body Tumor Burden in Adult Patients with Neurofibromatosis

Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease.We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors.WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10).WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The effect of cardiac resynchronization therapy on left ventricular diastolic function assessed with speckle-tracking echocardiography

Aims: Changes in left ventricular (LV) diastolic function after cardiac resynchronization therapy (CRT) in relation to LV reverse remodelling and heart failure aetiology have not been extensively characterized. The aims of the study were to evaluate changes in LV diastolic function with speckle-tracking echocardiography in relation to: (i) cardiac resynchronization therapy response (LV remodelling) and (ii) heart failure aetiology. Methods and results: A total of 192 heart failure patients undergoing CRT implantation were evaluated. Speckle-tracking echocardiography was performed before and 6 months after implantation and reliable analysis was obtained in 188 patients. Left ventricular diastolic function was assessed by measuring diastolic strain rate during the isovolumic relaxation period (SR ) and by calculating the ratio of peak transmitral E-wave to SR (E/SR ). Changes in LV diastolic parameters were evaluated in responders and non-responders and in patients with ischaemic and non-ischaemic cardiomyopathy. Response to CRT was defined a

Effect of biventricular pacing on diastolic dyssynchrony

ObjectivesThis study sought to examine the changes in diastolic dyssynchrony with cardiac resynchronization therapy (CRT).BackgroundLittle is known about the effect of CRT on diastolic dyssynchrony.MethodsConsecutive heart failure patients (n = 266, age 65.7 ± 10.0 years) underwent color-coded tissue Doppler imaging at baseline, 48 h, and 6 months after CRT. Systolic and diastolic dyssynchrony were defined as maximal time delay in peak systolic and early diastolic velocities, respectively, in 4 basal LV segments. CRT responders were defined as those with ≥15% decrease in LV end-systolic volume at 6 months.ResultsBaseline LVEF was 25.2 ± 8.1%; 63.5% patients were CRT responders. Baseline incidence of systolic and diastolic dyssynchrony, and a combination of both was 46.2%, 51.9%, and 28.6%, respectively. Compared to nonresponders, responders had longer baseline systolic (79.2 ± 43.4 ms vs. 45.4 ± 30.4 ms; p < 0.001) and diastolic (78.5 ± 52.0 ms vs. 50.1 ± 38.2 ms; p < 0.001) delays. In follow-up, systolic delays (45.4 ± 31.6 ms at 48 h; 38.9 ± 26.2 ms at 6 months; p < 0.001) and diastolic delays (49.4 ± 36.3 ms at 48 h; 37.7 ± 26.0 ms at 6 months; p < 0.001) improved only in responders.ConclusionsAt baseline: 1) diastolic dyssynchrony was more common than systolic dyssynchrony in HF patients; 2) nonresponders had less baseline diastolic dyssynchrony compared to responders. After CRT: 1) diastolic dyssynchrony improved only in responders. Further insight into the pathophysiology of diastolic dyssynchrony and its changes with CRT may provide incremental information on patient-specific treatments

Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders